CHAPTER-1

HISTORY, BRANCHES AND SCOPE OF PHARMACOLOGY

Pharmacology : (Greek word “pharmacon” = drug) Study of drug and its effect on living organism, which
include drug source, action, absorption, distribution, metabolism and excretion, clinical application, side
effect, toxic effect, dose and dose rate.
Drug : (French word "drogue"= dry herb) Any compound which is used for diagnosis, prevention, treatment
and mitigation of disease in human or animals.
History :
● Nakul (3000-2500 B.C). : Practiced Veterinary Medicine
● Hippocrates (460-375 B.C) : Father of Medicine (Modern medicine finds its origin with the "DoCtrine of
Hippocrates". Formed prnciple above all do not harm. Given concenpts of four elements of nature and body.
● Paracelsus (1493-1541 BC) : Started use of mercury in medicinefor treatment of syphillis. “All the
substances are poison ther is none which is not poison. Right dose differenetiates drug from poison.”
● Theophrastus (380-287 B.C) : Classification of medicinal plants.
● Dioscorides (77 B.C) : Wrote "Materia medica"
● Pedanius Dioscorides : Compiled first materia medica.
● Galen (131-2001 A.D) : Advocated polypharmacy, it means use of multiple drugs at single time and
preparation of galen termed as galenical preparation.
● John Hunter (1728-1793) : English physician deals with clinical pharmacology.
● William Withering (1741-1799) : Use of digitalis (foxglove) extract for treatment of dropsy and conges-
tive heart failure.
● Emperor Shennung (2753-2700 BC) : Compiled “Pan Taso”, (Chines Herbal Materia medica)
● Friedrich Serturner (1841) : Isolated morphine from opium
● Francois Magendie (1783-1855) : Introduced experimental pharmacology
● Claude Burnerd (1813-1878) : (French physiologist who pioneered animal experimentation and vivi-
section. Recognized as father of modern physiology and experimental medicine.
● Rudolf Buchheim (1820-1879 BC) : Established first pharmacology laboratory at the university of
dorpat, Estonia.
● Oswald Schmiedeberg (1838-1921) : Father of Modern Pharmacology. He was professor of phar
macology at University of Strasburg, France. He established pharmacology as an independent disciplene.
● Paul Ehrlich : Father of Chemotherapy.
● John J. Abel : Father of Pharmacology (USA). Isolated adrenaline and acetylcholine.
● L. Meyer Jones : Edited first edition of Veterinary Pharmacology and Therapeutics (1949).
Recognized as Father of Modern Veterinary Pharmacology.
● Kahun Papyrus (2000 BC) and Eberspapyrus (1550 BC) described collection of many herbal
preparations used by ancient egyptians.

Branches of Pharmacology and scope

● Pharmacology is a branch of science that deals with sources of drug,its physico chemical properties,
its absorption, distribution, metabolims and excretion of drug, clinical application of drug, adverse drug
reaction and toxicity of drugs. Different branches of pharmacology are discussed as under :

● Pharmacokinetics: It is study of absorption, distribution, metabolism and excretion of drug.

● Pharmacodynamics: It is study of mechanism of action of drugs i.e., its biochemical and physiological
effecst on body.
● Pharmacotherapy: It is the treatment of disease with the help of drug.
● Therapeutics: It is practical branch of medical science which deals with application of knowledge of all

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 sciences in the treatment of any disease.
● Pharmacotherapeutics: Study of drug effects in disease state. In other words it is the response of an
organism to drug in disease state.
● Pharmacy: It is collection, preparation, standardization and dispensing of drug in different dosage forms.
● Pharmacognosy: It is study of source and identification of drugs.
● Pharmacometrics: It is quantitative and qualitative measurement of drug effect in relation to dose
administered. i.e. intensity of effect. (dose-response relationship)
● Experimental pharmacology: Study of effects and mechanism of action of drug in the laboratory animals.
● Comparative pharmacology: It is study of Relative action of drug on different species of animals.
● Applied pharmacology: It is application of knowledge of pharmacological science in drug discovery
and development or to treat a disease.
● Clinical pharmacology: It is evaluation of drug in clinical condition.
● Chemotherapy: It is Branch of pharmacology which deals drugs that selectively inhibits or kills
specific agents that causing diseases.
● Toxicology: It is study of toxicity or adverse effect of drugs.
● Neuropharmacology: It is study of action and effects of drugs on nervous system.
● Immunopharmacology: It is study of drug induced immunosuppression and immunomodulation.
● Molecular pharmacology: It is study of chemical interaction between drug molecules and chemical
groups in cells at molecular level. It explains the mechanism of drug action and the effects observed.
● Pharmacoepidemiology: Study of the variations in drug response between individuals in a population
or groups of population.
● Pharmacogenetics: It is generally regarded as the study or clinical testing of genetic variation that gives
rise to differing response to drugs. It deals with the genetic basis of individual variation in response of drug.
● Pharmacogenomics : It is the study of prediction of drug response and its variation among the popu-
lation based on genetic make up.
● Pharmacoeconomics: It is the study of economics of drug used and derived effects or benefits. It
includes explaination regarding the cost-benefit analysis, cost-minimization analysis, cost-effective-
ness analysis and cost-utility analysis of the drug.
● Pharmacovigilance : It refers to the collection, investigation, maintenance and evaluation of spontane-
ous reports of suspected adverse events associated with use of marked medicinal products/drugs.
Basic Terms in Pharmacology
● Prodrug: It is a form of drug which after metabolic activation in vivo produces the therapeutic effect.
● Dose: It is total quantum of drug given at a time.
● Dosage: It is the amount of drug administered to a patient in order to produce the desired therapeutic
effect and expressed as quantity per unit body weight (mg/kg). Only exception in antineoplastic drugs
where quantity is expressed in mg/mt2 of body surface.
● Posology: It is science which deals with drug-dosage determination.
● Metrology: It is branch of science that studies weight and measures used in pharmacy.
● Placebo: It is reffered to an agent/substance/preparation consisting of a pharmacologically inert substance
(dummy drug) to simulate the real drug therapy in exerting psychological impact of medication in humans. A
placebo is usually given to the human patient with imaginary illness to satisfy the patient desire.
● Dosage regimen/dose schedule: It is described as the dose, frequency, duration and rate of the
administration of drugs. e.g. 10 mg/kg, P.O., bid for 5 days
● Loading dose: It relatively large dose of drug which is required to produce onset of the therapeutic effect.
● Maintenance dose : It is dosage given during course of therapy following loading dose to maintain
desired therapeutic effect/level produced by loading dose.
● Divided dose: It is defined as definite fraction of drug's full dose given frequently at shorter interval so that
full dose can be administered within a specified period of time (usually 24 hours but not morning to evening).
● Lethal dose: Dose of drug that produces death/mortality/lethality/fatality in animals.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER-2
SOURCES AND NATURE OF DRUGS
Sources of Drugs
1. Plants/vegetables 2. Animals 3. Minerals
4. Microbes 5. Synthetic source 6. Other natural sources
1. Plants : Majority of drugs are obtained from plants. Whole plant does not used as drug but some active
principle act as drug. Active principles have pharmacological effecst. eg. Ricin is active principle of castor.
a Alkaloids :
● Suffix is "ine"
● Basic heterocyclic nitrogenous compound of plant origin that are physiologically active.
● Insoluble in water, soluble in alcohol and form salt with mineral acid. Salt is used clinically
● Alkaloid containing O2 are solid in nature eg. Atropine
● Alkaloid do not containing O2 are liquid in nature. eg. Nicotine
● Many alkaloids are potent poisons.
● Alkloids and their salts are precipited by KMNO4 and tannic acids.
Examples of alkaloids: Morphine, cocaine, reserpine, atropine, quinine, strychnine, nicotine etc.
b. Glycosides:
● Non reducing organic compund with ester bond which upon hydrolysis gives a sugar (glycon)
and a non sugar part (aglycon).
● Non volatile, usually bitter in taste, soulble in water and polyorganic solvent.
● When glycon part is glucose than glycosides are called "glucoside"
● Agylcon (Non sugar) part is responsible for pharmacological activities.
● Glycon (sugar) part is responsible for water solubility, tissue permeability and duration of action.
Examples of glycosides : Digoxin, digitoxin, gitalin, ovanain, linamerine, dhurine

c. Oil : There are two types of oils.

i. Fixed oils:
They are glycerides (esters) of oleic, palmitic or stearic acids.
They exist in solid or liquid form.
Thay are non volatile in nature.
They form salt with alkali.
They are insoluble in water, sparingly soluble in alcohol but soluble in ether.
Edible oil : Mustard oil, Coconut oil, Peanut oil, Ground nut oil etc.
Medicinal value : croton oil, castor oil etc.
ii. Volatile oil / essential oil / aromatic oil / etheral oil
On room temperature, they get evapourated.
No nutritive value but have medicinal value
Not soluble in water, but soluble in alcohol, ether, esters and other organic solvent.
Alcoholic solution of volatile oil is known as essance which is used in perfumes.
e.g. turpentine oil, eucalyptus oil, peppermint oil, clove oil, asfoetida oil
iii. Mineral oil: Distillates of petroleum products. eg. kerosine, petroleum, vaseline, paraffin oil.

d. Gums : Secretory products of plants, chemically mucopolysaccharides, colloid in nature, used as

emulsifying agent e.g. gum acacia (emulsifier) and agar (purgative/laxative)

e. Tannins : It precipitate metals salts, alkaloids and proteins. Non nitrogenous complex phenolic
compound used as astringents e.g. catechu, Tannic acid.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 f. Resins : Formed by polymerization or oxidation of oil, examples of natural resins/terpenes inculdes
lac (insect) or rosin (plant)
g. Oleoresin: Combination of oil and resins, e.g. male fern extract, canada balsum
h. Saponins : Soap like activity, used for reduction of surface tension
2. Animal source:
i. Hormones: hormonal therapy
ii. Vitamins: vitamin A and D from shark liver, Cod fish liver oil
iii. Antisera: hyperimmune serum (antibody present)
iv. Blood and blood products
v. Bone powder: Sources of calcium and phospherous.
vi. Enzymes
3. Mineral source : Obtain from mining operations from rocks, soils etc. eg. MgSO4 , Aluminium trisilicate,
Ferrous sulphate (used for anaemia), Potassium chloride (used for liquefaction of cough)
4. Microbes : Antibiotic, antifungal, antihelmintics, antiviral, anticancer etc.
5. Synthetic source : Antimicrobials synthesized in laboratory through chemical processes
6. Other natural sources : Seaweed or marine algae is the source of iodine, many vitamins, certain
antibiotics and nutritional (protein) suppliments

Natural Sources of the drugs:

Ergot alkaloids (like ergometrine) and Claviceps purpurea
Lysergic acid derivative
Yohimbine Pausinystalia yohimbae (bark)
Reserpine Rauwolfia serpentina
Pilocarpine Pilocarpus jaborandi, P. microphyllus
Muscarine Amantia muscaria (Poisonous mushroom)
Nicotine Nicotiana tobaccum
Physostigmine Physostigma venenosum
Atropine Atropa belladonna
Dathura spp. like Datura stramonium
Picrotoxin Anamrita cocculus
d-Tubocurarine Strychnos toxifera
Chondodendron tomentum
Cocaine Erythroxylum coca
Digitoxin Digitalis purpurea, Digitalis lanata
Digoxin Digitalis lanata
Ouabain (Strophantin-G) Strophantus gratus
Strophantin-K Strophantus kombe
Penicillin-G (Benzylpeniciilin) Penicillium notatum
Penicillium chrysogenum
Sreptmycin Streptomyces griseus
Gentamicin Micromonospora purpurea
Oxytetracycline Streptomyces rimosus
Rifampicin Streptomyces mediterrance
Amphotericin-B Streptomyces nodosus
Griseofulvin Penicillium griseofulvin
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER - 3
PHARMACOLOGICAL TERMS & DEFINITIONS
1. Gastrointestinal tract:
● Mouth antiseptics : Inhibits growth of micro-organism in oral cavity eg. potassium chlorate, 4%
KMnO4, alcohol based mouth wash
● Dentifrices : Agents which clean teeth eg. tooth paste, powder
● Sialagogues/sialics : Drugs which increase volume of saliva mainly used to treat xerostomia eg,
pilocarpine, chewing gum
● Antisialagogues/asialics : Drugs which decrease volume of saliva manly used to treat ptylasism
eg. opium/morphin
● Emollients and demulcent : Drug which provide soothing, protecting and cooling effect to part on
which they are applied. Emollients are applied externally and demulcent are meant for internal
use, given orally for soothing GIT
● Stomachics : Drug which increase gastric secretion.
● Bitters : They are stomachics and bitter in taste, they stimulate appetite.
● Aromatic : Agents containing volatile oil and often are very pungent.
● Gastric antacid : Drug which decrease gastric pH by neutrilizing gastric HCL.
● Antistomachics: Agents which decrease gastric secretion.
● Gastric sedative : Drug which soothens gastric mucous membrane, relieve gastric pain and
control vomition.
● Emetics : Drugs which produce vomition.
● Antiemetics : Drugs which control or prevent vomition.
● Carminative : drug which prevent formation of gas and also help in expulsion of gases from
stomach and intestine.
● Purgatives/cathartics/evacuents/aperients/laxatives : Drug which increase evacuation of
bowel.
● Astringents: Agents that protect the inflammed intestinal mucosa by precipitating the
superficial proteins and help in reducing intestinal irritation and check bleeding.
● Antizymotics : Drug that arrest or control fermentation.
● Lavage : The agents used in aprocess of washing out the stomach/intestinere known as lavaging agent.
● Choleritics : Agents that increase bile formation and secretion.
● Cholagogues : Agents that help in contraction of gall bladder and increase bile flow into intestines.
● Lipotropics/Hepatotonics: Agents that increase hepatic function.
● Probiotics: Thes are the products containing microorganisms / compounds that supports the
useful and harm less microbes in body against the harmful ones. They are used to restore or to
establish desirable gastrointestinal balance to promote the health.
● Prokinetics: These are the agents that increase the motility of a segment of gastrointestinal tract
and thereby augument transient of material through that area.

2. Urogenital system :
● Diuretics : Drug which increase volume of urine formation.
● Urinary sedatives : Drugs which relieve irritability of urinary tract.
● Anaphrodisiacs : Drugs which decrease sexual desire.
● Aphrodisiacs : Drugs which increase sexual desire and libido.
● Ecbolics/oxytocics : Drugs which cause contraction of uterine muscles.
● Emmenagogues : Drugs that favours the occurance of heat.
● Galactagogues : Drugs that increase secretion of milk.
● Lactagouges: Drugs that stimulates letting down of milk.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 ● Tocolytics (uterine sedatives) : Drugs causes relaxation of uterine muscles.
● Contraceptives: Drugs which are used to prevent the conception after mating in females usually.
Now a days male contraceptives like spermicidal gel is also available.
3. Cardiovascular system:
● Haemostatics/Styptics/: Agents that arrest/stop bleeding.
● Haematinics: Agents that increase the formation of haemoglobin in RBC.
● Coagulants: Agents that promote blood clotting.
● Anticoagulants: Agents that prevent blood coagulation.
● Cardiac depressants/Antiarrhythmics: Agents that prevent cardiac arrhythmia.
● Vasoconstrictors: Agents that increase BP through constriction of blood vessels
● Vasodilators: Agents that decrease BP through dilatation of blood vessels.
● Antihypertensives: Agents that decrease the elevated BP.
● Antiangina drugs: Agents that promote coronary blood circulation and prevent cardiac arrest.
● Cardiac stimulants: Agents that stimulate the contraction of a failing heart.
● Cardiotonics: Agents that reduce size of enlarged heart by increasing the force of contraction.
4. Respiratory system :
● Expectorents: Drugs that increase liquefaction and facilitate expulsion of bronchial secretion.
● Analeptics/respiratory stimulants: Drugs that increase depth and rate of respiration.
● Bronchodilators : Drugs that causes dilatation of bronchioles for better resparation
● Antitussive : Drugs that supress cough reflex.
● Decongestant : Drugs which relieves nasal congestion
5. Nervous system:
● Sedatives: Are the drugs which reduce the excitement and calm the subject without inducing
sleep.e.g. phenobarbitone.
● Hypnotics: Are drugs that induces and/maintains sleeps, similar to normal arousable sleep.
● Narcotics: Are the drugs which induces deep sleep or narcosis in which the patient cannot be
easily aroused. e.g.Morphine.
● General anaesthetics: are the drugs which produces loss of all sensation and consciousness.
e.g.ether.
● Tranquillizers /Neuroleptics / Ataractics: Are the drugs which reduce mental tension and pro-
duce calmness in hyperactive subject without inducing sleep or depressing mental function.
● Analgesics: Are the drugs that selectively relieves pain by acting on the CNS or on peripheral pain
mechanisms, without significantly altering consciousness. eg. pethidine, aspirin etc.
● Antiepileptic/ Anticonvulsants: Are the drugs which are used in treatment or control of epilepsy
convulsion. eg. phenytoin.
● CNS stimulants: Are drugs whose primary action is to stimulate CNS or to improve specific brain
functions. They may be a convulsants (eg. strychnine). analeptics (eg.doxapram) Psychomimetics
(eg.amphetamines).
6. Peripheral nervous system:
Skeletal muscle relaxants : Are drugs that act peripherally at the neuromuscular junction/ muscle
fibre itself or centrally in the cerebrospinal axis to reduce muscle tone and / or cause paralysis,
eg. d-tubocurarine, dantrolene, mephenesin etc.
Local anesthetics: Local anesthetics are drugs which upon topical application or local injection cause
reversible loss of sensory perception, especially of pain, in a restricted area of the body. They block
generation and conduction of nerve impulse at all parts of the neuron where they come in contact,
without any structural damage.eg. Procaine, lidocaine etc.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
7. Eye:
● Mydriatics: Drugs that dilate pupil
● Miotics: Drugs that contract pupil.

8. Metabolism:
● Antipyretics/febrifuges: Drugs which reduce elevated body temperature.
● Alteratives: Drugs which modify tissue changes and improve nutrition of various organs.

9. Skin:
● Demulcents: Are inert substances which sooth inflammed/ denuded mucosa or skin by preventing
contact with air/ irritants in the surroundings. They are, in general, high molecular weight substances
and are applied as thick colloidal / viscid solutions in water.eg glycerin, gum acacia, propylene glycol
etc.
● Emollients: Are bland oily substances which soothen and soften skin. They form an occlusive film
over the skin, preventing evaporation, thus restoring the elasticity of cracked and dry skin. eg.
Olive oil, liquid paraffin.
● Adsorbants and Protectives : Are finely powdered, inert and solids capable of binding to
their surface (adsorbing) noxious and irritant substances. They are also called protective be-
cause they afford physical protection to the mucosa or skin. eg. zinc oxide, calamine, starch etc.
● Astringents : Are substances that precipitate proteins, but do not penetrate cells, thus affecting
the superficial layer only. They toughen the surface making it mechanically stronger and decrease
exudation. e.g. tannic acid, zinc oxide.
● Irritants: Are agents those stimulate sensory nerve endings and induce inflammation at the site of
application.
● Rubefacients : Irritants which cause local hyperemia with little sensory component are called
rubefacients.
● Vesicants : Stronger irritants which also lead to increased capillary permeability and collection of
fluid under the epidermis forming vesicles are termed vesicants.
● Counterirritants : Certain irritants produce a remote effect which tends to relieve pain and in-
flammation in deeper organs are called counterirritants. eg. turpentine oil, methylsalicylate.
● Keratolytics : Are drugs which dissolve the intracellular substance in the horny, layer of skin. The
epidermal cell swell, soften and then desquamate. They are used on hyperkeratotic lesions chronic
dermatitis, ring worms etc. e.g. salicylic acid, benzoic acid.
● Diphoretics : Drugs that increase sweating.
● Anhydrotics : Agents that decrease sweating.
● Depilatories : Agents that remove superficial hair (unwanted).
● Caustics : Agents that cause death of the tissue.
● Refrigerants : Agents that cause coolness of the areas of contact.
● Antipruritics : Agents that reduce irritation and itching.
● Detergents : Agents that are used as cleansing agents.
● Deodorants : Agents that eliminate or mask unpleasant odours.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER - 4
PHARMACOKINETICS
Routes of Drug Administration
There are different routes of admnistration of drug for aniaml body. The pharmacological effecst and therapeutic
outcome depend on routes of admnistration. Following factors affecst choice of route of administration.
1. Physicochemical properties: Hihgly lipophilic drugs are better aborbed from GIT. While polar / ionized
compounds are not absorbed through GIT.
2. Formulation: Water insoluble drug, suspension, emulsion should not be given through IV routes.
3. Nature of drugs: Acid labile drugs and peptides are not suitable for oral absorption bacause of inacti-
vation by gastric HCL and pepsin enzyme.
4. Onset of action: For quick response of treatment in emergency, IV route is most appropiate. For
delayed absorption, implants or depot preparation are given through SC route which provides prolong
duration of action.
5. Types of response required: Many drug produce multiple responses depending upon routes of ad-
ministration and dose.
The example is magnesium sulphate.
Laxative - Oral - 50 gm
Purgative - Oral - 100 gm
Muscle relaxation - IV or SC - 20 % solution
Euthaenasi - IV - Saturated solution
6. Site of desired action: To treat local lesion, topical routes is prefered. For obtaining systemic effects,
parenteral route is employed.
7. Rate of biotransformation : Drug having shorter half life is to be given via intravenous infusion. eg.
oxytocin
8. Condition of patients: Unconscious patients /head trauma / mouth injury do not allow oral admnistration.
Oral route is also not practical for furious animals. Anthelmintics should be given orally because, they
requires direct contact with parasites.
Routes of admnistration is classified in to three main categories.
1. Oral/enteric/per-orum / per-os
2. Parenteral: away from the enteric route (other than GI tract) e.g. Injection, inhalation
3. Topical/local/external
Oral route (P/O) :
● Absorption takes place in 30-60 minutes but in ruminants, it takes 3-4 hours.
● Mainly drug absorbed from small stomach and intestine.
● Empty stomach favours absorption.
● Presence of food may modify rate and extent of absorption.
● Too irritant drugs can not be give through oral routes.
● It is employed to produces systemic as well as local effecst. eg. Antacid produces local effecst by acid
neutrilization. Paracetamol produces systemic effects.
Advantages :
● Convenient and safe (self medication is possible)
● No sterility of drug is required
● Mass application of medication through feed and water is possible (in poultry).
● No specific equipment is required.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 ● Economical and cheaper.
Disadvantages:
● Slow onset of action causes delayed response.
● Risk of aspiration in animals is likely to cause aspiration pneumonia.
● It is not useful in vomition and diarrhea
● It is not poosible to use oral admnistration of drug unconscious / violent / un cooperative animals.
● Acid labile and pepsin substrate can not be given.
● Some time, it may cause gastric upset.
● Gastric barrier : Some drugs have poor oral bio availability. eg. Gentamycin, Neomycin,
● In ruminants, large amount of ingesta causes dilution of drug concentration.
Parenteral route :
Injectable route:
Advantages:
● Rapid onset of action
● It avoids hepatic bypass.
● It is practical route of drug admnistration for un-cooperative/furious/unconscious animals.
Disadvantages:
● Requies accurate dose, specifically in Intravenus administration.
● It is costly and less safe.
● Pain and injury at the site of injection,risky route of administration.
● Preparation should be sterile and pyrogen free.
● It requires skilled person for administration.
Intravenous route (I/V): Drug solution is directly injected into vains of body. In bolus injection, drug is given
at a time instantly. In infusion, drug is slowly injected over a period of time along with fluid.
Advantage:
● Fastest absorption (within seconds): same molecule circulates three times in one minute.
● No loss of drug i.e. 100% bioavailability
● Large quantity can be injected e.g. saline
● Used for irritant drugs
● Precise control over dose.
Sites of intravenous injection in different animals:
Cattle : jugular and ear vein Dog : recurrent tarsal, radial Cat : radial, femoral vein
Horse : only jugular vein Rat and mice: tail vein Rabbit : ear vein
Guinea pig : directly into heart Swine : jugular and recurrent tarsal vein
Sheep and goat : jugular, ear vein and sephanous vein in hind leg

Disadvantages:
● Only soluble substance can be administered (only clear solution).
● Not suitable for oily drugs (oil base injection cannot be given)
● Aseptic precaution, pyrogen free and sterile formulation, and skilled person is required.
● If there is leakage in perivascular space, it causes sever irritation and phlebitis.
● Chances of air embolism is always there.
● It provides shorter duration of action baceuse of faster metabolism.
● It is most risky route of drug administration as all the vital organs are directly exposed to higher
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 concentration of drugs.
Intramuscular route (I/M): The drug is injected deep within skeletal muscels. Skelatal muscles being a
highly vascular and less richly supplied with nerves are employed for IM injections. In large animals, gluteal
muscles or neck muscles are used for IM injection.
Advantage:
● Absorption of drug is farely rapid. 5-30 minutes is required for absorption
● Liquid / suspension / oily formulation can be given.
● Mild to moderately irritant drug can be given.
● The duration of action is longer as compared to IV and shorter as compared to SC.
Disadvantage:
● Large volume cannot be administered
● Maximum pain in I/M injection due to irritation.
● Incidence of formation of local abscess/scar/fibrosis.
● It is not suitable for emergency treatment.
● IM is most common way of drug administration in veterinary practice.

Subcutaneous route (S/C): Drug is injecetd sub cutaenously i.e. below skin. The loose skin folds is used
for SC injection.
Advantages :
● It provides prolong effects of drug.
● It is suitable for implantats and depots formulation.
● It provides sustained release / ix quantum release. It is alos employed for depot preparation
specially for hormone administration.
● Large volume can be administered.
● It is commonly used in In infants because of smaller veins.
● Vaccinations are given mainly SC routes. The absorption is very slow. This triggers the immune
system for longer period.
Disadvantages:
● Slow onset of action
● This route is not suitable for Irritant drugs. Irritant drugs lead to sloughing of skin
● Some time permanant marks/scars develop at the site of admnistration.
● In shock condition, reduction in peripheral perfusion reduces the absorption of drugs.

Intraperitoneal (I/P) : The drug is deposited in peritoneal cavity. Peritoneal membrane provides surface
for absorption. The intraperitoneal injection is most suitable for pediatric patients and labotaory animals.
Advantage :
● Large absorption area (volume), so we can inject large quantity
● Absorption is as good as I/V
Disadvantages:
● Leads to peritonitis

Intrathecal: Inside subarachnoid space of spinal canal e.g. local anaesthetics

Intracardiac: Drug is directly injecetd in heart. It employed only in emergency. For eg., adrenaline is injectd
in acute cardia failure in to heart.
Intraarticular: Drug is deposited in joint. This is used in arthritis. Steroids and NSAIDs are given via this
route for obtaining local effects.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
Intradermal: The drug is inject within layers of skin. It is used for allergy testing. eg. Diagnostic purpose
(tuberculine test, penicillin hypersensitivity testing)
Intraarterial: Drug is injectd into arteries. This distributes drugs in selective / restricted area. eg. Mainly
followed for anticancer drug, dye and contars media for diagnostic imaging in MRI/ CT Scan
Transmucosal: Across the mucosa i.e., Drugs go to mucosal layer
a. Sublingual route : Drug is kept below tongue. It provides rapid absorption without hepatic first pass
effects. It is used by heart patients for nitroglycerine drugs to have quick vaso dilation effect on coronary
artery.
b. Intramammary : Drug is injecetd inside teat canal for treatment of mastitis.
c. Transrectal : Introduce drug inside the rectum, used when animal is not cooperative or in vomiting
conditions.

Transcutaneous: Across the skin

1. Drug placed above the skin and crosses the skin and goes into the body
a. Inunction: Rubbing over skin, so drug go inside.
b. Iontophoresis: Application of galvanic current increases penetration of drug through skin layers.
c. Jet injection: Drug is injected with lot of force through tinny jets. so drug is able to cross the skin
directly (in this case needle do not touch the skin).
d. Transdermal patches: Trnsdermal patch directly deliver the drug to skin for longer duration. The
application of trasndermal patch is employed for analgesic drugs like fentyl in neoplastic pain.
2. Inhalation route : Drug is inhaled through respiratory tract and absorption takes place through lung.
Due to large pulmonary area, drug is quickly absorbed in blood circulation. Thus, absorption is quite
fast. eg. Gaseous anesthetics, aerosol and gaseous preparation.

3. Topical routes: In this route, absorption of drug donot take place. Drug remains at the site of injection.
Theorically drug should not entered the systemic circulation. This route is employed for local effecst.

a. Intraocular : Directly into eye. eg., eye drop

b. Intraaural: Inside ear eg, Ear drops
c. Intravaginal : eg.Pessary
d. Intrarectal : For local effect. eg. enema in constipation
e. Intrauterine : In case of pyometra
f. Intramammary : For local effect, teat canal
g. Topical application/skin application : For wound and ulcer
h. Buccal/oral cavity : eg. Mouth gels

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
Pharmacokinetics [Pharmacon = drug and Kinetics = movements]

Definition:
● It is study of time course of absorption, distribution, metabolism and excretion (ADME) processes of drug.
● It is study of temporal changes in concentration of drugs in relation to time.
● Pharmacokinetics helps to understands “What happens to drug in body? Or what body does on drugs?
Out of ADME, Absorption and distribution determine concentration of drug at the site of action in body.
Biotransformation and excretion are responsible for elimination of drug and termination of action of drug.
Study of pharmacokinetics is essential step to determine optimum dosage regimens of drugs.

Pharmacokinetics includes four main processes:

● Absorption from the site of administration
● Distribution within the body
● Metabolism/ Biotransformation
● Excretion

A. Translocation of drug molecule across biological membrane (Biotransport of drug): For any
drug to produce its effect, it is essential to achieve an adequate concentration in the fluid bathing near
the target sites of action. The drug molecules move around in the body along with blood streams to
long distances at faster speed. This movement is function of cardiovascular system. It is not affected
by chemical nature of drug. Another movement of drug (diffusional movement) involves movement of
drug over molecule by molecule over a short distance.

Tissue-Bound Drug

Free Drug in Distribution Fluids

Elimination
Site of Action Drug-Melabolizing
Receptor Distribution
Enzymes

Drug in Dosage Form

Biotransformation

Dissolution

Free Drug
Drug in Solution Absorption Unchanged Drug
Excretion
at +
Absorption Site Metabolities
Protein-Bound Drug Urine
(Plasma)

Figure-1 : Relationship between pharmacokinetic processes with the duration of action of drugs
(Source: Adams, 2001)
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
Passage of drug across the Cell membrane
The biological membrane is made up of lipid bilayers which regulates the passage of drug across cell
membrane. The thickness of lipid bilayer is 100 A. The polar ends of lipid bilayers are oriented at the two
O

surfaces and the non-polar chains are embedded in the matrix. The proteins freely float through the membrane
and some of the intrinsic ones surround aqueous pores of the channels. The plasma membrane of cell is
semipermeable membrane allowing only specific substances / nutrients to cross. For example, water and
glucose are freely permeable while sucrose can not cross the membrane.

1) Simple diffusion
(A) Passive transfer
2) Filtration

1) Facilitated diffusion

(B) Specialized transport 2) Active transport

3) Endicytosis

Figure-2 : Processes of movements of drugs across Cell membrane

(A) Passive transfer

1) Simple diffusion:
● Lipid soluble drug crosses the cell membrane through diffusion.
● Diffusion is a passive process/ no energy is required / non saturable process.
● Rate of diffusion is influenced by concentration gradients across the cell membrane, lipid solubility
as well as water solubility of drug.
● Highly lipid soluble drug cannot contact aqueous pores so cannot diffuse though cell membrane.
● Highly water soluble drug cannot penetrate cell membrane.
● So, optimum lipid and water solubility is required.
● Drug having molecular weight of 100 – 400 daltons can cross cell membrane easily.

pH and Ionization of Drugs

● Most drugs are either weak acids or weak bases and exist in solution as both non-ionized and
ionized forms.
● Non-ionized form is usually lipid soluble and can readily cross the biologic membranes.
● Ionized forms are virtually excluded from trans-membrane diffusion because of poor lipid solubility.
● The degree of ionization of a drug/organic electrolyte depends on its pKa (dissociation constant)
and pH of the environment.
● pKa value is the negative logarithm of the acidic ionization/dissociation. It is a constant value for
an acid or a base.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
The concept of pKa is derived from the Henderson-Hasselbach equation.

Molecular Concentration of Non-ionized acid

For an Acid : pKa = pH + log
Molecular Concentration of Ionized acid

OR

100
% Ionized drug =
1 + Antilog (pKa – pH)

OR

Molecular Concentration of Ionized drug

For a Base: pKa = pH + log
Molecular Concentration of non-ionized drug

OR

100
% Ionized drug =
1 + Antilog (pH – pKa)

From above equation,

● pH = pKa, conc. of ionized drugs = conc. of non-ionized drug = 50%. Thus, pKa is equal to pH at which
half of the drug is in ionized state
pH > pK, Unionized drug > Ionized drug This equation is right for basic drug,
●
● }
pK < pH, Ionized drug > Unionized drug vice-versa is true for acidic drug

Clincal significance of pH and pKa values:

● Alkaline pH favours dissociation of weak acid and hence absorption is reduced.
● Acidic pH favours dissociation of weak base and hence absorption is reduced.
● In other words, acidic drugs are better absorbed in acidic environment. eg. Aspirin is a acidic drug which
remains unionized/undissociated in stomach at acidic pH, so absorption is good compared to intestine.
● Alkaline drugs are better absorbed in alkaline environment.
● For acidic drugs, the lower the pKa, stronger is the acid, whereas for basic drugs higher the pKa,
stronger is the base.
● Weak acidic drugs are well absorbed from the GIT of dogs and cats.
● Similarly, acidic urine of carnivores helps in promoting passive absorption of acidic drugs (pKa values
ranging from 3.0 to 7.2) from the distal renal tubules. Conversely, urinary alkalization favors ionization
of organic acids and promotes/enhances their excretion.
● Acidic urine favors excretion of alkaline drugs.
● Alkaline urine favors excretion of acidic drugs
● Acidic drugs are more ionized when pH is higher than its Pka values.
● Basic drugs are more ionized when pH of aqueous phase is less than its pKa values.
● Most of the therapeutic drugs/agents have pKa value between 3.0 and 11.0
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 pKa Values of some Weak acids & Bases (at 25o C)
Weak Acids pKa Weak Bases pKa
Salicylic acid 3.00 Reserpine 6.60
Aspirin 3.50 Tylosin 7.10
Phenylbutazone 4.40 Lincomycin 7.60
Sulfadiazine 6.48 Quinine 8.40
Phenobarbital 7.20 Praciane 8.80
Barbital 7.91 Ephedrine 9.36
Boric acid 9.24 Atropine 9.65

Effect of pH on the Ionization of Salicylic Acid (pKa 3.0)

pH Percent Non-Ionized
1 99.00
2 90.00
3 50.00
4 9.09
5 1.00
6 0.10

2) Filtration:
● It is Process of drug movement through pores and channels.
● Molecules having mol. wt. less then 100 Dalton can pass these pores
● Polar / non-polar drugs are suitable for filtration.
● Hydrostatic pressure and osmotic pressure are forces behind filtration.
● It is energy dependent process.
● It is the least significance process for drug transport as size of pore in most of the tissues is of
lesser than 4 A unit.
O

● It is observed in capillary movement of drug because they are having larger pores.
● Capillaries in brains resist filteration.
● Examples includes renal excretion, removal of drug from CSF and movement of drug across the
hepatic sinusoidal.
Diffusion
Diffusion through
through aqueous
lipid channel Carrier

EXTRACELLULAR

MEMBRANE

INTRACELLULAR

Figure-3 : Routes by which solutes can traverse cell membranes (Source: Rang et al., 2003)
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
B) Specialized transport
1) Active transport:
● Movement of substances against a concentration or electrochemical gradient.
● It requires carries and energy dependent. It is saturable process.
● It is also inhibited by process of competitive antagonism.
● Hydrophobic and large polar substances are transported using this process. eg. Renal and
biliary excretion of drug
Types :
i. Primary: Only one substance is transported at a time.
ii. Secondary: Two substances are transported, one is driving solute and other is actual
substances.
iii. Co-transport: Both are transported in same direction eg. Sodium co-transport of glucose
and amino acid in intestinal epithelium.
iv. Anti-port: Both substances are transported in opposite direction eg. Sodium counter transport
of hydrogen ions.
2) Facilitated transport:
● It requires carriers but, not energy.
● Substrate does not move against a concentration gradient (Downhill).
● It is Saturable/structure specific/ competitive process eg. transport of glucose in RBC,
absorption of Vit B1/B2/B12 along with intrinsic factors.
3) Pinocytosis:
● Pinocytosis (cell drinking) is the process by which cells engulf small droplets and may be of
some importance in uptake of large molecules.
● Active process / saturable / competitive to structural similarity. eg. Cellular nutrients like fats/
starch/proteins/fat soluble vitamins / drug like insulin / oral polio vaccine are transported
using this process.

Differences amongst different transport systems

Characteristics Simple diffulsion Facilitated Active transport
Incidence Commonest Less common Least common
Process Slow Quick Very quick
Movement Along conc. gradient Along conc. gradient Against conc. gradient
Carrier Not needed Needed Needed
Energy Not required Not required Required

Drug absorption : Process of movement of drug from its site of absorption to general circulation / blood
stream is termed as absorption. Optimum rate and extent of absorption will in turn determine the
concentration at site of action.
If drug is absorbed completely but very slowly, therapeutic concentration is never achieved. Reversely, if
drug is absorbed rapidly, the onset of action is very fast with shorter duration of action because of rapid
excretion.
Acidic drug at acidic pH remains in unionized form so absorption occurs. Thus, acidic pH favours absorption
of acidic drug.The examples of acidic drugs are aspirin, phenybutazone, sulphadiazine, acetazolamide.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
Alkaline drug remains unionized at alkaline pH. Alkaline pH favours absorption of basic drug, eg. Morphine,
quinine, atropine etc. In general, more drug is absorbed through intestinal mucosa then gastric mucosa
because of larger surface area.

Factors affecting process of drug absorption and bioavailability

A) Physico-chemical properties of drug
B) Nature of the dosage form
C) Physiological factors
D) Pharmacogenetic factors
E) Disease states

(A) Physico-chemical properties of drug:

(i) Physical state: Liquids are absorbed better than solids. Crystalloids absorbed better than colloids.
(ii) Lipid or water solubility: Drugs in aqueous solution mix more readily than those in oily solution.
However at the cell surface, the lipid soluble drugs penetrate into the cell more rapidly than the
water soluble drugs. Thus, a drug with balanced water and lipid solubility will be absorbed better.
(iii) Ionization: Most of the drugs are organic compounds. Unlike inorganic compounds, the organic
drugs are not completely ionized in the fluid. These drugs exist in two forms. Unionized component
is predominantly lipid soluble and is absorbed rapidly and an ionized is often water soluble
component which is absorbed poorly. Most of the drugs are weak acids or weak bases. It may be
assumed for all practical purposes, that the mucosal lining of the G.I.T is impermeable to the
ionized form of a weak organic acid or a weak organic base.

Acidic drugs: Rapidly absorbed from the stomach e.g. salicylates and barbiturates.

Basic drugs: Not absorbed until they reach to the alkaline environment i.e. small intestine when administered
orally e.g. pethidine and ephedrine.
(B) Nature of the dosage form :
(i) Particle size and state: Small particle size is important for drug absorption. Drugs given in a
dispersed or emulsified state are absorbed better e.g. Vitamin A and D.
(ii) Disintegration time and dissolution time: Disintegration time : It is time taken by tablet to brake
and to disintegrate into smaller pieces in a bio-phase of absorption. Longer the disintegration
time, slower is the absorption and delayed onset of action.
Dissolution time: It is time taken by drug to enter into solution phase, or time taken to release the
drug from solid dosage form. Lipid solubility / Molecular size / pKa of drug / aqueous solubility will
influence the dissolution time. It is also influenced by dosage forms i.e. Aqueous solution / Oily
solution / Suspension / Tablets / SR tablets.
(iii) Formulation: Usually substances like lactose, sucrose, starch and calcium phosphate are used
as inert diluents in formulating powders or tablets. Fillers may not be totally inert and may affect
the absorption as well as stability of the medicament. So, a faulty formulation can render a useful
drug totally useless therapeutically.
c) Physiological factors:
i) Gastrointestinal transit time: Rapid absorption occurs when the drug is given on empty stomach.
However certain irritant drugs like salicylates and iron preparations are deliberately administred
after food to minimize the gastrointestinal irritation. But for some drugs, the presence of food in
the GI tract increases the absorption of certain drugs e.g. griseofulvin, propranolol and riboflavin.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 ii) Presence of other agents: Vitamin C enhances the absorption of iron from the GIT. Calcium
present in milk or antacids forms insoluble complexes with the tetracycline antibiotics and reduces
their absorption. Milk or milk products or antacids containing heavy metals impair absorption of
tetracyclines and certain fluoroquinolones (due to chelation).
iii) Area of the absorbing surface and local circulation: Drugs can be absorbed better from the
small intestine than from the stomach because of the larger surface area of the former. Increased
vascular supply can increase the absorption. Because of extensive area and rich blood supply of
its mucosal surface, small intestines are the principal site of drug absorption for all orally
administered drugs.
iv) Enterohepatic cycling: Some drugs undergo recycling between intestines and liver before they
reach the site of action. This increases the bioavailability e.g. phenolphthalein.
v) Metabolism of drug/first pass effect: Rapid degradation of a drug by the liver during the first pass
(propranolol) or by the gut wall (isoprenaline) decreases the bioavailability. Thus, a drug though
absorbed well when given orally may not be effective because of its extensive first pass metabolism.
(D) Pharmacogenetic factors: Individual variations occur due to the genetically mediated reason in drug absorption
and response. eg. Expression of drug transporters across the biological barriers varies in individuals.
(E) Disease states: Absorption and first pass metabolism may be affected in conditions like malabsorption,
thyrotoxicosis, achlorhydria and liver cirrhosis. Hypovolemic perfusions reduces blood supply. Bacterial
infections alter permeability of membrane. Diarrhea / constipation alter transient time.
Drug Absorption after Oral Administration: Solid and liquid dosage forms like tablet, powder, syrup, elixir
etc., are given via oral route. Three basic steps for absorption of any drug incude:
1. Release from the dosage form (dissolution).
2. Transport across the GIT mucosal barrier.
3. Passage through the liver.
Each of above three process affects the rate and extent of drug absorption i.e. bioavailability. The dissolution
is a rate limiting process. The dissolution of drug can be manipulated by use of water soluble salts of drugs.
Following its release, the drug in solution must be stable in the environment within the stomach (reticulo-
rumen) and small intestines. It must be sufficiently lipid soluble to diffuse through the mucosal layer/barrier
to enter the hepatic portal venous blood.
Rate of gastric emptying / motility of intestine / change in blood supply to intestine / diarrhea / constipation
/ poor solubility and stability of drugs are other important factors to be considered.
Rate of gastric emptying is an important determinant of the drug absorption following oral administration.
Prokinetics increase the gastric emptying time and reduces drug absorption while spasmolytics reduce
gastric emptying time and increase drug absorption.
Examples of drug absorption:
● Absorption of polar antibiotics is slow and incomplete e.g. aminoglycosides and quaternary ammonium
compounds like atropine sulfate, propantheline etc.
● Aminoglycosides: Poor absorption due to low lipid solubility.
● Penicillin V: better absorption as compare to Penicillin G due to acid resistance.
● Oxytetracycline HCl: Water soluble salts-good absorption-but with food containing cations gets cheleted.
● Cephalexin is an acid stable drug, so, it is fit for oral administration.
Pulmonary Absorption : Gaseous and volatile anesthetic agents given by inhalation are rapidly absorbed
into the systemic circulation by diffusing through/across pulmonary alveolar epithelium.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
Absorption after IV Injection : Injection of a drug solution administered directly into the blood stream gives
a predictable concentration of the drug in plasma and in most instances, produces an immediate
pharmacological response.
Absorption after IM/SC Injection
● An IM and SC route gives rapid absorption.
● Peak concentration (Cmax) is achieved within 30-60 hrs.
Factors Influencing absorption from IM/SC site
● Vascularity of site / concentration of drug / degree of ionization / lipid solubility of drug.
● Different sites give different rate of absorption eg. Injection in neck region and thigh region will give
different rates of absorption.
● Concurrent administration of drug may decrease or increase the absorption from injection site. eg.,
Epinephrine with lignocaine for local infilteration results in slower absorption of lignocaine and hence,
there is less toxicity and longer duration of action.
● No routes except IV gives 100 % bioavailability.
● Sustained release preparation gives longer effects eg, Procaine penicillin G (oil in aluminium
monosteareate), amoxicillin tryhydrate, oxytetracyclines base in 2 pyrilidone vehical system etc.
● Prolong duration time may also be due to reduced rate of release of drug from dosage (Longer
dissolution time)
● But disadvantage is unpredictable or uneven intensity of response.
● Extremely slow absorption can be achieved through insoluble drug incorporated in compressed palate.
eg. S/C implants of diethyl stilbosterol, testosterone, deoxycorticosteroids

Per cutaneous absorption

Systemic absorption after topical application depends upon several factors like :
● Drug must dissolve and release from dosage or vehicle.
● Lipid solubility is essential
● Oil in water emulsion increases absorption.
● Anionic surface active agent like sodium lauryl sulphate in aqueous cream increases absorption. As it
increases water solubility and permeability of skin.
● Di-methyl sulphoxide increases penetration.
● Skin abrasion increases absorption.
● For skin infection which is deeply located in the layers of epidermis, systemic therapy is essential for
optimum time.

Absorption from sustained-release preparations: The prolonged action provided by Sustained-release

preparations is due to their limited availability for absorption, which may be attributed to slow dissolution of
the drug.

Bio-availability (F): The fraction of an administered drug that reaches the systemic circulation intact is
termed as bioavailability. eg. if 100 mg of a drug is administered orally and 70 mg of the same is absorbed
intact (unchanged), the bio-availability of the same is expressed as 70%.

Determination of bio-availability
AUCoral
F= X 100 Where, AUC = Area under curve in plot of plasma conc. vs. time graph
AUC IV
85
For example: If AUCIV =112 µg.h.ml-1 and AUCoral = 85 µg.h.ml-1 then F= X 100 = 75.89 %
112
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
Factors influencing bio-availability :
● First-pass hepatic metabolism
● Solubility of the drug
● Chemical instability of the drug
● Nature of drug formulations
❖ Particle size of the drug
❖ Salt form of the drug
❖ Crystal polymorphism
❖ Presence of excipients/vehicles

Bioequivalence
Two related drugs are bioequivalent if they show comparable bioavialability and similar time (Tmax) to achieve
peak plasma concentrations (Cmax).

Therapeutic Equivalence
Two similar drugs are therapeutically equivalent if they have comparable efficacy and safety.

DRUG DISTRIBUTION
It is movement of drug from systemic circulation to different parts or organs of body including site of action.
Drug after absorption enters systemic circulation, from where, it enters extravascular space and reaches
to different tissues and organs. Drug is not uniformly distributed in all the organs/tissues of body. Some
organs may receive or retain higher concentrations of drugs than other parts.

Factors affecting drug distributions

i. Rate of blood flow to organ: Blood flow to the brain, liver and kidneys is greater than skeletal muscles,
whereas adipose tissue has a still lower rate of blood flow. Skin and keratinized tissues have least flow.
ii. Tissue/Capillary permeability
iii. Physico-chemical properties of drug.
iv. Transport/ carrier system
v. Rate of administration : Rapid absorption - more fast distribution
vi. Plasma protein binding

Protein binding: Most of the drugs possess physicochemical properties for protein binding. Acidic drugs
generally bind to plasma albumin and basic drugs to α1-acid glycoprotein. Bound form and free form of drug
exists in dynamic equilibrium. The binding to albumin has quantitative effects.

Binding of drugs with plasma proteins affect :

1) Drug distribution: High molecular weights of plasma proteins prevent bound drugs from diffusing out
of capillaries into the tissues. Thus, high plasma protein binding drugs has lower distribution.
2) Drug effects: Only free drug fraction alone is pharmacologically active since it penetrates the target
organ/receptor/tissue.
3) Drug elimination: Free drug alone is filtered at the glomerulus and also excreted into saliva and milk.

Clinical significance of plasma protein binding:

● Highly plasma protein bound drugs are largely restricted to the vascular compartment and tend to
have a lower volume of distribution (Vd).

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
● The bound fraction is not available for action. However, it is in equilibrium with the free drug in plasma
and dissociates when the concentration of the free drug is reduced due to elimination. Plasma protein
binding thus acts as a temporary reservoir/storage for the drug.
● High degree of protein binding generally makes drug long acting because bound drug fraction is not
available for metabolism and excretion.
● Two highly protein drugs should not be given together. They tend to displace each other while competing
for the same binding site and making available of freer drug molecules which can produce drastic
pharmacological response or toxic/harmful effects.
● Highly protein bound drugs should not be given to hypoproteinemic subjects. Due to lack of binding
sites, more free dug molecules can produce drastic pharmacological response or toxic/harmful effects.

Grading of Protein Binding of Drugs:

1) Extensively protein bound drugs (>80% protein binding) eg. warfarin: 99%, Phenybutazone: 98%,
Propanol: 97%; frusemide, digitoxin, propanol, quinidine, phenytoin, diazepam and valproate have protein
binding more than 80%.
2) Moderately protein bound drugs (50-80% protein binding)
3) Lowly protein bound drugs (<50% protein binding) eg. theophyline 1%, Codeine 10%, Morphine 12%

Accumulation of drug in specific tissue :

Eye (ratina); Chloroquine Hair: Arsenicals
Kidneys: Heavy metals Liver: Chloroquine, Paracetamol
Lung: Chlorpromezine, Antihistamine Skin: Chloroquine and Phenothiazine
Thyroid: Iodine Teeth and bone : Oxytetracycline, Fluoride, Lead

Blood Brain Barrier (BBB)

The BBB is composed of :
(i) Continuous layer of endothelial cells having tight junctions
(ii) Overlapping endothelial layer is continuous basement membrane.
(iii) Perivascular foot process formed by astrocytes that encircles 85% capillary diameter.

Above three characteristics form barriers for movement of molecules from blood stream to brain. Moderately
lipid soluble substances diffuse through BBB, but polar or ionized drugs cannot penetrate it. Region of
brains like Hippocampus, CTZ lacks BBB, so at these locations lipid insoluble or polar substance can enter
the brains.
● Inflammation in form of meningitis, can disrupt the integrity of BBB, allowing normally impermeable
substances to enter brain e.g. penicillin in the treatment of bacterial meningitis.
● Several peptides, including bradykinin and ekephalins, increase BBB permeability by increasing
pinocytosis and this process/approach is used as means of improving access of chemotherapy during
treatment of brain cancer.
● Some water soluble drugs like L-Dopa and methyl dopa, endogenous sugars and aminoacids are
transferred across BBB through active process.

Other biological barriers :

● Choroid plexus forms blood CSF barriers.
● Trophoblast cells separating maternal and foetal blood vessels provide blood placenteal barriers.
● Other barriers included blood testis barriers, blood prostrate barriers, eye globe barriers.

Factors affecting drug distribution between various body fluid compartments :

1) Permeability across tissue barriers 2) Binding with compartments
3) PH partition 4) Fat (Lipid): water partition coefficient
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
Volume of Distribution: Apparent volume of distribution is the hypothetical volume of the body fluid that is
needed to dissolve the total amount of the drug to attain the same concentration as that in the blood.
Q
Vd = where Q = total amount of drug in the body; Cp = conc. in plasma
Cp
Following IV route,
Dose (mg/kg)
Vd area (L / kg)= where β = Rate constant (slow) of elimination phase
β x AUC
Following Extra vascular route (IM/SC/PO),
Dose (mg/kg)
Vd area (L / kg)= xF
β x AUC

Elimination Half Life (t1/2): Elimination half-life (t1/2) is the time required by the body to eliminate 50% of the
administered drug. About 96.9% of drug is eliminated in 5 half-lives and 98.4% drug is eliminated in 6 half-lives.
Drug elimination: Drugs elimination involves bio-transformation (drug metabolism) and drug excretion.
DRUG METABOLISM: Drugs are chemical substances, which interact with living organisms and produce
some pharmacological effects and then, they should be eliminated from the body unchanged or by changing
to some easily excretable molecules. The process by which the body brings about changes in drug molecule
is referred as drug metabolism or biotransformation.
Enzymes responsible for metabolism of drugs:
a) Microsomal enzymes: Present in the smooth endoplasmic reticulum of the liver, kidney and GIT eg.
glucuronyl transferase, dehydrogenase, hydroxylase and cytochrome P450. They are inducible by
drugs, diet and other factors.
b) Non-microsomal enzymes: Present in the cytoplasm, mitochondria of different organs. eg. esterases,
amidase, hydrolase. They are non inducible.
Microsomes: Spherical vesicles of endoplasmic reticulum. They can be separated by ultracentrifugation.
Metabolism of drug takes places in two phases:
1. Phase-I reactions : It is also known as non synthetic or non conjucative phase and involved Oxidation,
reduction and hydrolysis reactions.
2. Phase-II reactions (conjugations/synthetic reactions): Glucuronidation, sulfate conjugation,
acetylation, glycine conjugation and methylation reactions.
Phase-I and Phase-II reactions take place mainly in the liver, though some drugs are metabolized in sites
other than liver. This is known as extra hepatic biotransformation. It is of least importance.
Examples of extrohepatic biotransformation :
Plasma: Hydrolysis of suxamethonium by choline esterase
Lungs: Various prostanoids, Nortryptiline, Baclomethasone, Aldrenine, Acetophenon, Phenol, isoprenaline.
GIT : Tyramine,Ssalbutamol, Terbutaline, Isoproterenol, Morphine
Skin : Dapsone, Betamethasone, Capcichine, Propanolol, Monoxidil
Phase-I Reactions: Phase-I reactions usually either unmask or introduce into the drug molecule polar
groups such as-OH,-COOH and NH2. In phase-II reactions, these functional groups enable the compound
to undergo conjugation with endogenous substances such as glucuronic acid (i.e. glucuronidation), acetate
(acetylation), sulfate (sulfuric acid ester formation) and various amino acids. These drug conjugates are
water soluble and invariably inactive pharmacologically. Although Phase-I reactions usually yield products
with decreased activity, some may give rise to products with similar or even greater activity.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
1) Oxidation
● Microsomal oxidation is the most prominent phase-I reaction in the metabolism of lipid soluble drugs
and steroid hormones.
● It increasing hydrophilicity of drugs by introducing polar groups like -OH.
● Microsomal enzymes have a specific requirement for reduced nictinamide adenine dinuleotide phosphate
(NADPH) and molecular O2 and are classified as mixed function oxidases (MFOs).
A wide range of oxidative reactions, are known to occur in microsomes and examples include:
Reduction : The reduction reaction takes place by the enzyme reductase which catalyze the reduction of
azo (-N=N-) and nitro (-NO2) compounds.

Reduction Reactions Parent Drug Metabolite

Nitroreduction Chloramphenicol Arylamine
Azoreduction Protonsil Sulfanilamide (Antimicrobial)
Alcohol dehydrogenases Chloarl hydrate Trichlorethanol

Hydrolysis
Hydrolytic reactions do not involve hepatic microsomal enzymes and occur in plasma and many tissues.
Both ester and amide bonds are susceptible to hydrolysis.

Reactions Parent Drug Metabolite

Hydrolysis Acetylcholine α Choline + acetic acid
Procaine P-Aminobenzoic acid + Diethylaminoethanol

Phase-II Reactions (Conjugation/Synthetic Reactions)

(Also referred to as Detoxification process)
This is synthetic process by which a drug or its metabolite is combined with an endogenous substance
resulting in various conjugates such as glucoronide, ethereal sulfate acetate, glutathione, methylated
compound and amino acid conjugates. All phase-II enzymes are of non-microsomal type except enzyme
which catalyzes glucoronidation. The major conjugation reactions are:
1) Glucuronide synthesis/Glucuronidation
2) Sulfate conjugation
3) Acetylation
4) Glutathione conjugations
5) Methylation
6) Amino acids conjugations
Oxidative Reactions Parent Drug Metabolite
Hydroxylation Phenybutazolne Oxyphenybutazone
Phenobarbital p-Hydroxyphenobarbital
Aliphatic hydroxylation (side chain oxidation) Pentobarbital Pentobarbital alcohol
Ddealkylation Phenacetine Acetaminophen
N-oxidation Trimethylamine Trimethylamine oxide
Sulfoxidation Chlorpromazine Chlorpromazine sulfoxide
Deamination Amphetamine Phenylacetone
Desulfuration Parathion Paraoxon
1) Glucuronide synthesis/Glucuronidation
● It is most important metabolic pathway for drugs and certain endogenous compounds like steroid
hormones, thyroxine, bilirubin etc.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
● The activated donor form of glucuronic acid is the nucleotide-uridine diposphate glucuronic acid (UDPGA).
● Synthesis of glucuronide involves transfer of the conjugating agent from the nucleotide to an acceptor
molecule which is mediated by glucuronyl transferase- a microsomal enzyme.
● Some drugs are excreted largely as glucuronides (morphine, slaicylates, acetaminophen/paracetamol,
chloramphenicol etc.).
● Glucuronides are more water soluble than the parent drugs and are highly ionized at physiologic pH
which facilitates their excretion.
● Glucuronides that are excreted into bile may undergo hydrolysis by β-glucuronidase (elaborated by gut
microflora) in the intestine and the liberated free drug may then be absorbed and an entero-hepatic
cycle may be established (characterized by appearance of secondary peaks).
● Certain breeds of fish do not synthesize glucuronides due to deficiency of UDPGA.
● Defective synthesis of glucuronides in cats is due to low level of the transferring enzyme “glucuronyl
transferase” rather than deficiency of UDPGA.
2) Sulfate conjugation
● Sulfate conjugation is an important metabolic pathway for phenols and aliphatic alcohols.
● The enzymes for sulfate conjugations are cytoplasmic sulfotransferases and the co-factor (Endogenous
donor) is 3’ phospho adenosine 5’ phospho sulfate (PAPS).
● Some drugs that form ethereal sulfate include phenol, acetaminophen, morphine, isoproterenol, ascorbic
acid etc.
● Capacity for sulfate conjugation in pigs is limited and subject to saturation due to low level of
sulfotransferase.
3) Acetylation
● Conjugation with acetate is restricted to amines.
● Acetylation is carried out by a cytoplasmic enzyme acetyltransferase.
● The acetyl donor is Acetyl coenzyme- A.
● Acetylation of all types of amino groups takes place in human beings and several species of animals.
Dog and fox do not acetylate aromatic amino group.
● Dogs appear to have a specific deficiency in arylamine acetyltrasferase due to the presence of a
natural specific inhibitor of this ezyme.
● Acetylation is the principal metabolic pathway for sulfonamides in man, rabbits and rats but is
accompanied by aromatic hydroxylation in ruminants.
● Acetylation decreases water as well as lipid solubility.
4) Glutathione Conjugation
● Glutathione is g-glutamyl-cysteinyl glycine tripeptide that occurs in most tissues especially in the liver.
● Glutathione-s-transferase catalyzes the reaction between glutathione and aliphatic halides. The
conjugate product is further hydrolyzed with the removal of glutamyl and glycine residues followed by
N-acetylation by acetyltrasferase.
● The end product of glutathione conjugation is mercapturic acid which is highly water soluble and easily
excretable in urine.
5) Methylation
● Adrenaline is methylated to metanephrine by catechol-o-methyl transferase. Here the source of methyl
group is S-adenosyl methionine (SAM).
6) Amino acids (Glycine and Glutamate) Conjugation
● Carried out by mitochondrial enzyme N-acetyl transferase and is restricted to carboxylic acids, especially
aromatic ones.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
Metabolic Biotransformation Mediated by GI Microbes
Ruminal microflora can also catalyse hydrolysis and reduction reactions e.g. cardiac glycosides are
hydrolyzed in the rumen and chloramphenicol is inactivated by reduction of the nitro group.
Bio-activation/Lethal Synthesis
Conversion of an inactive/non-toxic parent compound to an active/toxic metabolite is termed as bioactivation/
lethal synthesis. Some examples of lethal synthesis are:

Non-toxic parent compound Toxic lethal metabolite

Fluoroacetate Fluorocitrate
Parathion Paraoxon
Malathion Malaoxon
List of some Inactive drugs that produce active metabolites
Inactive parent compound Active metabolite
or prodrug
Cortisone Hydrocortisone
Prednisone Prednisolone
Cyclophosphamide Phosphoramide mustard
Chloral hydrate Trichlorethanol
Azathioprine Mercatopurine
Enalapril Enalaprilat
Zidovudine Zidovudine triphosphate
List of some active drugs that produce toxic metabolites
Active parent compound Active metabolite
Heroin Morphine
Codeine Morphine
Propranolol 4-OH Propranolol
Imipramine Desmethyl imipramine
Diazepam Nordiazepam & Oxazepam
List of some active drugs that produce active metabolites
Active parent compound Toxic metabolite
Paracetamol N-Acetyl-p-benzoquinone imine
Halothane Trifluoroacetic acid
Sulfonamide Acetylated metabolites
Methoxyflurane Fluoride
Microsomal Enzyme Induction
● The phenomenon of increase in the microsomal enzymes expression or activity is known as enzyme
induction and those agents, which cause enzyme induction, are called enzyme inducers.
● A number of drugs like phenobarbital (barbiturates), rifampicin, ethanol, carbamezepam, griseofulvin,
etc. and carcinogenic agents like 3-methylcholanthrene are known to induce microsomal enzymes.
● Enzyme induction can increase drug toxicity if its metabolite is toxic eg. paracetamol whose Phase-I
metabolites are mainly responsible for their toxicity will increase.
● Enzyme inducers can enhance the metabolic rate of self as well as other co-administered drugs with
significant clinical implications like reduction in efficacy and duration of action of drugs.
● Mechanism of enzyme induction is incompletely understood. However, the inducers appear to promote
the transcription of cytochrome P450 gene (CYP450).
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
Microsomal Enzyme Inhibition
● The phenomenon of decrease in the microsomal enzymes activity is known as enzyme inhibition and
those agents, which cause enzyme inhibition, are called enzyme inhibitors.
● Certain drugs/chemicals are also known to cause enzyme inhibition.
● Competitive enzyme inhibitor: Quinidine-potent inhibitor of cytochrome P2D6.
● Non-competitive inhibitors include drugs such as ketoconazole which forms a tight complex with haeme
iron (Fe3+ form) of cytochrome P3A4 causing reversible non-competitive inhibition.
● Other examples of inhibitors are cimetidine, chloramphenicol, erythromycin etc.
First Pass-Effect/Pre-Systemic Metabolism: The liver or sometimes the gut wall metabolizes some
drugs so efficiently that the amount of intact drug reaching the systemic circulation is less than the actual
amount absorbed. It is loss of drug before it reaches systemic circulation. This phenomenon is known as
pre-systemic metabolism or first-pass effect and is important for many clinically used drugs. Pre-systemic
metabolism or first-pass effect is encountered only with oral/enteral routes of administration.
Pre-systemic metabolism or first-pass effect is generally a nuisance in clinical practice because a much
larger dose of the drug is required when it is to be given by oral route.

Drugs Undergoing Substantial Pre-systemic Metabolism

Aspirin Lignocaine Chlormethiazole
Metoprolol Chlorpromazine Morphine
Dextropropoxyphene Nortryptaline Glycerine trinitrite
Pethidine Imipramine Propranolol
Isosorbide dinitrate Salbutamol Levodopa
Verapamil

Drug excretion: Excretion of drugs means the transportation (removal) of either unaltered or altered metabolized
form of drug out of the body. The major processes of excretion include renal excretion, hepatobiliary excretion
and pulmonary excretion. The minor routes of excretion are saliva, sweat, tears, milk, vaginal fluid, nails and
hair. The rate of excretion influences the duration of action of drug. The drug that is excreted slowly, the
concentration of drug in the body is maintained and the effects of the drug will continue for longer period. Polar
drugs and compounds with low lipid solubility are mainly excreted through kidneys and bile.

Renal excretion
● Compounds with limited lipid solubility and predominantly in ionized state at physiologic pH are excreted
through kidneys in urine. A major part of excretion of chemicals is metabolically unchanged or changed.
● Drugs excreted unchanged- most of the penicillins, cephalosporins, aminoglycosides, most tetracyclines
(except doxycycline), diuretics (except ethacrynic acid), cardiac glycosides, d-tubocurarine, gallamine etc.
The excretion of drug by the kidney involves.
i) Glomerular filtration
ii) Active tubular secretion
iii) Passive tubular reabsorption.
The function of glomerular filtration and active tubular secretion is to remove drug out of the body, while
tubular reabsorption tends to retain the drug back in the body.
i) Glomerular filtration: It is a process, which depends on (a) the concentration of drug in the plasma
(b) molecular size, shape and charge of drug (c) glomerular filtration rate. Drugs which are not bound
with the plasma proteins can only pass through glomerulus. All the drugs which have low molecular
weight can pass through glomerulus e.g. digoxin, ethambutol, etc. In congestive cardiac failure, the
glomerular filtration rate is reduced due to decrease in renal blood flow.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
ii) Active tubular secretion: The cells of the proximal convoluted tubule actively transport drugs from
the plasma into the lumen of the tubule e.g. acetazolamide, benzyl penicillin, dopamine, pethidine,
thiazides, histamine.

iii) Tubular reabsorption: The reabsorption of drug from the lumen of the distal convoluted tubules into
plasma occurs either by simple diffusion or by active transport and is affected by the pH of urine being
formed. When the urine is acidic, the degree of ionization of basic drug increase and their reabsorption
decreases. Conversely, when the urine is more alkaline, the degree of ionization of acidic drug increases
and the reabsorption decreases.

Hepato-biliary (Bile) Excretion

● Compound with molecular weight > 300 Da, presence of polar groups and conjugation with glucuronic
acid facilitates biliary excretion.
● Endogenous steroids, chloramphenicol, morphine, digoxin, bilirubin etc. form glucuronide and excreted
through the bile.
● Depending on lipid solubility, some drugs are reabsorbed from the small intestine (eg. tetracyclines)
and produce entero-hepatic recycling/ re-circulation leading to delay in elimination and increase in
drug half-life.

Gastrointestinal excretion: When a drug is administered orally, a portion of the total drug remains
unabsorbed and excreted unchanged in the faeces. The drugs which do not undergo enterohepatic cycle
after excretion into the bile are also subsequently passed with faeces eg. aluminium hydroxide changes the
faeces into white colour, ferrous sulfate into black and rifampicin into orange red colour.

Pulmonary Excretion: Drugs that are readily vaporized, such as many inhalant anaesthetics and alcohols
are excreted through lungs. The rate of drug excretion through lung depends on the volume of air exchange,
depth of respiration, rate of pulmonary blood flow and the drug concentration gradient.

Sweat: A number of drugs are excreted into the sweat either by simple diffusion or active secretion e.g.
rifampicin, metalloids like arsenic and other heavy metals.

Mammary excretion: Many drugs, mostly weak basic in nature, are accumulated into the milk. Therefore,
such drugs should be used cautiousally in lactating animals age they may enter into young one through
dam milk and produce harmful effects eg. ampicillin, aspirin, chlordiazepoxide, coffee, diazepam, furosemide,
morphine, streptomycin.
Relationship between total body clearance (ClB), volume of distribution (Vd) and half-life (t )
½

Rate of elimination
Clearance (ClB) = = β x Vd
Plasma conc.

0.693 0.693 x Vd
Half life (t ) = =
½ β ClB

ClB x t = 0.693 x Vd
½

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER - 5
PHARMACODYNAMICS
● Pharmacodynamics is the study of biochemical and physiological effects of drugs and their mechanism
of action. In laymen term it means “what drug does to the body?”
● A drug can’t initiate new cellular function but can modify existing cellular functions.
● A drug produces its effect by interacting with certain macromolecular components of cells/tissues
called receptors. Thus, Receptors may be defined as functional macromolecular component of the
cell/tissue with which the drug interacts and produce its effect.
TARGETS FOR DRUG ACTION
1) Receptors eg. Receptors for hormones, neurotransmitters (NTs)
2) Ion-channels eg. sodium, potassium, chloride chanels
3) Enzymes eg. Na+ - K+ - ATPase target for cardiac glycosides, dihydrofolate reductase, AChE,
cytochrome oxidase etc.
4) Carrier molecules eg. Plasma proteins involved in transport processes
5) Structural proteins eg. tubulin.
6) Cellular constituents like Membrane sterols e.g. nystatin, amphotericin-B bind to ergosterol.
7) Nucleic acid- Cancer chemotherapy
I. Receptors :
● The receptors are also interacted by the natural endogenous substances like NTs (e.g. ACh, NE etc.),
hormones (eg. estrogen, androgens etc.), autacoids (eg. histamine, serotonin etc.) which regulates
the function of the organisms.
● Drugs interact with receptors and produce their effect by either stimulating or suppressing the ongoing
cellular processes.
● The natural drug receptors are mostly enzymes located in the cell membranes. The interaction between
a drug and these receptors produces either a direct effect on the cell or an indirect effect through
activating or promoting synthesis or release of another intracellular regulatory molecule called the
second messengers.
● The direct effects of the receptors include alteration in the activity of trans-membrane enzymes, ion-
channels, guanine nucleotide binding proteins (G-proteins) etc.
● The second messenger concept includes stimulation or inhibition of adenyl cyclase (for synthesis of
cAMP) or guanyl cyclase (for synthesis of cGMP), phospholipase etc.
II. Enzymes : Some drugs instead of acting on receptors, directly act on enzymes.
1) Direct inhibition of enzymes eg. NSAIDs inhibit cyclooxygenase (COX) enzymes. Neostigmine
inhibit acetylcholinestrase enzyme.
2) False substrate: Drug act as false substrate eg. methyldopa. Dopamine is converted in nor-epinephrine
(act as neurotransmitter) with an enzyme dopamine α-oxidase. In some diseases more concentration
of dopamine is required, so drug methyl DOPA is given. This methyl DOPA acts as false substrate.
When enzyme acts on it, it converted into methyl norepinephrine or meta-norepinephrine.
III. Carriers : These are molecules responsible for transport of big substance across (amino acid, glucose,
bigger ions) cell membrane. Many drugs bind to carrier and inhibit its function eg. Furosemide act as
diuretic, given in case of anurea, it acts on “Na+ carrier” and inhibit it. Hemicholium inhibit transport of
choline, hence stop the formation of acetylcholine.
IV. Ion channels: Drugs directly interact with ion channel and modulates transport of ions through channels.
Eg. local anesthesia directly block local Na+ ion channels in neurons. Ameloride, a diuretic, it blocks
channel of Na+ ions reabsorption. Verapamil and diltiazem are calcium channel blockers.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
Drug binding to Receptors: Binding of drugs to receptors takes place through the following
physicochemical ineteractions:
1) Ionic forces
2) Hydrogen bonding
3) Hydrophobic interactions
4) Vander-Waal forces
5) Covalent bonding- duration of drug action is prolonged generally.
● Vanderwall bond, ionic bond, hydrogen bonds are weaker bond and are easily breakable and reversible,
so drug action is temporary. Covalent bond are stronger and if formed generally are irreversible.
Difference between specific receptors and non-specific receptors: For specific receptors, minor
change in molecular structure of the drug causes major change in the pharmacological response, whereas,
non-specific receptors have very low specificity for chemical structural requirements.

Drug action and Drug effect: Drug action is be defined as method, manners or ways by which drug influences
the cell functions. Drug effects/pharmacological effects/response is results of drug action on cellular processes.
Penicillin on microbes or aspirin on headache or pain eg. Penicillin interferes with incorporation of essential
amino acids/compounds into cell wall (“ACTION”) and cause cell lysis/death (“EFFECT”). Aspirin inhibits
prosta glandins (PGs) synthesis (“ACTION”) and relieves headache or pain (“EFFECT”).
Drug-Receptor Interaction: The drug-receptor interaction is the first step which initiates the subsequent
physiological and/or biochemical changes which are observed as effects/response of the drug.

Stimulus
Drug + Receptor à Drug-Receptor Complex Effects
Classification of receptors: Receptors are classified into 4 categories
1) G-protein coupled receptor:
● They are transmembrane protein present on cell membrane and linked with with Guanine nucleotide,
so called G-protein coupled receptors.
● They have haptamer structure and are serpentile in shape.
● Discovered by Gilmer and Gudberg.
● These are membrane bound receptors which mediates there action throgh guanine nucleotides.
● They are many types like Gs (s for stimulatory), Gi (i for Inhibitory), Go, Gq and G13.
2) Kinase coupled receptor:
● Membrane bound/present on cell membrane.
● It has 2 domains, 1 outside and 1 inside the cell.
● Outer domain called - ligand binding domain.
● Inner domain called - Catalytic domain. eg. insulin receptor, tyrosine kinase linked receptor, guanine
cyclase linked receptor.
3) Ion channel coupled receptor:
● Present on cell membrane and associated with ion channel.
● When drug bind with this, it regulate closing and binding of channel.
● These are fastest acting receptors.
eg. Nicotinic receptors, GABA receptors, Glutamate receptors
4) Steroid receptor:
● Situated inside the cell, so also called as cytosolic receptors.
● They are soluble in nature, number are variable.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 ● When drug act on it, bring out translocation, transcription for protein synthesis, so it is slowest
receptor in action. It takes 22-24 hours.
eg. mineralocorticoids, glucocorticoids

Theories of drug action : The drug-receptor interactions as the basis of drug-induced effects gave rise to
different theories of drug action.
1. Drug receptor theory : The receptor concept of drug action was first proposed by Paul Ehrlich, and
subsequently by J.N. Langley (1878). According to this theory each drug act on its matching receptor,
which is structure specific, to produce a pharmacological response. All drugs have different receptors.
One type of drug will not react with the receptors of another type i.e. specific receptors for specific
drugs just like “Lock and Key” system where a only particular key can open a particular lock e.g.
noradrenaline will interact only with adrenergic receptors.
2. Occupancy theory: Proposed by A.J. Clark (1936). Pharmacological or drug response is directly
proportional to portion of receptors occupied by drug. Maximum response is obtained when all the
receptors are occupied. This theory could not explain the phenomenon that partial agonist occupies
full population of receptors but fails to elicit maximum response.
3. Stepheson theory: Stepheson (1956) coined term efficacy. The efficacy is defined as ability of drug
to produce response. According to him, highly efficacious drug produces maximum response even
though they combine with small fraction of receptors. On contrary, poor efficacious drugs can not
produce maximum response even though they combine full fraction of receptors.
4. Rate theory: W.D.M. Paton proposed in late 1950s. Drug response is directly proportional to drug receptor
complexation. The drug response is determined by rate at which drug combines with receptors and leaves
the receptors, i.e., greater rate of association and dissociation between drug and receptors, greater is the
response. Antagonist combines with receptors at faster rate but dissociate at very slow rate.
5. Drug induced protein chanhe theory : Drug induces some temporary changes in the structure of
receptors making it active.
6. Two State Receptor theory: Receptor theory states that “an agonist combines with a site on a
receptor and the receptor becomes activated and triggered a response from the cell. When the drug
leaves, the receptor returns to the non-activated state, i.e. regenerated which is essential for further
cycles”. Receptor theory is also known as macromolecular perturbation theory / model theory.

Principles of Drug Actions

Drug affinity: The ability of a drug to interact or combine with its receptor is called drug affinity.
Intrinsic activity: The ability of a drug to produce the pharmacological response (Both drug affinity and
intrinsic activity depends on chemical structure of drug).
Drug efficacy: The maximum effect a drug can produce which depends on both drug affinity and intrinsic
activity.
Agonist: An agonist is a drug that interacts with its receptors and produces an positive effect i.e. it has both
affinity and efficacy e.g. isoproterenol, histamine, morphine etc.
Full agonist: Agonist which is able to produce maximum response.
Antagonist : An antagonist is a drug, which interacts with the receptors and prevents an agonist from
binding to the receptors to produce its effect e.g. atropine, propranolol, chlorpheniramine, naloxone etc.
Inverse agonist: Drug binds withreceptor like agonist but produces opposite effect. eg. B-carboliones on
benzodiazepine receptors.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
Partial agonist : An antagonist having some effects similar to agonist is called a partial agonist or mixed
agonist-antagonist. They have high affinity but low intrinsic activity. e.g. nalorphine
An agonist fully participates in the drug-action-effect sequence, whereas an antagonist has only action.
Agonist has affinity and efficacy while antagonist has only affinity and no efficacy.
Value of Intrinsic activity (IA) : For Full agonist = 1; Antagonist = 0; Partial agonist = > 0 but < 1, Inverse
agonist = 0 to -1.

Non-Receptor Mediated Drug Action : Non specific actions of drugs inculdes physical actions and chemical
actions. Physical actions are due to the physical properties of drug eg. osmotic diuretics, saline purgatives
(MgSO4), adsorbents. Chemical actions include simple chemical nutrilization of pH eg. Antacids (Aluminium
hydroxide), alkalizers like sodium bicarbonate.
DOSE-RESPONSE RELATIONSHIP OF DRUGS
The response to a drug varies according to its dosage i.e. the magnitude of the drug effect is a function of
the dose administered. The relationship between the responses produced by different doses is expressed
by graphical representation called dose-response curve.
There are two types of dose-response curves- graded dose-response curve and quantal (“All” or “None”)
dose-response curves.

(A) Graded-Dose or Gradual-Dose Response Curve : The graded dose-response curve gives the
relation between dose of the drug and intensity of the response in a single biological unit. The curve
depicts that when the dose exceeds a critical level (threshold dose) the response also increases
progressively until it reaches a steady level called ‘ceiling effect”. The threshold dose may be defined
as the minimum dose that is required to produce an observable response. The dose that produces the
ceiling effect, is called the ceiling dose, and may be defined as the amount of drug that is required to
produce a maximal response. Any further increase in the dose above the ceiling dose will not increase
the level of response. The shape or such graded response curve is hyperbola on simple graph paper,
but sigmoid in shape when dose is taken as log value on logarithm scale.

Threshold Dose Celling Dose

Response

Response

Log Dose Dose

(B) Quantal Dose-Response Curve

The quantal (“All” or “None”) dose-response curve represents the percent response of animals to
doses of a drug in a group of population. Each animal receiving a dosage is categorized as “responding”
or “not responding”. The population responding to each doses, are recorded as % dead, % alive, %
responded or % not responded. The relation is based on “all” or “none” phenomenon, which cannot be
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 quantitatively measured such as occurrence of sleep, convulsions, emesis etc. These quantal
responses, when plotted against log doses, does not show a linear regression. However, the percent
response is converted/transformed to probits, the relationship becomes linear. The graph is sigmoid
in shape in both normal & logarithmic graph paper. This type of curve is used for estimating/determining
median effective dose (ED50) and median lethal dose (LD50) values.

Applications of dose response curve:

(1) To know margin of safety of any drug
(2) To compare potency of drug
(3) To compare efficacy of two drug

Median Effective Dose (ED50) : Median effective dose may be defined as the amount of drug that would
be expected to produce a desired therapeutic effect among 50% of the population to which it has been
exposed. It is used for drug response.

Median Lethal Dose (LD50): Median lethal dose may be defined as the amount of drug/compound that
would be expected to produce a lethal effect (mortality) among 50% of the population to which it has been
exposed. It is used for toxic compounds.

ED50 and LD50 indicate therapeutic and toxic potency of drug, respectively. Based on value of ED50, drug
are classified into less effective, more effective and most effective. Similar for LD50,less toxic, more toxic
and most toxic.

MEASURES OF SAFETY
Therapeutic Index (TI) : It is the ratio between LD50/ED50. The wider the TI, safer is the drug. Ideal TI is
8-10 but some drugs like anticancer and anaesthetics have low TI.
Therapeutic Ratio (TR): It gives more precise margin of safety; as in quantal dose response curve,
portion between 16 to 84 per cent is more linear in nature. TR= LD25/ED75. Ideal value of TR is 4.
Standard safety margin: SSM is the ratio between LD1/ED99 or LD0.1 / ED99.9. The drug safety could be
better expressed by using a ration derived from two extremes of respective quantal response curves i.e.
ratio of least toxic dose and most effective dose.
Certain safety factor: It represents dose effective in 99 out of 100 or 999 out of 1000.
CSF = [(LD1/ED99)-1]/100

TERMS USED IN RELATION TO DRUG ACTIONS

Potency : It is defined as dose required to get predetermined effect. Potency & safety have no any
relationship. Potency and dose are inversely related. Higher the potency, less dose is required. Potency is
a relative term, it is not used isolated, and there must be comparison to other drug (reference/standard).
For example, Morphine @ 0.2 mg/kg and hydromorphine @ 2.0 mg/kg produce same response, then
hydromorphine is 1/10th Potent than morphine.
Latent period / Latency: It is time interval between termination of administration of drug and time at which desired
therapeutic response is observed. It’s value is the shortest for IV route of administration and longest after oral route.
Duration of action: It is a time interval during which drug continuously maintains desired therapeutic
response. The value depends on route of administration. The shortest for IV and longer for IM and SC
routes.
Onset of action: It is a interval between administration of drug and appearance of its first sign of drug
action.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
Reserve receptors: Reserve receptors are excess of drug receptors that are required for the maximal
response of the drug. Reserve receptors are also known as spare receptors.
Silent or inert receptors: Silent or inert receptors are receptive substances with which the drugs bind,
but do not produce any effect e.g. plasma pproteins.
Orphan receptors : Receptors whose ligand are not yet known or discovered.
Tachyphyalxis: Tachuphylaxis is a phenomenon in which the effect of a drug diminishes when it is given
continuously or repeatedly. This phenomenon often develops in the course of a few minutes e.g. effect of
repeated administration of tyramine on blood pressure. Tachyphylaxis is also termed as desensitization.
Tolerance: Gradual decrease in responsiveness to a drug. Requires day to week to develop e.g. tolerance
to alcohol.
Refractoriness: Loss of therapeutic efficacy.
Tachyphylaxis, tolerance and refractoriness may be due to following mechanisms:
a. Change in receptors
b. Loss or down-regulation of receptors.
c. Exhaustion of mediators.
d. Increased metabolic degradations due to induction of microsomal enzymes.
e. Physiological adaptations.

Drug resistance: Referred to loss of effectiveness of antimicrobial agents.

Summation/ Additive effects: If the pharmacological effect of two drugs administered together is
quantitatively equivalent to the sum of the individual expected effects, when administered alone, this
phenominon is called “additive effect or summation”. Such drugs generally share the same mechanism/
mode of action e.g. ephedrine + aminophylline as bronchodilator, streptomycin + dihydro-streptomycin as
antibacterial.

Synergism: If the pharmacological effect of two drugs administered together is quantitatively greater than
that is explainable on the basis of simple summation of their individual effects is called “synergism”. Though
the dresired effects are same, the drugs do not share common mode of action e.g. penicillin + streptomycin
as antibacterial, codeine + aspirin as analgesic, pyrimethamine + sulfadiazine as choloroquine-resistant
antimalarial, trimethoprin + sulfamethoxazole as antibacterial.

Potentiation: When the effect of a drug is considerably increased due to concurrent administration of
another drug or chemical is known as potentiation e.g. potentiation of acetylcholine by physostigmine.

Target tissue (Organ) : It is the site where the drug is intended to produce its effect e.g. anesthetics on the
CNS.

Therapeutic effect: It is the beneficial/useful desired effect produced by either direct or indirect action of
the drug.

Placebo: Derived from a Latin word meaning “I may please you”. A placebo is an agent or preparation
consisting of an inert pharmacological agent (usually starch or lactose) to stimulate the psychological
impact of medication in man. Placebo plays an important role in clinical drug trials in human beings.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 FACTORS AFFECTING / MODIFYING DRUG ACTION AND DRUG DOSAGE

Dosage or dosage regimen: Refers to the dose schedule of the drug to be employed for accomplishment
of an intended purpose and includes duration of therapy and frequency of drug administration.
Dose: refers to the total amount of a drug to be used through a specified route to elicit the intended effects
in a given subject.
Dose rate: It is an expression of a dose in terms of amount of the drug per unit body weight e.g. mg/Kg or
mg/m2 (unit per surface area in case of cancer chemotherapy).

Factors affecting drug effect & drug dosage are:

1) Physiological factors: Species, age, sex, circadian cycle
2) Genetic factors: Intra-species variations
3) Pathological factors: Hepatic dysfunction, renal dysfunction, GIT disorders
4) Environmental factors: Ambient temperatures, dietary factors
5) Therapeutic factors: Route of drug administration, pharmaceutical factors,

1) Physiological factors
● Species
The same drug may produce variying degree of response qualitatively and quantitatively in different
speceis. eg, Morphine-CNS excitation in cats while in other speceis it causes sedation.
Atropine from Atropa belladona leaves is non toxic in rabbits as it has enzyme atropinase which hydrolses
the atropine.
❖ Cats are highly susceptible to aspirin toxicity due to deficiency of glucuronyl transferase enzyme.
❖ Carnivores and primates respond to central or local emetics (apomorphine or Zinc sulfate/copper
sulfate). Ruminants and equines do not respond to emetics due to absence of efficient vomiting
mechanisms/reflex.
● Age: Very young and very old (geriatric) man and animals require low dosage compared to adults.
Neonates owing to immature metabolic and excretory function, they are more prone to toxic effecsts
of drugs. Older patients because of reduces hepatic and renal activity due to ageing needs lower dose
of drug than adults.
● Sex: Variation is less frequent but do occurs. It is due to difference between physioloigcal function and
endrocrine profile. E.g., Red squil is more toxic in femal as compared to male rats.
● Body weights: Dose of drug is calculated on the basis of body weight. Variation in body weights
especilly in pregnancy, dehydration, edema, obesity and other condition must be considered while
determing the dosage of drugs.

2) Genetic factors
● Idiosyncrasy is defined as unusual response of drugs to normal dose. It may be due to some genetic
factors.
● The collie breed of dog is more susceptible to ivermectin toxicity. This is due to lowere expression of
eflux drug transporter protein (P-GP) genes.

3) Pathological factors
● Liver diseases- Slower metabolic biotransformation/slower biliary excretion.
● Kidneys disorders- Slower excretion of drugs/drug retention.
● GIT disturbances-Diarrhoea (absorption of drugs), vomiting (non-retention of oral drugs) and constipation
(- absorption of drugs).
● Presence of abscess or purulent conditions- Effect of LAs is reduced.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
4) Environmental factors
● Ambient conditions can interfere pharmacokinetic profile of many drugs.
Temperature , humiduty and other environmental factors directly or indirectly influences the drug
response and dose.
❖ High altitude with low atmospheric pressure reduces oxidation of drugs due to low availability of O2.
❖ - Ambient temperature- induces procaine toxicity in pups due to rapid absorption owing to vasodilation.
❖ Ethanol toxicity is more pronounced in winter as it causes excessive vasodilation (skin). Presence of
chilled air exagreat the heat loss.
● Dietary factors
❖ Quality and quantity of food present in stomach interferes /reduces drug absorption (eg. astemizole,
captopril, many antibiotics).
❖ Presence of divalent cations (Al, Mg, Ca) reduces absorption of oxytetracyclines and fluoroquinolones.
❖ High fat/oil intake increases bioavailability of griseofulvin.
❖ Use of tea infusion/decoction can interfere with absorption of alkaloids notably ephedrine, codeine etc.
❖ Vitamin-C and copper ions increases iron absorption by reducing ferrous for to ferric state for quicker
absorption and assimilation.
❖ MAO-inhibitors and Tyramine rich food (cheese, alcoholic beverages, yeast extract, broad beans etc.)
leads to hypertensive crisis.

5) Therapeutic factors: Route of drug administration and frequency of drug administration depends on
tolerance. Repeated exposure and frequent treatment may cause down regulation and tolerance.
Reversly due to some genetical changes, receptors may exhibits supersensitivity and produces
exagreated response.

Pharmaceutical factors: Liquid dosage are more rapidly absorbed as compare to solid. In solid dosage
formulation, size of particles, dissolution time, disintegretion time is crucial factors in determining
absorption of drugs. Vehicle system or drug delivery system play important role in prodicung
pharmacological effecst.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER-6
DRUG SCREENING AND BIOASSAY OF DRUG
Drug screening denotes all methods by which pharmacological effecsts of newer drugs are being evalu-
ated. The primary target of screening is to identifye potenctially the new chemicals having known /unknown
or suspected pharmacological effects.
The basically there are three types of screening.
(1) Simple screening: It involves study of one or two pharmacological effects of chemials under investi-
gation. For eg., Screening for hypoglycemic effecs.
(2) Programmed screening: It involves screening of chemicals through series of well planned test or
procedures. For e.g., screening of chemical for antihypertensive effecst conducts all the tests includ-
ing urinary output, cardiovascular functions, heart rate, blood pressure, blood perfusions etc.,
(3) Blind screening: When ever, no information is available on substances under investigation or nothing
is known abour test substances, blind screening is employed. It involves extensive pharmacoligical
tests. If results are prominent, then substances are subjectd to simple or programmed screening.
Type of drug assay :
1. Bioassay or biological assay
2. Chemical assay: Estimation by chemical method and it is the most commonly used method.
Different techniques used are spectrophotometry, fluorimetry and sophisticated chromatographic
methods. Many drugs can be assessed by chemical methods. They have high sensitivity and
specificity but may be costly.
3. Immunoassay: It is a physicochemical assay which depends on the reaction between an antigen
(e.g. a hormone) and its specific antibody in the test tube. The antibodies are obtained from sera
of previously sensitized animals like rabbits. It is highly sensitive and can measure hormones and
other biologically active substances. Radio receptor assay and Enzyme Linked Immunosorbent
Assay (ELISA) are other types of Immunoassays.
Bioassay: It is short hand term used for biological assay. It refers to estimation of the potency of drug
(biologically active substance) by using biological method. It may be quantitative or qualitative.
Qualitative bioassay : It is used when it is not possible to quatify the response produced by drug, eg.,
abnormal deformity, induction of sleep and mood alteration.
Quantative bioassay : it is used when it is possible to quantify the response produced by drug , eg.,
Principle : To compare the test substance with the standard preparation of the same to find out how
much test substance is required to produce the same biological effect as produced by the standard.
Thus the stander and the test drugs should as far as possible are identical. Dose Response curve
forms the basis of bioassay.
Methods for bioassay :
1. Interpolation method
2. Direct matching or bracketing assay : This is the simplest method. In this method the responses
of different doses of known standard solution of the drug and a fixed dose of unknown test solution
(T) are recorded. Finally the dose of standard solution producing the response which exactly
matches T will be found. As this method involves repeating T inside a bracket of standard doses, it is
also called bracketing assay.
3. 2+1 or Three point assay: In this method, repetition of three doses, two of the standard (S1, S2)
and one of the unknown (T) is done randomly to obtain a series of responses. Then the concen-
tration of unknown is calculated graphically.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
4. 2+2 or Four point assay: Four point assay involves two doses of standard and two doses of test
solution.
Bioassay can be carried out either on intact animals or isolated tissues. For bioassay of a particu-
lar drug appropriate animal or isolated preparation should be selected.
Following are some examples of isolated tissues or animals selected for bioassay of different drugs
Drug Animal/Preparation of choice
Adrenaline Cat/dog-Rise in B.P.
Noradrenaline Spinal cat - rise in B.P.
Histamine Isolated guinea pig ileum contraction
Acetylcholine Isolated frog rectus abdominis contraction
Digitalis Guinea pig- death due to cardiac arrest
Insulin Mice-hypoglycemic convulsions

Advantages:
1) Sensitivity: sometimes when concentration of active substance is below the limit detect
by chemical or other methods, bioassay can be used.
2) When structure of active substance is unknown.
3) When the response of drug and concentration is poorly correlated.
4) When nature of drug to be tested is very complex and it’s concentraion is not measurable in biological
matrix.

Disadvantages:
1) Biological variation- errors arising due to it.
2) Time consuming, tedious.
3) Experimental animal needs to be sacrificed.

Indication & Uses of bioassay: Indicated for substances derived from plant or animal sources. Synthetic
drugs usually don’t required bioassay.

Bioassay can be used for:

1) Standardization of drugs of natural origin (biostandardization).
2) Estimation of biologically active substances like acetylcholine, adrenaline, noradrenaline, serotonin
etc. in body fluids and extracts.
3) Screening of new compounds for biological activity-including synthetic compounds.
4) When drug is a complex mixture of substances of varying structure and activity e.g. digitalis,
posterior pituitary extract.
5) Diagnosis and Research:Concentration of gonadotropins in blood of mice estimated by injecting these
fluids in animal (chemical methods if available are preferred).
6.) Estimation of ED 50, LD 50 and thus to establish therapeutic and toxic profile.

Requirement of Bioassys:
It must be accurate, precise, specific, sensitive, stable and simple to perform.
1) The animals to be used in bioassay must be easily available.
2) It should cause minimum pain to animals.
3) The bioassay must use least numbers of live animals.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER - 7
ADVERSE DRUG REACTIONS
Drugs are chemical that affects the living system. All drugs are harmful at (refer Pharmacological antagonism
high doses. Some drugs cause side effects and/or adverse effects.
● Side effects: Side effects of a drug is due to normal pharmacological action of the drug e.g. constipation
due to morphine when used as analgesic or CNS depression by conventional anti-histamines.
● Adverse or untoward effects: Adverse or untoward effects of a drug occurs following prolonged
therapeutic use e.g. prolonged use of antibiotics in chronic infections leads to development of super-
infections, ototoxicity (due to aminoglycosides0 or nephrotoxicity (due to sulfonamides).
● Iatrogenesis: derived from a Greek word “iatros”= physician. Iatrogenesis means physician-produced
disease.The term refers to the production of abnormal or pathological conditions due to the drug
administered e.g. oral administration of aspirin or indomethacin for prolong period may precipitate
peptic ulcers.
● Idiosyncrasy: It is defined as a genetically-determined abnormal response to a drug or a chemical
e.g. hemolytic anemia following administration of primaquine (antimalarial drug) due to deficiency of
glucose-6-phosphate dehydrogenase.
● Hypersensitivity/allergic reactions: It is an acute adverse reactions that results from prior sensitization
to a particular drug or chemically-related substances. Most frequently seen in man e.g. penicillin allergy.
● Anaphylaxis: An anaphylactic reaction occurs when an animal is exposed to a protein to which it had
been previously sensitized. The initial exposure does not cause any reactions, but the second or
subsequent exposure to the same protein triggered severe reactions characterized by acute
bronchoconstriction and cardiovascular shock e.g penicillin anaphylaxis.
DRUG TOXICITY: Toxicity is defined as the inherent capacity of a substance to cause harmful effect.
Type of toxicity: 1. Acute toxicity, 2. Sub-acute toxicity, 3. Chronic Toxicity
Acute Toxicity
● Occurs when an animal gets exposed to a single high dose of the compound.
● Toxic signs – tremors, vomition, convulsions, dyspnoea, coma and death may be observed.
● Experimental acute toxicity studies helps in calculating LD50 values of the compound.
Sub-acute and chronic toxicity :
● Repeated exposure of low doses for 3-6 months, Routine pathology, Histopathology of vital organs
● Teratogenecity: Derived from the word “tera”= monster. It is the inherent capacity of a drug/substance to
produce teratogenesis/fetal abnormalities when the drug is exposed to pregnant animals during the first
trimester of pregnancy e.g. thalidomide tragedy. Thalidomide, an antemetic produced “phocomelia” or
“sealed limbs” in thousands of children born to mothers who had taken the drug to prevent morning sickness
during early pregnancy.
● Carcinogenecity: It is the inherent capacity of a drug/substance to produce carcinogenic (tumor-
inducing) effect e.g. DDT, 2,4-D, 3-methylcholanthrene etc. Mutagenecity: It is the inherent capacity of
a drug/substance to produce gene mutagenesis e.g. many carcinogens.
● Ototoxicity: It is the inherent capacity of a drug/substance to produce hearing impairment including
deafness e.g. aminoglycoside antibiotics.
● Nephrotoxicity: It is the inherent capacity of a drug/substance to produce renal damage e.g.
sufonamides, aminoglycosides etc.
● Hepatotoxicity: It is the inherent capacity of a drug/substance to produce hepatic damage e.g. CCl4,
chloroform, paracetamol etc.
● Neourotoxicity: It is the inherent capacity of a drug/substance to produce toxic/harmful effects on the
brain e.g. many CNS acting drugs.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER - 8
DRUG INTNERACTION
One drug may alter the dose or effect/s of another drug when two are used concurrently, these are called
drug interactions, that leads to
● Increase in response to one or both drugs
● Decrease in response to one or both drugs
● Abnormal alteration in response to one or both drugs
Drug interactions are of two types:
I) Pharmacokinetic interactions: One drug alters the pharmacokinetics of second drug thereby affecting
the concentration (and effect) of one / both drug in system.
● Antacids decrease absorption of aspirin, warfarin, ciprofloxacin etc.
● Phenylbutazone displaces warfarin from albumin binding sites.
● Phenobarbitone, rifampin etc. induces hepatic microsomal enzymes causing increased metabolism
of pentobarbitone, digitoxin, warfarin, morphine etc.
● Chloramphenicol inhibits hepatic microsomal enzymes causing decreased metabolism of
pentobarbitone, tolbutamide, phenytoin etc.
II) Pharmacodynamic interactions: There is no alteration of pharmacokinetics of either drug but there
is alteration of biological response to one / both drugs.
● Atropine antagonize effect of acetylcholine (pharmacological antagonism)
● Adrenaline (bronchodilator) and Histamine (brochoconstrictor)
● Aminoglycosides and cephalosporins potentiate nephrotoxicity.
Addition: Two drugs are said to be additive if combined effect produced by them when used together is not
more then sum of their individual effects (2+3=5). eg Aspirin + paracetamol as analgesic, Ephedrine +
Theophyline as brochodilator
Potentiation: One drug have less or no effect but in combination with another drug it shows significant
effects. e.g. isopropanol alone is not showing hepatotoxic effect but along with ethanol it shows h i g h
hepatotoxic effect. ( 0 + 3=5)
Synergism: combined effect is more than additive drug effect.(2+3=8) e.g. Sulphonamide + trimethoprim,
adrenaline + desipramine, Captropril+diuretics
Antagonism: When two drugs used simultaneously or one after another produce effect that is less than
sum of their individual effects. (7+3= 6) eg. tannins + alkaloids – chemical antagonism
Glucagon + insulin-physiological antagonism
Morphine + naloxene, Diazepam + bicuculine-pharmacological antagonism.
Examples of few drug-drug interaction :
● Procaine with adrenaline: adrenaline cause vasoconstriction and decrease absorption of procaine.
● Amoxicillin with clavulanic acid : clavulanic acid inhibit â-lactamase enzyme which hydrolyse
amoxicillin.
● Chloramphenicol with pentobarbital: Effect of pentobarbital increased as chloramphenicol inhibits
metabolism of pentobarbital by inhibiting hepatic microsomal enzymes.
A general rule that would reduce or avoid adverse effect due to drug-drug interaction is as follows:
“Never mix a cationic drug with an anion drug unless there is some definite reason to use them”. Cationic
drugs include atropine, aminoglycosides, local anesthetics, lincosamides, polymyxins, marolids,
chlorpromazine and promethazine. Anionic drugs include sulfonamides, penicillins, cephalosporins, heparin,
EDTA and barbiturates.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER - 9
DRUG DESIGNING, DEVELOPMENT AND BIOPROSPECTING
Drug designing: The design of grug involves many approach. Most dominant approcah includes modifica-
tion of existing structure of drug using SARs. The combinatorial chemistry and medicinal chemistry are
core branches of science which are involved in drug designing. The design of drug depends mainly on
identification of target and probability of interaction with target. Addition or deletion of certian chemical
groups or functional moiety give rise to series of compound with diversified pharmacological prospectus.
They are frist screened for pharmacological activities. Now a days modern approachs like HTS, in silico
testing ect are used. These techniques gives faster and cheaper results.
Drug development: Development of new drug is a complex process consuming huge time and financial
resources depending upon regulatory frame work of country in which drug is to be approved for market.
The basic process of drug development is discussed here.
Pre-clincal studies: After screening, promising candidates are subjectd to pre-clnical evaluation or
studies. It includes acute, sub acute and chronic toxcity study. Caricinogenicity, mutagenicity and repro-
ductive toxicity are also included in this phase. Pharmacokinetics data in different species of laboratory
animals are also generated.
Clincal evaluation: It includes four phase of drug testing.
Phase-I: It included pharmacokinetics of drug in small group of healthy volunteers. Pharmacokinetics and
pharmacodynamic parameters are worked out.
Phase II: It covers pharmacokinetics and pharmacodynamics, dose ranging, efficasy and safety study in
small group of patients (50-300 patients).
Phase III: Large scale controlled clincal trial for safety and efficasy in large group of patients (500 to 1000 plus)
Phase IV: It is also known as post marketing surveliance. It is collection of reports regarding adverse drug
reaction, relative comparison with existing drugs and pharmacoeconomics.

BIO-PROSPECTING
It is defined as search for plant and animal species from which medicinal drugs and other commercially
valuable compounds can be obtained. Bioprospecting is the process of discovery and commercialization
of new products based on biological resources. Bioprospecting can be defined as the systematic search
for and development of new sources of chemical compounds, genes, micro-organisms, macro-organisms,
and other valuable products from nature. It entails the search for economically valuable genetic and
biochemical resources from nature.

Advantage:
● Stimulates authentic research in natural sources of drugs.
● It provides economical compensationn and scientific credits to owner country.
● It increases foucsed research efforts in the herbal medicine.

Disadvantage:
● Pharmaceutical companies or researchers shows dicinclination towards economic compensation
and scientific credtis to host country to which these resoures belong.
● Natural resources and biodiversity are exposued to higher human interferance and invasions.
● The legal frame work regarding use of bio resources and sharing of discovery has not attained mature.
This leads to conflict at local and international level causing hinderance in development of new drugs.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER - 10
BIO PHARMACEUTICS AND GENE THERAPY
The term ‘biopharmaceutical’ was first used in the 1980s and came to describe a class of therapeutic
protein produced by modern biotechnological techniques, specifically via genetic engineering or by hybridoma
technology (in the case of monoclonal antibodies). This usage equated the term ‘biopharmaceutical’ with
‘therapeutic protein synthesized in engineered (non-naturally occurring) biological systems’. More recently,
however, nucleic acids used for purposes of gene therapy and antisense technology have come to the front
and they too are generally referred to as ‘biopharmaceuticals’. Moreover, several recently approved proteins
are used for in vivo diagnostic as opposed to therapeutic purposes.

Biopharmaceutics: It is modern branch of pharmcology which deals with production and therapeutic
application of biopharmaceuticals.

Biopharmaceutical: ‘Biopharmaceutical’ includes ‘therapeutic protein synthesized in engineered (non-

naturally occurring) biological systems’. More recently, nucleic acids used for purposes of gene therapy
and antisense technology are also included in ‘biopharmaceuticals’.

Terms like ‘biologic’, ‘biopharmaceutical’ and ‘biotechnology medicine’ can be differentiated by following
definitions:-

Biopharmaceutical: A protein or nucleic acid based pharmaceutical substance used for therapeutic or in
vivo diagnostic purposes, which is produced by means other than direct extraction from a native (non-
engineered) biological source.

Biotechnology medicine/ product of pharmaceutical biotechnology: Any pharmaceutical product used

for therapeutic or in vivo diagnostic purposes, which is produced in full or in part by biotechnological means.

Biologic (Biological products): A virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component
or derivative,allergenic product or analogous product, or arsphenamine or its derivatives or any other trivalent
organic arsenic compound applicable to the prevention, cure or treatment of disease or conditions of human
beings.

Several example includes function human proteins (ADH, oxytocin, GnRH, TSH, ACTH, Insulin,
Somatostratin); enzymes (Proteins, antibiotics, antibodies, hormones, cytokines).

GENE THERAPY: Gene therapy in simple terms is the introduction of a gene into a cell, in vivo, in order to
ameliorate a disease process. Human clinical trials have focused on the correction of monogenic deficiency
diseases, cancer and AIDS. It is prevention and treatment of diseases through manipulation of gene functions.
It involves replacement of defective genes or supplementation of non functional genes or supression of
abnormal genes. Recominant DNA technology forms the basis of synthesis of therapeutic genes.

Entire process is of two steps. First step involves insertion of therapeutic gene to vectors. Second step
included introduction of vectors containing gene in to patient through in vivo-ex vivo means. In-vivo means
includes injection of suspension of the vector having therapeutics genes intravenously in to targets or local
tissues. Ex vivo means includeds insertion of therapeutic gene in to steam cells followed by intravenous
injection. Gene therapy has proved very promising teratment for the diseases like haemophilia, thalesemia,
immunity disorder. These diseases are not treated by conventional treatment. IL-12 based gene therapy
has been tried for antitumor effect on spontaneously occurring tumors in large animals and proved safe and
well tolerated by the animals.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER 11
DIGESTIVE PHARMACOLOGY
CONTENTS :
1. Sialagogues/salivary stimulants 2. Antisialagogues/asialics/sialic inhibitors
3. Appetite stimulants/appetizers 4. Anorexigenic
5. Stomachics 6. Antistomachics/gastric sedatives
7. Astringents 8. Antidiarrhoeal drugs
9. Demulcents 10. Carminatives/antiflatulants
11. Antizymotics 12. Antiulcers
13. Rumenotonics 14. Prokinetics
15. Antacids 16. Purgatives
17. Emetics 18. Antiemetics
1. Sialogogues: Sialogogues or sialics are the salivary stimulants which increases volume and fluidity
of saliva.
Use:
1) Iatrogenic (drug induced) hypoptylism (less secretion of saliva)
2) As an ingradient in tonics preparation.
3) Xerostomia (dryness of mouth due to lack of normal secretion)
Classification :
a) Reflex sialogogues/bitters
b) Cholinergic sialogogues
c) Direct acting sialogogues
a) Reflex sialogogues/bitters: eg. gentian: Its main active principle is gentiopicrin (bitter glycoside),
obtain from root and rhizome of Genatina lutea; Cinchona (quinine); Chirrata : It is available from
Swatia chirrata, active principle is chirrata; and Turpentine oil; Outer covering of orange: active
principle is limonene and terpene
Precautions to be taken while using bitters :
i. Bitter salts should not used chronically because they may produce gastritis, gastric catarrh.
ii. Bitter should not be used in gastritis.
iii. Bitter should be given half an hour before the milk or food to achieve their full effect.
iv. Bitter should not give for more than 1 weak.
v. If given in large dose, initially it will stimulate secretion and then response to irritation or stimulation
decrease.
b) Cholinergic sialogogues: eg. Nicotine, Cholinesters, Cholinomimetic alkaloids like carabachol,
AchE inhibitors etc.
c) Direct acing sialogoges: eg. alcohol, Iodine etc.
2. Antisialogogues/asialics/sialic inhibitors: Decrease saliva secretion
Use: For preanaesthetic medication to reduce excessive salivation that may occur during anaesthesia
eg. atropine, hyoscymine, glycopyrolate (synthetic antimuscarinic drug)
3. Appetite stimulant:
● Drug which increase appetite (desire to eat)
● Appetite is psychological function.
● Appetite stimulants also called as appetizers.
● Used to overcome anorexia
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
Examples include :
i. Diazepam (particularly benzodiazepam): they act on CNS produce sedation, stimulate hunger centre
and modifies appetite.
ii. Glucocorticoides: antistress, gluconeogenesis
iii. Cyproheptadine: they are 5-HT antagonist and prevent their stimulatory action on hypothalamic satiety
centre.
iv. Betazole: histamine antagonist
v. Anabolic steroids: increases appetite, weight gain, haematopoesis. eg. stanazolol 0.25 mg/kg P/O
daily
Adverse effects: Hepatotoxicity, msculinization, early closure of epiphyseak plate.
4. Anorexigenic: Drugs which produce anorexia or suppress appetite by acting on CNS.
Classification:
a) Centrally acing anorexigenics:
● Amphetamine: Act on α-receptor. It is misused to reduce body weight.
● Mephentamine
b) Drug which act by blocking 5-HT receptor:
● They are called as SSRI (Selective Serotonin Reuptake Inhibitor) eg. Fenfluramine, fluoxetine
5. Stomachics: Drugs which promote functional activity of stomach by increasing secretion and gastric
motility.
Uses: (a) Hypochlorhydria; (b) Achlorhydria; (c) Anorexia and (d) Ruminal atony: Commonly encountered
in field because constimation causes decreasesd ruminal motility.
Examples include :
i. Muscarinic agents: Ach (Acetylcholine), Carbachol, Bethanechol, Pilocarpine, Neostigmine and
Physostigmine
ii. Histamine (H2) agonist: Histamine, Betazole
iii. Dopamine antagonist:
eg. Metoclopramide (Perinorm®)
● It increases tone in the lower cardiac sphincter.
● It increase frequency and force of gastric contraction(gastrokinetic effect)
● It relaxes pyloric sphincter.
● It increases peristalsis in duodenum and jejunum.
● It has local antiemetic action.

Uses of dopamine antagonists:

● To promote gastric emptying in pre-operative condition
● Oesophageal spasm
● Oesophageal obstruction
iv. Alkaline salts: (sodium bicarbonate, carbonate salt)
MOA: They liberate CO2 which increases secretion and vasodilation in gastric mucosa.
v. Bitters: (gentian, ginger, turpentine oil)
MOA: They cause stimulation by irritation
vi. Cisapride, mosapride, neostigmine: Increases Ach secretion in myentric plexus by acting on
5HT4 receptor and increases gastric motility and intestinal motility.
6. Antistomachics/gastric sedatives:
Drugs which supress functional activity of stomach by decreasing secretion and gastric motility.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 Uses: (a) Hyperacidity; (b) Diarrhoea and (c) Ulcer
Classification :
i. Antimuscarinic agents (e.g. atropine)
ii. Adrenergic drugs (e.g. adrenaline)
iii. Antispsmodic (e.g. morphine, codeine, pethidine),
Morphine and nicotine decreases motility and act as antidiarrhoeal agent
iv. H2 blockers (e.g Ranitidine, Cimetidine)
v. Cholecystokinin
vi. Gastric inhibitory peptides
7. Astringents: Drug which help in forming a protective layer and exert protective action on intestinal
mucosa against the irritants by precipitating surface proteins in the mucosa. eg. Tannic acid (in strong
tea), catechu powder (in crata and chalk), aluminium hydroxide gel etc.
Uses: (a) Gastritis; (b) Enteritis; (c) Mouth ulcer and (d) Diarrhoea
8. Antidiarrhoeal drug: They act against diarrhoea, mainly used for treatment of acute diarrhoea.
Classification:
a) GI mucosal adsorbent or protectant
b) GI motility inhibitors/spasmolytic/antispasmodic
c) Anti-infective agents/antimicrobial agents
d) NSAIDs
a) GI/mucosal adsorbent or protectant: They reduce the irritation of intestinal mucosa caused by
bacterial toxins and other non specific toxins by adsorption of these toxins on their surface. Most
adsorbents itself are biologically inert.

Examples include
i. Activated charcoal:
● Adsorbs toxins, so used for medical purpose as a part of universal antidote in toxic cases.

● Made from wood source by burning them at high temperature under high pressure in vaccum.
● 1-2 gm/kg BW

ii. Kaolin (China clay/aluminium magnesium silicate)

iii. Pectin (Indigestible carbohydrate derived from apples)
iv. Bismuth salts: (carbonate, subsalicylate etc)
● Useful in acute diarrhoea of animals
● Can be used against E. coli toxins
● Also posses antimicrobial activity against H. pylori.
● Bismuth subsalicylate has anti-COX enzyme property, so it also has anti-inflammatory effect.

b) GI motility inhibitors/spasmolytic/antispasmodic:
● Reduces motility of GIT and supresses muscular spasms, associated with diarrhoea
● Spasm is increased/prolonged contraction of muscles.

Classification :
i. Opium derivatives: Morphine (used in ancient time to releive pain but abused today), pethidine etc.
ii. Atropine
iii. Loperamide : It is an opoid drug. It is agonist of µ−receptor in myentric plexus of large intestine.
Contraindicated in cat and children below 2 years of age as it produces toxicity Dose: 0.08 mg/kg BW
iv. Diphenoxylate : It is centrally acting opoid drug, and often combined with atropine to treat acute
diarrhoea.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 v. Dicyclomine: It is also known as dicycloverine. It is an antispasmodic and antimuscarinic agent.
It relieves smooth muscle spasms of GIT and act as a smooth muscle relaxant. It blocks action
of Ach on muscerinic receptor present on a smooth muscles. It is mainly used in spastic colic of
equine and other animals like cattle, buffalo, sheep, goat, cat and dog.
c) Anti-infective agents/antimicrobial agents: Diarrhoea is associated with microorganisms
Amoebiasis/giardiasis: Metronidazole, tinidazole, ornidazole and furazolidone
Traveller’s diarrhoea: It occur due to contaminated food and water consumption during journey.
Drugs used to treat it are ciprofloxacin, ofloxacin, amoxicillin, metronidazole, sulpha antibiotics, neomycin
and nitrofuran
d) NSAIDs: Meloxicam, aspirin etc.
9. Demulcent: Drugs which reduce irritation and provide soothing, protecting and cooling effect to the
part on which they are applied (Lubrication, coating, protection). They are given orally for soothing GI
tract.
Uses:
I. To prevent animal from effect of toxicant like calcium carbide (fruit ripening agent) if eaten by animal.
II. To mask unpleasant tastes, stabilize emulsions and act as suspending agent (eg. gums) eg.
Starch, honey, gum, glycerine, propylene glycol, liquid paraffin, proteins (egg albumin and gelatin),
liquorice (from Glycerrhiza glabra plant)
10. Carminative/antiflatulants: They causes expulsion of gases from the stomach or rumen and relieves
distension of stomach rumen and associated pain.
Actions : They have a mild irritant action on mucous membrane and tend to relax the GI musculature
particularly the cardiac sphincter of stomach which play role in the releasing gas from the stomach.
Uses: In Tympany/bloat. eg. Turpentine oil, mineral oil (liquid paraffin), asafoetida, peppermint oil (Mentha
piperita), ginger (Ginger officinale), clove (Eugenia caryophylus), cardamon (Eattaria cardamon),
coriander (Coriander sativum: its seeds are popular mouth freshner), Caraway (Cumin carvi), anise
seed (Pimpenella anisum, Active principle is anethone), nutmeg (Miristica fragrance), fennel seed
(Foeniculum vulgare: variyali).
Anti-foaming agents : Many antiflatulants are anti-foaming agents which act as surfactant and are
used to treat froathy bloat The defoaming action of surfactants relieves flatulence by dispersing and
preventing formation of mucous surrounded gas pockets.eg. arachis oil, turpentine oil, organic silicsns
(dimethicone, simethicone).
Note:
1) Dose of turpentine oil : Large animals:15-60 ml; Sheep, Goat: 5-15 ml
2) Pudina contains mentha or menthol and used to make peppermint oil.
3) Panacea of GI disturbance : Ginger
11. Antizymotics: Drugs which prevent or decrease bacterial or enzyme fermentation which is used to
prevent further gas production in tympany and bloat in ruminants. eg. Chloroform, chloral hydrate,
turpentine oil (It is also an anti-foaming agents), ethyl alcohol, formaline, phenol, polymerised methyl
silicon, polyethylene Glycol (PEG) surfactant.
Treatment of tympany/Bloat : Drugs are given intra-rumianlly through rumen puncture.
Cattle: Turpentine oil (30 ml) + groundnut oil/linseed oil/vegetable oil (25-300 ml)
Sheep, goat: Turpentine oil (4-8 ml) + groundnut oil/linseed oil/vegetable oil (30-60 ml); Formaline
(4-6 ml) + water (300 ml)
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
12. Anti-ulcers: To treat the ulcers produced by gastric hyperacidity
Classification :
i. Antacids: Neutralize gastric acid (Systemic and non-systemic)
ii. Antimuscarinic drugs: Decrease GIT secretion and produce anti-ulcer effect eg. Pirenzepine
iii. H2 receptor blocker : Decrease gastric HCl secretion by blocking histamine (H2) receptor eg.
Ranitidine, Cimetidine, famotidine
iv. Proton pump inhibitors: Proton pump inhibitors are inactive at neutral pH and becomes active
at pH < 5. They inhibits H+ - K+ ATPase enzymes and block entry of H+ from ECF into ICF, so HCl
is not synthesized. eg. Omeprazole, Lansoprazole, Esomeprazole etc.
v. Prostaglandin analogue: eg. Misoprostol (a methyl analogue of PGE1 : methyl-PGE1-ester) it
produced cytoprotective effect and used as antiulcer agent.
vi. Ulcer-protectives : eg. Sucralfate, colloidal bismuth subcitrate (CBS)
● It is a complex formed from combination of sucrose octasulfate and polyaluminium hydroxide.
● In acidic environment, this octasulfate polymerise to form viscous and sticky substance which
form the coating over ulcerated mucosa and thus prevent the back diffusion of H+ and protect
ulcer from acid.
● It also inhibit the bile and pepsin activity
● Also increase prostaglandin synthesis
● These agents also produce cytoprotective effect in the ulcer.
vii. Anti-Helicobacter pylori drugs: H.pylori is gram negative bacilli which decreases mucosal
protective mechanism and cause ulcers. Anti bacterial agents which are effective against H.
pylori are amoxicillin and or clarithromoycin in combination with metronidazole or tinidazole.
13. Rumenotonics: Drugs which increases ruminal motility. A mixture of compounds are used as
rumenotonics. eg. Antimony potassium tartrate, cobalt sulphate/cobalt chloride, ferrous sulphate, copper
sulphate, manganese sulphate, zinc sulphate, choline chloride/thiamine monohydrate, nicotinic acid,
dried yeast sodium acid phosphate etc.
14. Prokinetics: Drugs which promote downward movement of ingesta through the GIT by inducing
coordinated GIT motility. They improve gastro-duodenal motility and facilitated gastric emptying.
Uses: (a) Gastritis; (b) Impaction; (c) Reflex oesophagitis (Oesophageal reflux); and (d) ruminal atony
Classification:
a) Dopamine antagonist:
b) 5-HT4 Agonists: (By increase release of Ach)
c) Cholinomimetic agents: (by inhibition of AchE enzyme)
a) Dopamine antagonist: eg. Metoclopramide, Domperidone (D2 antagonist). Metoclopramide and
Domperidone are dopamine D2 receptor antagonists. Within the gastrointestinal tract, activation
of dopamine receptors inhibits cholinergic smooth muscle stimulation; blockade of this effect is
the primary prokinetic mechanism of action of these agents. These agents increase oesophageal
peristalsis, increase tone of cardiac sphincter (contraction), decrease tone of pyloric sphincter
(relaxation) and enhance gastric emptying but have no effect upon small intestine or colon motility.
Metoclopramide and Domperidone also block dopamine D2 receptors in the chemoreceptor trigger
zone (CTZ) of the medulla, resulting in potent antinausea and antiemetic action.
Dose : Dog and cat: 0.2-0.5 mg/kg, P/O or S/C, TID
b) 5-HT Agonists: (By increase release of Ach) : These are chemically related to Metoclopramide
but these promote gastric emptying and enhance small and large intestine motility but have no
effect upon oesophageal motility. eg. Cisapride, Mosapride (5-HT2 and 5-HT4 Agonists)

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 c) Cholinomimetic agents (AchE enzyme inhibtors) : Neostigmine can enhance gastric, small
intestine, and colon emptying. Other example is pyridostigmine.
15. Antacids: Agents that neutralize gastric acid and increase the pH value of gastric contents. They are
not much popular in vet. medicine as requires frequent administrations.
Uses: (a) Acidity/acidosis (b) Abomasal/peptic ulcer (c) Abomasistis/gastritis (d) Reflex oesophagitis
(GERD= Gastro-Esophageal Reflux Disease)
Mechanism of Action : They neutralize gastric HCl to form salt and water. Their action is for short
period (2-3 hours). They are not absorbed locally. They also induce PGE synthesis locally which gives
cytoprotective effect.
Classification: Antacids are of two types :
A. Systemic antacids: Which are absorbed in the blood. eg. Sodium acetate, sodium bicarbonate, sodium
citrate
B. Non-systemic antacids: Which are remain primarily in the GI tract. They are mostly used in combination
with each other along with protectant, adsorbent and astringents.Unreacted alkali is readily absorbed,
causing metabolic alkalosis when given in high doses or to patients with renal insufficiency. They are
not absorbed at therapeutic dose and does not produce toxicity, but at higher dose given for longer
period, they may cause renal toxicity.
They can be classified further as:
a) Buffered antacids : Control pH rise below neutrality. eg. Aluminium hydroxide, aluminium
phosphate, magnesium trisilicate
b) Non-buffered antacids: Control pH rise beyond neutrality i.e. beyond pH 7.0 eg. magnesium
oxide, magnesium hydroxide (milk of magnesia), magnesium carbonate, calcium carbonate,
calcium phosphate, tribasics
Adverse effects:
1) Antacids change the pH value of gastric and intestinal contents so pepsin becomes inactive so pepsin
digestion is altered.
2) They neutralizes acid in stomach and intestine, so negative feedback mechanism activate, which
increases in gastrin hormone secretion, this gastrin enhance gastric HCl secretion.
3) NaHCO3 : Alkalosis, acid rebound effect, pepsin inactivation
4) Al(OH)3 : Constipation and Mg(OH) 2 : loose stool/diarrhoea. Aluminium salt produces constipation
where as magnesium salt produces purgation, so generally combination of both is used.
eg. Gelucil® contains magnesium trisilicate and aluminium hydroxide
6) Ca(CO)3 : Constipation, alkalosis, acid rebound effect
Sodium bicarbonate: (Baking soda)
● Stable in dry air but decomposes in moist air.
● Because of its high water solubility it is immediately effective in neutralizing gastric pH and increase
pH towards alkaline side. But NaHCO3 has acid rebound effect, means after decreasing pH, it again
increases pH (antacid like Ca(CO)3 also show acid rebound effect)
Mechanism: NaHCO3 liberates CO2 which accumulates and produce distension of gastric mucosa
because of this there is reflex secretion of gastric acid resulting in acidity again.
MOA :
1) Increases gastric pH to 4
2) Neutralizes prefound acid
NaHCO3 + HCl NaCl + H2O + CO2

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
3) Rapid antacid action, short duration due to absorption. 1 gm NaHCO3 neutralizes 12 meq HCl.
Side effects :
1) Sodium bicarbonate changes the pH value of gastric and intestinal contents so pepsin function is
inhibited.
2) It has acid rebound effect.
3) CO2 production causing discomfort, risk of ulcer production.
4) Metabolic alkalosis
5) Na+ retention in Chronic Heart Failure.
Drug interactions:
It influences absorption and excretion of many drugs.
1) Increases absorption of levodopa, valproic acid
2) Increases absorption of Ca2+
3) Decreases absorption of antimuscarinic drugs, H2 antagonist, tetracycline, iron products.
4) Increases excretion of weakly acidic drugs.
Doses: Cattle: 50 gm, P/O, BID or TID Horse: 30 gm, P/O, BID or TID
Sodium citrate:
● It does not produces CO2
● 1 gm sodium citrate neutralizes 10 meq HCl
Aluminium hydroxide:
● Al (OH)3 + 3 HCl AlCl3 + 3 H2O.
● Aluminium hydroxide also decreases phosphate absorption.
● It is good adsorbent (adsorb toxins)
Dose:Cattle: 30 gm, Cat: 50-100 gm, Dog: 100-200 gm.
Magnesium hydroxide : (milk of magnesia)
● Prompt and prolong action
● Control rise in pH beyond 7.0
● Also exert laxative property.
Side effect: After long therapy: renal dysfunction or retention of magnesium.
Doses: Dog: 1-2 ml, Cat: 1-5 ml, Cattle: 60-100 ml
Calcium carbonate:
● Calcium carbonate (e.g. Tums, Os-Cal) is less soluble and reacts more slowly than sodium bicarbonate
with HCl to form carbon dioxide and CaCl2.
● Excessive doses of calcium carbonate with calcium-containing dairy products can lead to
hypercalcemia, calciurea, hypophosphataemia, constipation, renal insufficiency, and metabolic alkalosis
(milk-alkali syndrome).
● Shows gastric acid rebound effect.
16. Purgatives:
Purgatives: Drugs that promote defecation by enhancing its frequency or by increasing faecal volume
or consistency.
Laxatives: The cause mild purgation/ smooth evacuation of bowel; also known as aperients
Cathartics : They are potent or super purgatives which cause severe/drastic purgation
Uses:(a) Constipation; (b) Elimination of toxicants; (c) To prevent straining while defecation in case of
advance pregnancy; (d) Before gastrointestinal surgery

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 Contraindication:
● Should not given in advanced pregnancy (causes abortion)
● Should not given in obstruction in GIT (causes rupture of intestine)
● Should not given in lactating animals (if given causes young one diarrhoea)
Classification:
i. Bulk forming purgatives
ii. Osmotic purgatives
a) Saline osmotic purgatives
b) Carbohydrate osmotic purgatives
iii. Irritant/stimulatory purgatives
a) Direct irritant purgative : Anthraquinone derivatives/emodines, diphenylmethanes (DPM)
b) Indirect irritant purgative : Vegetable oils
iv Lubricating/emollient purgatives
v. Neuromuscular purgatives
vi. Drastic purgatives
vii. Faecal softeners/stool surfactant agents
i. Bulk forming purgatives: Bulk-forming laxatives are indigestible, hydrophilic colloids that absorb
water, forming a bulky, emollient gel that distends the colon and promotes peristalsis. eg.Methylcellulose,
carboxy methylcellulose, psyllium (Isabgul), Agar, Acacia, Polycarbophil (Synthetic fibers) compounds.
Mechanism of action:
Hydrophilic colloids/fibre foods Cellulose/hemicelluloses in the vegetable fibres

Not absorbed in the intestine Digested /fermented by bacteria

Draw water and sweets providing bulk to intestinal Release fatty acid
contents
Hygroscopic in nature
Distension of intestine
Bulk formation
Stimulate intestinal motility in reflex

ii. Osmotic/saline purgatives: The colon can neither concentrate nor dilute fecal fluid: fecal water is
isotonic throughout the colon. Osmotic purgatives are soluble but non-absorbable compounds that
result in increased stool liquidity due to an obligate increase in faecal fluid. eg. Nonabsorbable Salts
like MgO, Mg(OH) 2 , MgSO4 and Na2SO4, Nonabsorbable sugars like Sorbitol and Lactulose, Balanced
Polyethylene Glycol
Mechanism of action:
Inorganic salts particularly of magnesium ions into intestine

Draw water into intestinal lumen due to their osmotic pressure

Water retention increases that the form bulk of contents

There must be free access to water otherwise it may cause dehydration or haemoconcentration.

Magnesium salt also stimulate cholecystokinin (CCK) which further increases GIT motility

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 Dose:
Cattle: 250-400 gm foal/calf: 25-50 gm
Horse: 50-100 gm Dog: 5 gm
Cat: 2-5 gm Sheep, goat, swine: 25-100 gm
iii. Irritant/stimulatory purgatives:
a) Anthraquinone derivatives/emodine purgatives: Glycosides derivatives of 1,8-dihydroxy
anthraquinone.They are also known as contact purgatives. eg.
● Natural emodines : Aloe (leaf powder of Aloe vera and Aloe chinensis), Senna (leaflet of Casia
acutifoia), cascara, sagrada, rhubarb
● Synthetic emodines eg. danthrone, dose: Cattle: 20-40 gm, Horse: 15-45 gm, Sheep: 2-5 gm
MOA:
After oral administration

Glycosides are hydrolysed into emodines by colon bacteria

This increases peristalsis by stimulating neural plexus

Increased purgation

Diphenylmethane (DPM) purgatives: eg. Phenophtheline, bisacodyl, Bisacodyl should not be used
in obstructive impaction. Its onset of action duration is 6 to 8 hours after per oral and 15 minute to 1
hour after rectal administration.
b. Indirect irritant purgatives : eg. Vegetable oils (castor oil, linseed oil). These oils after digestion in
small intestine provide linolenic acid (fatty acid) and cause formation of irritant soap with bile
(saponification) and leads to irritation to intestine and purgation
Use : (a) Prolapse/advance pregnancy; (b) Post-operative GIT surgery; (c) Dog and cat, in anal leakage
iv. Lubricating/emollient purgatives: eg. Mineral oil (liquid paraffin), soft paraffin, glycerin suppository,
Mineral oil (liquid paraffin) : It decreases water absorption from the feces and act as emollient
purgatives. Its chronic use causes the deficiency of fat soluble Vitamins A, D, E, K)
Dose: Dog: 2 mg/kg, Cat: 10-15 mg/kg
v. Neuromuscular purgatives: eg. Carbachol : Horse and cattle - 2.5 mg/kg, S/C, Sheep - 0.25-0.50
mg/kg, S/C, Physostigmine : Cattle - 30-45 ml/kg, S/C, Neostigmine : Cattle - 0.001-0.02 ml/kg, S/C
vi. Drastic purgatives: Not used clinically, used for malafied intension. eg. Croton oil, jatropha oil, barium
chloride.
vii. Faecal softeners/stool surfactant agents: These agents soften faecal material, permitting water
and lipids to penetrate. They may be administered orally or rectally. eg. docusate (oral or enema)
Docusate is anionic surface agent with wetting and emulsifying property. It reduced surfacetension
and does allow water / fat to penetrate the ingesta.
17. Emetics: In emesis the stomach empties in a retrograde manner. The pyloric sphincter is closed while
the cardia and esophagus relax to allow the gastric contents to be propelled orally by a forceful,
synchronous contraction of abdominal wall muscles and diaphragm. Closure of the glottis and elevation
of the soft palate prevent entry of vomitus into the trachea and nasopharynx.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
The reflex mechanism of vomition: Vomiting is regulated centrally by the emetic centre and the chemoreceptor
trigger zone (CTZ), both located in the medulla. The CTZ is sensitive to chemical stimuli and is the main site
of action of many emetic and antiemetic drugs. The blood-brain barrier in the neighbourhood of the CTZ is
relatively permeable, allowing circulating mediators to act directly on this centre. The CTZ also regulates
motion sickness (eg. hill travelling) a condition caused by conflicting signals arising from the vestibular apparatus
and the eye. Impulses from the CTZ pass to the emetic centre which reulates the vomiting.
Classification:
i. Central emetics: Stimulate emetic centre via CTZ and vestibular apparatus (in motion sickness) eg.
xylazine, apomorphine
ii. Local acting / reflex emetics: They act locally by irritating gastric mucosa. eg. NaCl, Na2SO4, CuSO4,
ZnSO4, H2O2 etc. H2O2 is used in dogs and cats to induce vomition in the case of recent oral toxicoses
Contraindication for reflex emetics:
● Should not give in corrosive poisoning
● Should not give in opium poisoning
● Should not give in CNS stimulant toxicity
● Should not use in the unconscious animal
iii. Mixed emetics: eg. Ipecacuanha (Syrup of ipecac) : it is obtain from plant Carapichea Ipecacuanha.
It act by local irritation of gastric mucosa as well as centrally by stimulation of CTZ.
18. Antiemetics: Drugs which suppress the vomition or nausea (feeling of vomition). They are commonly
used in simple stomach animals like dogs and cats (monogastrics).
Classification :
i. Local acting antiemetics
a. Anticholinergics or muscarinic receptor antagonists
eg. Glycopyrronium, methcopolamine, propantheline
b. Local anaesthetics like benzocaine and prokinetics like domperidone also helps prevent emesis
c. Demulcent, protectant, gastric antacids may also act as local acting antiemetics.
ii. Centrally acting antiemetics
a. H1 Antihistamines: eg. Piperazine derivatives, Ethanolamine derivative, phenothiazine derivatives
● Piperazine derivatives : These drugs are useful in motion sickness induced emesis or
inner-ear disease induced emesis where vestibular apparartus is affected. All antimotion
drughs are effective when taken half to one hour prior to journey eg. Cyclizine, meclizine,
cinnarizine. Meclizine and cyclizine are longer acting drugs and used in dogs and cats.
● Ethanolamine derivative eg. diphenhydramine,
● Phenothiazine derivatives (tranquilizers): eg. Acepromazine, chlorpromazine,
prochlorperazine
b. Antidopaminergic: eg. D2 receptor antagonists like metoclopramide is useful in emsis caused
by uraemia or viral enteritis.
c. 5HT3- antagonists/antisecretory agents: eg. Ondansetron, Granisetron, cyproheptadine etc.
Ondensetron and granisetron are drug of choice in cancer therapy induced vomition. They are
also useful in controlling post-operative vomition.
d. Miscelleneous:
● Glucocorticoids liike dexamethosone
● Sedative and anxiolytic like diazepam is used as adjunct to metoclopromide or ondansetron to
control pyschogenic or behavioural vomiting.
● Nabilone is a synthetic cannabinol derivative which supresses CTZ.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER - 12
CVS PHARMACOLOGY
Contents:
1. Cardiotonics and Myocardial stimulants
2. Anti-arrhythmic drugs
3. Anti-hypertensive drugs and Vasodilators
4. Haematinics (Haemopoietic drugs)
5. Haemostatics (Blood coagulants)
6. Antihaemostatics
1. Cardiotonics and Myocardial stimulants
● Cardiotonics is a general term used for the drugs which increase the functional capacity of cardiac
muscles without increasing the O2 demand.
● Term ‘myocardial stimulant’ is specifically used for the drugs which increase the force of contraction
of myocardium muscles and thus increases cardiac output.
● Cardiac glycosides have property of both cardiotonics and myocardial stimulant.
● They possess only positive inotropic effect whereas other cardiotonics have both positive inotropic
(force of contraction) as well as positive chronotropic effect (rate and rhythm of contraction of heart).
Classification of myocardial stimulants:
i. Cardiac glycosides (Digitalis)
ii. PDE inhibitors e.g. Xanthine derivative (theophylline, aminophylline etc), Amrinone
iii. α-adrenoceptor agonist (Sympathomimetic drugs) e.g. Adrenaline, dopamine, dobutamine,
isoprenaline.
iv. Miscellaneous e.g. CaCl2 (10% solution), calcium borogluconate (CBG)
Cardiac glycosides:
● The whole group is also referred as ‘digitalis’ as their prototype member was obtained from leaf
of plant Digitalis purpurea (Purple Fox Glove).
● Their cardiac effects were described by William Withering (1775). About 200 years ago cardiac
glycosides were used in the treatment of dropsy.
● Cardiac glycosides contain two parts: Glycon (Sugar) responsible for solubility and membrane
permeability functions and aglycon responsible for its pharmacological activity.
Cardiac glycosides and their sources:
Plant name Plant part Glycoside
Digitalis pupurea Leaves Digitoxin, Gitoxin, Gitalin, Gitaloxin
Digitalis lanata Leaves Digitoxin, Gitoxin, Digoxin, Lanatoside-C
Strophanthus gratus Seed Ouabain (Strophanthin-G)
Note: Ouabain is most potent cardiac glycoside.
MOA of cardiac glycosides:
● They bind to the extracellular side of Na+-K+ ATPase at K+ binding site of enzyme and thus reversibly
inhibit Na+-K+ pump.
● Due to failure of pump, intracellular conc. of Na+ increases which further favour inflow of Ca2+ in
exchange of Na+. Then intracellular rise in Ca2+ leads to increase in the myocardial contraction.
Pharmacological effects on heart:
● Positive ionotropic effect results in improved cardiac output, reduced diastolic pressure and
reduction in size of dialated heart. These effects are more pronounced in dysfunctional heart
rather than in normal heart.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
● Negative chronotropic effect by direct as well as indirect way. Directly, it acts on AV node which causes
decrease in conductivity and increase in refractory period. Indirectly it acts by vagal nerve stimulation.
Extra-cardiac effects:
● Increase colloid osmotic pressure of blood and increased renal blood flow results in diuretic effect.
So, decrease oedema in CHF (Congestive Heart Failure) cases.
● Higher dose may stimulate CTZ (vomition).
Digitalisation:
● It is a procedure to be followed for administration of the digitalis e.g. digoxin in CHF.
● It consists of administration of loading dose of digitalis leading to production of desired cardiac activity.
● Methods of digitalization:
i. Slow digitalization: In mild CHF, 1/5th of total dose is to be given at 10 hours interval within 2 days
ii. Rapid digitalization: In moderate CHF, 3 equally divided doses are given at 6 hours interval
iii. Intense digitalization: In severe CHF and emergency, 1/2th of total dose at a time, 1/4th of total
dose after 6 hours, 1/8th of total dose at 4 to 6 hours interval
● Signs and symptoms of digitalization: Relief in coughing, Diuresis / decreased body
weight, Improved ECG changes
Dose rates in dogs:
(a) PO: Loading dose: 0.02 – 0.06 mg/kg o.i.d.; maintenance dose: 0.01 -0.02 mg/kg. (Half life of
digoxin in dogs = 24-55 hours)
(b) Rapid IV: 0.01-0.02 mg/kg in divided doses (in pattern of intense digitisation at interval of 1-2 h)
Toxicity of digitalis:
● They have narrow margin of safety with therapeutic index of only 1.5 to 3.0.
● Their dosage should be calculated on lean body weight. Obese and ascites mass should not be
taken into consideration.
● Therapeutic drug monitoring should be done and serum digoxin concentrations should be
maintained below 2.5 ng/ml.
● Common toxicities are anorexia, nausea, dyspnoea, palpitation, cardiac arrhythmia and necrosis
of myocardium.
Clinical indications:
● In congestive heart failure (CHF), especially in dilated cardiomyopathy (DCM).
● In cardiac arrhythmia (Supraventricular tachycardia like artrial fibrillation)
PDE inhibitors
● PDE (Phosphodiesterase) inhibitors inhibit PDE enzymes responsible for degradation of cAMP in
heart and other organs. Thus, they cause increase in intracellular cAMP concentration which
gives positive inotropic effects.
● Methylxanthines like theophyllin and aminophyllin are non-selective inhibitors of PDE enzyme.
● Drugs like amrinone and milrinone are selective blockers of cardiac PDE-III enzyme.
α -adrenoceptor agonists
● Sympathomimetic drugs having beta adrenergic agonist effect, with or without dopaminergic
agonistic property, have positive inotropic and vasodilator properties.
● Adrenaline (á and â) and isoprenaline (â1 and â2) are non-selective adrenoceptor agonist whereas
dobutamine selectively stimulates â1-adrenoceptor.
Miscellaneous
● Calcium gluconate and calcium chloride (CaCl2) may be used carefully by slow infusion for
stimulation of heart.
● Glucagon hormones found to has positive inotropic effect.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
2. Anti-arrhythmic drugs
● These are cardiac depressant drugs, used in the treatment of cardiac arrhythmia.
● They are mainly used to control abnormal fast cardiac rhythms i.e. tachyarrhythmias.
Classification of anti-arrhythmic drugs (Vaughan Williams and Singh, 1969):
Class I : Sodium channel blockers
Class II : Beta (â1) adrenoceptor antagonist
Class III : Potassium channel blockers
Class IV : Calcium channel blockers
Class I: Drugs that block voltage-sensitive Na+ channels
● These are membrane stabilizer drugs (exerts like local anesthetic effect)
● Reduces rate of depolarization
● Harrison (1979) proposed sub-classification of class I drugs based on their main
electrophysiological action while blocking sodium ion channel:
❖ Class IA: Shows intermediate dissociation, e.g. Quinidine, Procainamide, Disopyramide
❖ Class IB-: Shows fast dissociation, e.g. Lignocaine (Lidocaine), Phenytoin
❖ Class IC: Shows slow dissociation, e.g. Flecainide
Class II: α1-adrenoceptor antagonists
● Inhibits sympathetic activity of heart by inhibiting â1-adrenergic receptor. e.g. Propranolol, Esmolol,
Atenolol, Sotalol
● Sotalol prolongs repolarization by blocking potassium channels; hence, it is also included in class
III drugs.
Class III: Potassium channel blockers
● These drugs that prolong the repolarization and increases duration of cardiac action potential and
refractory period.
● They do not affect resting membrane potential.
● They are used in ventricular and supra-ventricular tachyarrhythmias. e.g. Amiodarone, Bretylium
Class IV: Drugs inhibiting voltage sensitive calcium channel
● Decreases calcium influx into cardiac cells (L-type calcium channels)
● Shortens plateau phase of action potential
● Slows AV conduction which depends on calcium current. e.g. Verapamil, Diltiazem, Nifedipine,
Amlodipine
● Verapamil>Diltiazem>Nifedipine (effect on calcium channels of cardiac cells)
● Diltiazem is preferred over verapamil for long term therapy as it has less negative inotropic effect.
● Dihydropyridine (‘dipines’) derivatives like nifedipine and amlodipine have more affinity to calcium
channels in vascular smooth muscles than heart. Thus, they have more vasodilator effects than
anti-arrhythmic effect.
3. Anti-hypertensive drugs and Vasodilators
● Antihypertensive agents are drugs which are used to lower the elevated blood pressure in systemic
hypertension.
● Vasodilators are drugs which cause dilation of blood vessels due to the relaxation of vascular
smooth muscles.
● Vasodilators reduce myocardial workload, promote cardiac output, and reduce blood pressure.
Thus, they are primarily used as anti-hypertensive drugs.
Classification of antihypertensive drugs:
i. Centrally acting sympatholytic drugs (α2-stimulation in CNS). e.g. Clonidine, Methyldopa
ii. Adrenergic Neurone blockers
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 ● These drugs lower blood pressure by preventing release and storage of nor-epinephrine from
postganglionic sympathetic neurons e.g. Reserpine, Guenethidine
iii. Adrenergic blockers
a. β-adrenoceptor blockers e.g. Atenolol, Metoprolol
b. Selective α1 blockers e.g. Prazosin
c. β plus α blockers e.g. Carvediol, Labetalol
iv. Diuretics e.g. Thiazides, Furosemide, Spironolactone, Amiloride
v. Vasodilators
a. Arteriolar vasodialtors e.g. hydralazine, diazoxide, minoxidil and calcium channel blockers
like Nifedipine, Amlodipine
b. Mixed (Arterial and Venous) vasodilators e.g. Nitroprusside, Glyceryl trinitrite (nitroglycerine):
These drugs are better known as anti-anginal drugs. They increase the release of nitrous
oxide and the concentration of cGMP. They increase guanylyl cyclase activity. This causes
vasodilation by relaxation of vascular smooth muscles by nitrous oxide pathway.
vi. Drugs acting on Renin-Angiotensin System (RAS)
a. Renin inhibitors e.g. Aliskiren, Remikiren
b. Angiotensin-Converting Enzyme (ACE) Inhibitors e.g captopril, enalapril, lisinopril,
ramipril, fosinopril etc. All ACE inhibitors are pro-drugs except captopril and lisinopril.
Enalapril is pro-drug of enalaprilat. ACE is also known as kininase II enzyme and
involved in metabolism of bradykinin. Side effects of ACE inhibitors include dry cough
and angioedema due to increased bradykinin level.
c. Angiotensin antagonist (AT1 receptor blockers) e.g. Losartan, Telmisartan etc. Like
ACE inhibitors losartan produces peripheral vasodilation and blocks aldosterone
secretion but do not increase kinin level.

4. Haematinics (Haemopoietic drugs):

● These drugs promote haemoglobin synthesis and/or erythropoesis (synthesis of RBCs) and are used
in the treatment of anaemia (anti-anaemic drugs).
● Anaemia may occur due to deficiency of Fe, Cu, Co, vitamin B12, folic acid and erythropoietin.
Classification:
i. Nutraceuticals (minerals and vitamins)
● Iron deficiency: Ferrous sulphate and ferrous gluconate (oral forms), Iron dextran and iron
sorbitol (parenteral injection)
● Copper deficiency: Copper sulphate, Copper glycinate, Copper heptonate
● Cobalt deficiency: Cobalt sulphate, cobalt chloride and cobalt oxide. Cobalt is needed by
ruminal microflora for synthesis of vitamin B12, hence is important for erythropoiesis.
● Vitamin B12 deficiency: It causes pernicious anaemia. Cyanocobalamine is used at dose rate
of 2-5 µg/kg/day, I/M.
● Folic acid deficiency: It causes megaloblastic and macrocytic anaemia. Dietary supplement
is main source of folic acid.
ii. Haematopoietic growth factors
Erythropoietin (epoetin):
● It is glycoprotein hormone produced by peri-tubular renal cells, essential for normal erythropoiesis.
● It is secreted during hypoxia which occurs in anaemia. Hypoxia is sensed by renal peritubular
cells and they release erythropoietin.
● This erythropoietin act on bone marrow and increase formation of Hb and erythroblast
maturation.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 iii. Anabolic steroids : e.g. Nandrolone:- Testosterone like structure, they stimulate production of
erythropoietin.
5. Haemostatics (Blood coagulants)
● They promote blood clotting and used to prevent haemorrhage (hemostasis) or blood oozing
from minute blood vessels.
● Based upon their use, they can be classified into topical and systemic haemostatics.

Topical haemostatics: These agents are applied directly to bleeding surface to prevent superficial
capillary or minute blood vessels bleeding. Following agents are used as topical haemostatics:
i. Clotting factors. e.g. Thromboplastin, fibrinogen, thrombin
ii. Occlusives. e.g. Fibrin foam, calcium alginate, cellulose, gelatine sponge
iii. Vasoconstrictors. e.g. adrenaline
iv. Styptics (Astringents). e.g. Alum, tannic acid, silver nitrate, ferric sulphate, ainc chloride etc.

Systemic haemostatics: These agents are administered by IV, IM or oral routes to prevent internal
haemorrhages. It includes drugs vitamin K analogues, blood components (platelets, fibrinogen),
fibrinolytic inhibitors like aminocaproic acid and tranexamic acid, other agents like protamin sulphate,
adrenochrome monosemicarbazone, ethamsylate etc.

6. Antihaemostatics
● They prevent haemostatis by interfering blood-coagulation process, lyses formed thrombi, inhibit
thrombi formation or platelet functions and accordingly classified into three broad classes: i)
anticoagulants, ii) thrombolytics (fibrinolytics) and iii) anti-thrombotics (anti-platelet) drugs.
● Anticoagulants
❖ In vitro anticoagulants: They are used for laboratory or blood transfusion purpose. e.g. Oxalate
mixture, sodium fluoride, EDTA, heparine, ACD etc.
❖ Oral in vivo anticoagulant: They are slow acting systemic anticoagulants. e.g. Dicoumarol, warfarin,
ethylbiscoumacerate etc.
❖ Parenteral in vivo anticoagulant: They are fast acting systemic anticoagulants. e.g. Heparin, orgaran
♦ Thrombolytics and Fibrinolytics. e.g. Streptokinase, urokinase, streptodornase, alteplase.
❖ Streptokinase and streptodornase are derived from streptococcus bacteria and act as plasminogen
activator. Urokinase and alteplase are derived from cell culture of human kidney cells and melanoma
cells, respectively.
♦ Antithrombotics (Antiplatelets)
❖ They inhibit platelet activation and aggregations. They do not dissolve existing thrombi but prevent
their growth and reoccurrence. So, they are mainly used for prophylaxis of thromboembolic disorders.
eg. Aspirin (used in canine heartworm and feline cardiomyopathy), dipyrimidole, dazoxiben

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER-13
RESPIRATORY PHARMACOLOGY
Contents :
1. Antitussive drugs
2. Expectorants (Mucokinetics)
3. Mucolytics
4. Bronchodilators
5. Analeptics (Respiratory stimulants)
6. Nasal decongestant
1. Antitussive drugs: Drugs which help in suppressing or relieving cough.
Cough is a protective reflex that removes foreign material and secretions from the bronchi and
bronchioles. Cough is of two types: (a) Productive cough: It is always associated with removal of
mucous from respiratory tract & considered as protective mechanism. (b) Unproductive cough: It is
always painful, stressful & exhaustive. In certain cases unproductive cough is to be suppressed.
Indications : Antitussive drugs are indicated for unproductive coughs.
Classification :
A. Pheripheral acting drug : eg. benzonatate (Mucosal Anaesthetic) and demulcents like honey, syrup,
glycerine, liquorice etc.
B. Centally acting drug:
i. Opoid or narcotic : Codeine, butorphanol and hydrocodon
ii. Non-narcotic : Pholcodine, dextromethorphan and noscapine
Codeine:
● Direct acts on medulla oblongata (depresses cough centre)
● It is methyl morphine (natural as well as semi-synthetic opiate alkaloid).
● It posses lesser analgesis, respiratory depressent and constipation properties than morphine.
Pholcodine:
● Longer duration of action as compared to codeine
Dextromethorphan:
● It is d-isomer of levorphanol (a codeine analouge)
● Directly suppress cough centre, increases cough threshold
● Used in both human and veterinary medicine because of non-addiction property
Butorphenol:
● Opiate partial agonist
● Potent analgesic & antitussive action (100 times more potent than codeine)
Hydrocodon:
● More potent than codeine
Noscapine:
● It produces relaxation of smooth muscles in bronchi & also cause histamine release in large dose
but is having excellent antitussive action.
● It is bronchodialator.
2. Expectorant: Drug which increases the fluidity & volume of bronchopulmonary secretion & promote
the productive coughing.
● Also used to remove the inflammatory debris during pneumonia & bronchitis.
● Also called as mucokinetics drugs.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 Classification:
A. Inhalant expectorant:
E.g. menthol, turpentine, benzoin, water steam
B. Secretory expectorant :
● Act by stimulating mucous membrane secretion in respiratory tract.
● Their expectorant property is very less as compared to inhalant.

Sub-classes of secretory expectorant :

i. Saline expectorant : eg. (NH4) CO3, NH4Cl, KI
ii. Reflex acting expectorant : eg. Syrup, balsum of tolu, onion, ipecac, sulphur compounds, volatile
ammonia.
Syrup has mainly soothing demulcent action on mucosa.
iii. Direct acting stimulant expectorant : eg. eucalyptus oil, turpentine oil, guaiacol, guaiphenesin
iv. Anodyne expectorant : Reflexly acting having Antitussive as well as pain relieving action & increase
repiratory secretion 400 times. eg. camphorated tincture of opium

3. Mucolytics : Drugs which reduce the viscosity of mucous secretion in the respiratory tract & facilitate
the expectoration.
Examples includes :
● 10-20% solution of sodium acetyl cysteine as nasay spray
● Bromhexine : It is synthetic derivative of vasicine, an active principle obtained from Adhatoda
vasica plant (Ardusi)
● Ambroxol : It is active metabolite of bromhexine.

4. Bronchodilator:
● These agents dilate bronchioles and used in asthma, general broncho-pneumonia, chronic
bronchitis, tracheo-bronchitis, COPD (Chronic Obstructive Pulmonary Disease) in various species.
● In asthma there is constriction of bronchiole muscle or reduction of air passage volume.
● Acute asthma is always related with hyperparasympathomimetic activity & liberation of
prostaglandins, histamine, 5-HT etc.

Classification:
A. Sympathomimetics:
● Selective β 2 adrenoreceptor agonists are preferred for treatment of asthma to relieve
bronchoconstriction and bronchospasm. eg. Salbutamol, terbutaline, clenbuterol, fenoterol.
● Clenbuterol is long acting selective β2 receptor agonist.
● They antagonize the bronchospasm of any course & also inhibit release of histamine, PG2,
TNF-α & PAF.
● In addition, they also posses mucolytic action i.e. increase ciliary action in clearing mucous.
● In case of hypersensitivity allergy & anaphylaxis, non selective β2 adrenoreceptor agonist like
adrenaline (epinephrine) and isoprenaline can be used as life saving drug as there is profuse
vasodilation in these conditions & these drug prevent this.

B. Methylxanthine derivatives :
● They exert direct relaxant action on bronchiole muscle through inhibition of phosphodiesterase
(PDE) enzyme which than result in increase in cGMP and cAMP, thus produces relaxant
effect on smooth muscles. eg. theophylline, theobromine, caffeine.
● Increase cAMP also inhibit release of histamine and SRS-A (Slow Reacting Substance of
Anaphylaxis)
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 C. Parasympatholytics (Muscarinic receptor antagonist) : For bronchodilation, eg. Atropine (Used
in horse to treat pneumonia), glycopyrrolate, ipratropium etc.
Dose of hetropine : 0.02-0.04 mg/kg, IM, SC, or IV
D. Anti-histamine: eg. Promethazine, diphenhydramine, ephedrine
E. Mast Cell stabilizers: eg. Cromolyn (cromoglycate) and nedocromil
● Bronchiole relaxant
● Act through inhibition of histamine & leucoriene release
● Also inhibit release of PAF
F. Leukotrienes receptor inhibitors : These have bronchiole dilation effect by preventing action of
leukotrienes.eg. Zafirlukast and Montelukast
G. Anti-inflammatory agents : Corticosteroids and NSAIDs.
eg. Beclomethasone, Budesonide, Flunisolide, Fluticasone (used as Inhalor), Mometasone,
Triamcinolone, Prednisolone (used in horse) for relief from COPD.

5. Analeptics (Respiratory stimulants): Drugs which stimulate the respiration & they are used to relieve
the respiratory depression especially due to overdose of anaesthesia or due to toxicity of other CNS
depressant drugs. Example includes :
a) Doxapram :
● It direct excites neurons of medullary respiratory center.
● It also act indirectly by reflex activation of carotid and aortic, chemoreceptor
● Causes transient increase in respirotary rate and volume.
Dose : Horse: 0.5-1.0 mg/kg, I/V
Dog and cat: 1.0-5.0 mg/kg, I/V
Foal: 0.02-0.04 mg/kg, I/V
b) Nikethamide
Dose: 2-4 mg/kg, P/O or I/M or I/V
c) Methyl xanthine: Stimulate the medullary respiratory centre. eg. caffeine
d) Bemegride: General CNS stimulant with wide margin of safety. It is non-specific barbiturate
antagonist.

6. Nasal decongestant : It is used in allergic and viral rhinitis to reduce swelling and oedema of nasal
passage. It is not used commonly in veterinary medicine. eg. Ephedrine, phenylnephrine (α1
adrenoreceptor agonists).

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER- 14
RENAL PHARMACOLOGY
CONTENTS :
1. Diuretics
2. Urinary Alkalizers
3. Urinary Acidifiers
4. Urinary Antiseptics
1. Diuretics : Diuretics increase the excretion of Na+ and water. They decrease the reabsorption of Na+ and
Cl- from the filtrate, increased water loss being secondary to the increased excretion of NaCl (natriuresis).
Indication : (a) Oedema (eg. pulmonary oedema in congestive heart failure) (b) Hypertension
(c) Renal disorders (d) Liver cirrhosis
Classification:
i. Low efficacy diuretics
a) Osmotic diuretics
b) Carbonic anhydrase inhibitors
c) Potassium sparing diuretics
d) Xanthine diuretics eg. theophylline
ii. Moderate efficacy diuretics
a) Thiazide diuretics (low ceiling diuretic)
iii. High efficacy diuretics
a) Loop diuretics (high ceiling diuretic)
b) Mercurial diuretics
i. Low efficacy diuretics:
a) Osmotic diuretics:
Osmotic diuretics are pharmacologically inert non-electrolyte substances that are filtered in the
glomerulus but not reabsorbed by the nephron eg. Mannitol, sorbitol, glycerine.
Site of action: Mainly proximal tubule, descending limb of the loop of Henle, distal tubules.
MOA : Water passive reabsorption is reduced by the presence of non-reabsorbable solute (Osmotic
diuretics) within the tubule; so a larger volume of water remains within the proximal tubule. So, more
amount of water is excreted and along with it minor increasing in Na+ excretion (secondary) occurs.
INDICATIONS:
1. Used in cerebral oedema to decrease intracranial pressure (eg. mannitol is choice of fluid therapy
in CNS toxicities).
2. To decrease intraocular pressure and to maintain urinary flow in tubules
3. Used to increase GFR and to enhance urinary excretion of toxins
Side effects:
1. IV injection may increase the osmolarity of plasma, so water is allow to move into plasma from
extravascular compartment so expansion of the extracellular fluid volume (hypervolemia).
2. Hyponatraemia and Hyperkalemia
Contradictions: Dehydration, Pumonary oedema and Progressive renal failure
ii. Carbonic anhydrase inhibitor:
● Carbonic anhydrase is an enzyme, mainly present in PCT, where it catalyzes the H2CO3 (carbonic
acid) and produces free H+ ions which are used for NA+-H+ exchange.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 ● Clinically CA inhibitors have limited usefulness as diuretics because they are much less efficacious
than thiazides and loop diuretics By blocking carbonic anhydrase, these inhibitors block Na+
reabsorption and cause diuresis. eg. acetazolamide, methazolamide, diclophenamide
● Acetazolamide loses its effect after one month because cell will adopt for alternate source of H+
i.e. it has a self limiting action. It is also used for treatment of glaucoma and metabolic acidocis. It
is also used as urinary alkalizer
Side effects : Hyponatremia,hypokalaemia and renal crystalluria
ii. Potassium sparing diuretics:
● These diuretics prevent K+ secretion by antagonizing the effects of aldosterone in the principal
cells of collecting tubules.
● Inhibition may occur by antagonism of mineralocorticoid (aldosterone) receptors (eg. antagonist
like spironolactone, canrenone) or by inhibition of Na+ influx through ion channels in the epithelial
cells (Na+ channel blockers like amiloride, triamterene).
MOA:
Aldosterone antagonists: They binds to aldosterone receptors and prevent synthesis of AIPs
(aldosterone induced proteins). So, Na+ channel remains in dormaint stage. Also, Na+ absorption is
inhibited and along with it K+ are not excreted in the tubular lumen. Hence retain the K+ instead of
wasting it (natriuresis and K retention results).
Sodium channel blockers: direct inhibitors of Na+ influx (block Na+ channels) in the principal cells of distal
collecting tubules of nephron causes natriuresis and indirectly inhibits K+ excretion, thus K+ retention results).
Spironolactone:
Indications:
1. In primary hyperaldosteronism (Spironolactone is drug of choice) eg. adrewnal adenomas
2. Used as adjuncts with thiazide or loop diuretics to prevent hypokalaemia.
3. Refractory oedema associated with hepatic cirrhosis and nephritic syndrome
Contraindications: Metabolic acidosis, hyperkalemia, acute renal disease and anuria
Adverse Effects:
1. Electrolutic imbalance like Hyperkalemia and hyponatremia (Two potassium sparing diuretics are
not used concurrently as it causes severe hyperkalaemia).
2. Gynecomastia, impotence, decreasedc libido (because these drugs are synthetic steroids)
ii. Moderate efficacy diuretics/ Thiazide diuretics
● These are also called “Low ceiling diuretics” or “Na+-Cl- symport inhibitors”
● They are sulphonamide derivatives and have similar structure to sulpha-drugs.
● Some derivatives are pharmacologically similar like thiazides but structurally different and knoen
as thiazide like diuretics.
Short acing thiazides: eg. Hydrochlorothiazide (HCTZ), chlorothiazide sodium (earlier it was
categorized under carbonic anhydrase inhibitors class), benzothiazide, and xipamide (thiazide like).
Long acting thiazides: eg. Methylchlorthiazide, bendrofluazide, Polythiazide.
Metalozone, Dopamine and Indapamide are thiazide like long acting drugs.
MOA:
● Thiazides act on DCT (luminal side) and block Na+/Cl- cotransporter (an enzyme) and thus, prevents
Na+ resorption. Function of this enzyme is modulated or changed by thiazides.
● Thiazides also produce vasodilation (so used in hypertension), K+ loss and hyperglycaemia.
● Thiazides also called as “low ceiling diuretics” because if thiazides are given in high dose, the
volume of urine remains same i.e. not increase.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 ● Out of total Na+ reabsorption, about upto 95% reabsorbtio already occur in PCT before urine
mass reaches to DCT where only 5% reabsorption occurs for Na+.
Indications:
1. Hypertension
2. Cardiac or hypoproteinaemic oedema
3. Diabetes insipidus
4. Nephrolithiasis (because produce hypocalcinuria) i.e. calcium oxide uroliths.
5. Osteoporosis (because produce hypercalcemia)
6. Post-parturiient udder oedema in dairy cattle.
Contraindication:
1. Cardiac arrhythmia
2. Renal failure with anuria
3. Hypotension
4. Diabetes mellitus
Side effects:
1. Hypokalemic and hypochloraemic metabolic alkalosis
2. Hypokalemia (more common than with “loops diureics”), So, give K+ supplementation or use it in
adjunct with K+-sparing diuretics.
3. Hyponatremia
4. Hyperuricemia (gout)
5. Hyperglycemia
6. Hyperlipidemia (except indapamide)
7. May cause sulpha-drug hypersensitivity like skin reactions.
iii. High efficacy diuretics
a. Loop diuretics:
● Most potent group of diuretics with maximal natriuretic effect.
● Loop diuretics selectively inhibit Na+/Cl- reabsorption in the Thick Ascending Loop of Henle (TALH).
● Due to the large Na+/ Cl- absorption capacity of this segment and the fact that the diuretic action of
these drugs is not limited by development of acidosis, as seen with the carbonic anhydrase
inhibitors, loop diuretics are the most efficacious diuretic agents. eg. Furosemide (or frusemide),
ethacrynic acid, bumetanide, torsemide, piretanide, mazolamine
MOA:
● They block the Na+ / K+ / 2Cl- symporter in luminal side of TAHL. Ion symport is inhibited by binding
with chloride binding site. So there is no Na+, K+, Cl- reabsorption, hence there is loss of Na+, K+, Cl-
along with H2O.
● Also reduces aldosterone secretion.
Pharmacological Effects of Furosemide:
1. Decreases ECF and decreases B.P (Reduces central venous presssure)
2. Produce dehydration
3. Produce Hypokalemic metabolic alkalosis
4. Produce hypocalcemia
5. Produce hypomagnesemia
6. Posses weak CA inhibitory action (but ethacrynic acid do not have this property)
Pharmacokinetics:
1. Oral bioavailability is excellent.
2. Extensive protein binding.
3. Half life in dogs is 1-1.5 h and duration of action is 4-6 h
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 Indications:
1. Pulmonary oedema
2. Mammary oedema: occur during the large stage of pregnancy due constriction of mammary vein
by foetus.
3. Brisket oedema, hydrothorex ascites and non-specific oedema
4. Hyperkalemia
5. Acute renal failure
6. Anion overdose: treating toxic ingestions of bromide, fluoride, and iodide.
Contraindication:
1. Hepatic cirrhosis
2. Borderline Renal failure
3. Pre existing electrolytic imbalance
Side effect :
1. Hypokalemic and hypochloraemic metabolic alkalosis : increase K+ and H+ loss
2. Hyperuricemia: Gout
3. Ototoxicity in cats (also increases ototoxicity of aminoglycoside antibiotics). Ototoxicity is more
seen with use of ethacrynic acid.
4. Hypomagnesemia
5. Hypocalcemia
6. Allergic reactions (except for ethacrynic acid as it do not have sulpha like structure): skin rash,
eosinophilia, haemolytic effect.
Misuse: Furosemide is used in dopping in horses during horse shows because it reduces ECF so
clear cut demarcation of muscles is there. In race horses, it is believed to diminished incidences of
epitaxis by reducing central venous pressure.
2. Urinary alkalizers
● Produces alkaline urine
● These are metabolized to produce cations which are excreted with bicarbonate and produces
alkaline urine. eg. NaHCO3, potassium citrate, potassium acetate
Indications:
i. To reduce toxicity of sulphonamide and paracetamol
ii. To promote excretion of weakly acidic drugs like salicylate, barbiturates.

3. Urinary acidifiers
● Produces acidity in urine. eg. ammonium chloride, ascorbic acid, methionine, sodium acid
phosphate
Indications:
i. To enhance the excretion of basic substances
ii. To increase the antibacterial activity in urinary tract

4. Urinary antiseptics
● Drugs which are used to produce antiseptic effect in part of urinary tract
● For action of urinary antiseptics, urine is required to become acidic. eg. sulphonamide, gentamicin,
ciprofloxacin, methanamine, hexamine
Methanamine : It is converted into NH3 and formaldehyde and this released formaldehyde acts as antiseptic
at acidic pH. At pH 5 about 20 % formaledhyde is released where as at pH 6 it is only 6 %. Addition of
mandelic acid or hippuric acid to methamin helps to acidify the urine, and thus enhance its pH depended
antibacterial activity.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER- 15
REPRODUCTIVE PHARMACOLOGY
Contents:
1. Aphrodisiacs
2. Anaphrodisiacs
3. Ecbolics (uterotonics)
4. Oxytocics
5. Tocolytics
6. Abortificients
1. Aphrodisiacs : Agents that increase the sexual desire. eg. yohimbine
2. Anaphrodisiacs : Drugs that decrease the sexual desire. eg. coriander, salix, mashua
3. Ecbolics : Drugs that stimulate the non-pregnant uterus motility and tonicity. These are used for the
purpose of cleaning effect in the atonic uterus. eg. oxytocics, prostaglandins, ergot alkaloids
4. Oxytocics: Drugs that induce or facilitateds birth by stimulating the contraction of uterine muscles at term.
Classification : A) Natural oxytocics B) Ergot alkaloids C) Prostaglandins
A. Natural oxytocics: eg. oxytocin
Oxytocin : It is synthesized in supraoptic nuclei of hypothelemus and stored in the posterior pituitary.
It is nona peptide. One USP unit of oxytocin is equivalent to 2-2.2 mcg of pure oxytocin.
Pharmacological Actions of Oxytocin:
i. On uterus: Oxytocin act on myometrium and contract the pregnant mammalian uterus and expel
the foetus. It is sensitive to pregnant uterus. It can only stimulate non pregnant uterus if given at
very high doses.
ii. On mammary gland: It causes the contraction of myoepithelial cells causing letting down of milk
but does not have any effect on the synthesis of milk.
iii. Sperm transport: oxytocin facilitates the sperm transportation in the female vagina after coitus.
iv. It is having weak ADH like action and it is contraindicated in heart patient and kidney disease.
Pharmacokinetics :
i. Oxytocin is not administered orally because it is peptide and digested by digestive enzymes, So,
it is given IV in normal saline because it has ultrashort half life, but when mixed with saline it
continuous available to uterus and metabolize continuously.
iii. Onset of action : IV : 1-2 minutes, IM : 5-10 minutes,
iv. Duration of action:IV : 3-5 minutes, IM : 60 minutes
Indications :
i. Secondary uterine inertia
ii. Speeding up expulsion of foetus unless foetal presentation and position is normal.
iii. To facilitate the uterine involusion in post partum retained placenta and metritis cases.
iv. In case of retained placenta.
v. To facilitate letting down of milk in agalactia.
Note : Epidosine is an example of synthetic oxytocin
Doses of oxytocin:
Species IM route IV route
Cow and mare 10-40 IU 2.5-10 IU
Ewe, doe and sow 2.5-10 IU 0.5-2.5 IU
Bitch 01-10 IU 0.5 IU
Queen 0.5-5.0 IU
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
2) Ergot alkaloids:These are obtained from fungus Claviceps purpurea. eg. ergometrine, ergotamine
● Ergometrine is having rapid and long acting vasoconstriction and oxytocic effect. Control post-
partum haemorrhage.
● Ergot is itself not used because it produces spasmodic contraction.
● Ergot alkaloids particularly methylergometrine cause prominent uterine contraction (increases
force, frequency and duration of contraction).
● A gravid uterus and puperial uterus is more sensitive for ergot alkaloids.
● Vasoconstrictor and uterotonic activity of ergot alkaloid is due to partial agonist action of 5-HT receptor.
● It is used in the active management of 3rd stage of labour.
Indications :
i. Uterine atony
ii. Uterine inertia
iii. Metrorrhagia: after abortion uterine discharge of blood and exudate
iv. Post-partum haemorrhage control
v. Sub involution of uterus: means retain normal size and shape
Dose of methylergometrine : Cow and mare, 10-20 mg, Sow :0.5-1.0 mg, Bitch : 0.2-1.0 mg
3) Prostaglandins: eg. PGE2 (Dinopristone) and PGF2α (Dinoprost)
● These are synthetic analogue of prostaglandin.
● These cause cervical relaxation of muscles due to direct relaxant effect and contraction of uterine body.
● It is not drug of choice because it induces prolong uterine contraction.
● Luteolytic effect : It lyses corpus luteum after parturition, after it reproduce cyst under control of
oestrogen and cycle rotate again and if cycle persist then progesterone continuously liberated
and oestrous cycle not repeated.
Commonly used PGs in veterinary practice: Carboprost (synthetic PG analogue of 15-methyl
PGF2α), Germeprost (synthetic PG analogue of PGE1), dinoprost
5. Tocolytics (Uterine sedative) :
● Drugs which suppress the premature labour by relaxation of uterine muscles are called as tocolytics.
● These are also called as anti-contraction or labour depressant or uterine relaxant or uterine
sedatives or uterine spasmolytics.
Example includes :
i. Magnesium sulphate (MgSO4 ) : It is muscle relaxant so inhibit the uterine contraction by inhibiting
the myosin light chain
ii. Ethyl alcohol : Inhibit the uterine motility
iii. Ca+2 channel blockers : eg. nifedipine.
● Produce the relaxation of myometrium
● It delays the parturion for 4-27 days
iv. α 2
–adrenoreceptor agonist : eg. retodrin, terbutaline
● Used to delay premature labour/ threaten abortion.
● To reduce the foetal stress during transport of mother to hospital during preparation for
operative delivery of foetus.
v. Relaxin
● It is decapeptide secreted by corpus luteum, placenta and uterus when the animal approach
parturition.
● Its physiological role in the parturition is to induce softening/relaxation of cervix and pelvic ligament.
6. Abortificients : Drugs that induce the abortion before completion of term. eg. Mifepristone.

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 CHAPTER - 16
PHARMACOTHERAPEUTICS OF HORMONES AND VITAMINS
Sr Hormone Use Species Dose and Administration
No.
1 Gonadotropin releasing a. Cystic ovaries Cow 0.1 mg/kg IM or IV
hormone (GnRH)
2 Thyrotropic hormone (TSH) a. Acanthosis nigricans Dog 1-2 U/Kg I/M For five days
3 Leutinizing hormone (LH) a. Stimulation of follicles Cattle & 25 mg I/V; repeat after 1-4 weeks
or interstitial cell stimulating b. Ovulation Horse, 5 mg2.5 mg1 mg
hormone (ICSH) c. Cystic ovaries Sheep,
d. Increase testosterone Swine,
production Dog
4 FSH-P a. Folliculogenesis and Cow 5 mg/each 12 hr for a total dose of
superovulation 40 mg I/M on cycle days 10-14+
40mg PGF2α I/M 48 hr after first
FSH injection.
5 Pregnant mare serum a. Oestrus Cattle/ 1000-2000 U S/C, I/M or I/V100-
gonadotropin (PMSG) b. Stimulation of follicles Horse 500 U200-800 U25-200 U25-100 U
c. ovulation Sheep
Swine
Dog/Cat
6 Human chorionic a. stimulation of ovaries Cattle/ 1000-2000 U I/V, 10,000 U I/M400-
gonadotropin (HCG) b. cystic ovaries Horse 800 U I/V500-1000 U I/V100-500 U
c. cryptorchidism Sheep I/V100-500 U I/V( I/M for lyeding cell
d. IC stimulation Swine stimulation)
Dog/ Cat
7 Testosterone propionate a. Sterility Stallion & 100-250 mg S/C or I/M for three
(in oil) b. Hypogonadism Bull times.20-25 mg5-15 mg
c. Reduced libido Ram
d. Aspermia Dog
8 Diethylstilbesterol (DES) a. Misalliance Dog 0.5-1 mg/kg/day orally
b. Urinary incontinence Dog 0.5 mg/kg orally on fifth day of
c. Anal oedema
d. Prostrate hypertrophy
9 Metranol a. Misalliance mating
10 Estradiol cypioate a. Uterine atony Cow & 10mg I/M
b. Poor uterine discharge Mare
c. Abortifacient in early
pregnancy
11 Progesterone (in oil) a. Prevention of Mare & 50-100mg I/M
embryonic death cow
Ewe 10-15 mg
Swine 10-20 mg
Dog/Cat 2.5-5 mg
12 Megestrol a. Oestrus suppression Dog 2 mg/kg I/M for 8 days during
prooestrus
0.6 mg/kg I/M for 30-32 days
during anoestrus.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
13 Melengestrol a. Increase weight gain Feedlot 0.2-0.5 mg/heifer/day orally
b. In crease feed heifers (withdraw 48-72 hr before
efficiency slaughter)
c. Suppres oestrus
14 Pregnant mare serum a. Superovulation Cow 1500 IU on 15th or 16th day of
gonadotropin (PMSG) oestrus
Ewe 700-1400 IU I/M on any day from
4-13 days of oestrus
Goat 1000-15000 IU I/M on day 16, 17
or 18 of oestrus
15 PMSG and PGF2 alpha a. Superovulation Cow PMSG 2000 IU I/M on any day
between 9-12 days of oestrus
followed by (48 hr) 750-1000
micro g of PGF2 alpha I/M
16. PGF2 alpha a. Synchronization of Cow 25-30 mg I/M on any day of
oestrus oestrus between 8-12 days or 30
mg I/M with a 10 day gap
Sheep 10-15 mg I/M on any day from 5-
and Goat 14 days of oestrus
Vitamins
Vitamins Deficiency signs/disease Therapy
Fat soluble Keratinization of epithelial surfaces, night Farm animals : 100-200 units/kg/day
vitamins blindness, low sperm quality, foetal resorption, i.e. 1-2 g/day.
Vitamin A nutritional roup, low egg production and poor
egg hatchability in poltry. Poultry : 0.07-022 g/kg feed/day.
Vitamin D Rickets in young animals and osteomalacia in Cattle : 50-100 IU/kg/day.
adults. Horses, Sheep and Pig
chicks : 150-300 IU/kg/day
Dogs : 200-400 IU/kg/day
Vitamin A Muscular dystrophy in young animals (cattle, All young : 25 mg/kg s/c or i/m stock
sheep, dog, pig and goat). White muscle disease Calves and lambs: 40 mg/kg/day orally
of stiff lamb disease in sheep. Pig : 500 mg/day orally
Dog : upto 300 mg/kg orally
Cat : 30 mg/kg/day
Poultry : 390 mg/bird
Vitamin K Delayed clotting and spontaneous haemorrage in Warferin poisoning in all species :
all the species (more in poultry) Menaphtone or Menadione @ 5mgi/m.
Sweet clover poisoning : Menaphtone
@1.1 mg/kg i/m.
Deficiency: Small animals 2-10 mg/kg
orally.
Large animals: 100-400 mg/kg orally.
Poultry: Menaphtone@1-2 g/ton of feed

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 Water soluble vitamins
Vitamins Deficiency signs/disease Therapy
Thiamine Nervous signs, vomition and diarrohoea. Certain Horse = 100 mg s/c or i/m or oral
(B1 or plants contain antihistaminase like Equistem spp., Calf = 100 mg s/c or i/m or oral
Aneurine) bracken rhizomes, whose ingestion causes Pig = 2.5-15 mg s/c or i/m or oral
thiamine deficiency. Cat = 1-5 mg/kg s/c or i/m or oral
Dog = 1-10 mg/kg s/c or i/m or oral
Riboflavin Curl toe paralysis in young chicks. Anaemia, Horse : 40 mg daily in feed
(B2) dermatitis and scours in calves. Slow growth, Pig: 5 mg orally
low fertility, eye discharge, irritation and
photophobia in horses and pigs.
Pyridoxin Acrodynia (dermatitis characterized by Same as thiamine antidote to cyanacet
(B6) hyperkeratitis and acanthosis of skin) in dogs. hydrazide or dictycide overdose.
Degeneration of spinal and demeyelination of
peripheral nerves.
Nicotinic Pellagra in man. Calf : 25 mg/day s/c
acid and Black tongue or brown mouth in dog. Pig: 0.1-0.3 g s/c or 0.2-0.9 g orally
niacin Rough scaly skin, oral and GI ulceration and Dog and: 5-10 mg/kg i/m
(pellagra diarrhea in pig. Perosis , dermatitis and Cat: 10-30 mg/kg orally
preventing inflammation of tongue in chgicks.
factor)
Hydro- Antipernicious anaemia factor Dog and cat : 2-4 mg/kg/day i/m.
xycobala- In ruminants due to cobalt deficiency (bush
mine (B12). sickness, nakuruitis or grand taverse disease)
Hind limb weakness or incoordination, loss of
wool, stunted growth etc. in all anim als.
Biotin Fatty liver and kidney syndrome in broiler 100 ug/chick orally
(vitamin H, chicken fed entirely on wheat ration. Egg white
bis 11b, contains an antibiotic : avidine
coenzyme
R)
Choline Perosis (slipped tendon in poultry). Fatty liver Dog : 544 mg/kg/day orally
ana ataxia in dogs, cats, pigs etc. Cat : 25-50 g orally or s/c also used in
milkfever or ketosis.
Vitamin C No definite signs are described. Horse: 2-4 g s/c
Bull: 1-2 g s/c every 3-4 days up to 6
weeks.
Cow : 1-2 g i/v and 2 g s/c before mating
or 2 g s/c once or twise a week
for up to 6 doses.
Dog : 25-75 mg orally or s/c per day

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER - 17
DERMATO-PHARMACOLOGY
Contents :
1. Demulcents 2. Emollients 3. Dermal protectants
4. Astringents 5. Counter-irritants 6. Caustics (corrosive)
7. Escharotics 8. Keratolytics 9. Keratoplastics
10. Anti-seborrhoeics 11. Topical Antiseptics
1. Demulcents:
● Inert agents which act as soothing agent on inflamed or denuded mucosa or abraded skin and
lessen the irritation.
● They are substances of high molecular weight which are water soluble i.e. hydrophilic colloidal nature.
● They form a coating layer over the mucous membrane.
● Act as vehicle for many skin medicinal preparations. eg. Glycerine, Propylene glycol, PEG
(polyethylene glycol), gum acacia, glycyrrhiza etc.
2. Emollient:
● Like demulcents, it acts like soothing agent on abraded skin and mucous membrane and forms
an occlusive film layer.
● Emollients are fatty or oily in nature and this term is mainly used for skin applications.
● Additionally, they posses humectant property i.e. they prevent moisture loss and increases water
holding capacity of the dermis.
● Used as base for skin ointments. eg. Arachis oil, linseed oil, cocoa butter, lanolin, soft & hard
paraffin, bee-wax etc.
3. Dermal Protectants:
● They are insoluble, finely grounded, inert solid substances applied topically over skin or mucous
membrane to provide protection or to prevent friction.
● They generally posses adsorbent property and protect skin from toxins or irritants. e.g. Hydrated
magnesium silicate (talc powder), zinc stearate, bentonite, calamine, starch, zinc oxide etc.
Note : By function, demulcent, emollient and dermal protectants all are protective agents.
4. Astringent:
● These are substances which precipitate surface cellular protein and reduce cell membrane
permeability, mechanically toughen the skin or mucosa and promote the healing.
● They do not penetrate the skin.
e.g. salts of zinc and aluminum like zinc sulphate, aluminium acetate, alum, tannic acid.
● Astringents that used to stop local bleeding by promoting coagulation are known as styptics.
5. Counter-irritants:
● These are locally applied agents on intact skin to produce local hyperaemia (increases blood
circulation) and hasten the process of inflammation to varying degree.
● They are used to relieve pain or to facilitate healing of underlying tissue. eg. Turpentine oil, eucalyptus
oil, wintergreen oil (methyl salicylate), menthol, camphor, ammonia, ammonium hydroxide, red
iodide of mercury.
● Depending upon their concentration used, and various degree of irritation produced by them,
these agents can be classified into:-
❖ Rubefacients: Mild counter-irritants that produce local hyperaemia or erythema.
❖ Irritants: Produce hyperaemia as well as inflammation; have sensory component.
❖ Vesicants (Blisters):- strong conuter-irritants that produce vesicles or blisters (alter capillary
permeability and accumulate fluid under the epidermis).

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6. Caustics (corrosives):
● These are topical agents which cause destruction of tissue at the site of application.
● Used to destroy warts, granulation tissues, keratoses etc.
● Used as disbudding agent in calves destroy warts. e.g. silver nitrate, antimony trichloride, phenol,
glacial acetic acid, trichloroacetic acid.
7. Escharotics (cauterizant):
● Agents which facilitate the formation of scab and scar are known as escharotics.
● Many caustics act as escharotics.
8. Keratolytics:
● They soften & dissolve the intracellular cementing substances of horny layer (stratum corneum)
of skin.
● They increase hydration of keratinocytes and desquamation process of epidermal cells.
● Used as anti-hyperkeratosis agents eg. In cases of warts, psoriasis, cornified skin etc. e.g. Salicylic
acid, benzoic acid, sulfur, benzoyl peroxide, urea etc.
9. Keratoplastics:
● They normalize the cornification (keratinisation) process by slowing epithelial turnover
● Inhibits basal cell prolification by inhibiting DNA synthesis.
● Prevents skin scaling and hypertrophy. e.g. Coal tar, salicylic acid, sulfur etc.
Note : Most of keratoplastic agents have keratolytic and anti-seborrhoeic property.
10. Anti-seborrhoeics:
● Drugs which decrease sebum secretion from sebaceous glands of skin.
● Useful in seborrhea which causes oily skin, dandruff and itching. eg. selenium sulfide, benzoyl
peroxide etc.
11. Topical antiseptics:
● Topical antiseptics are the agents which inhibit growth of micro-organisms from living surfaces
like skin.
● May or may not be irritating.eg. Povidone iodine (as skin scrub for surgery), chlorhexidine, hydrogen
peroxide (sporocide on clostridial spores), benzalkonium chloride, cetrimide etc.

BIOENHANCER : Bioenhancers are molecules, which do not possess drug activity of their own but promote and augment the
biological activity and/or bioavailability when used in combination therapy. Synergism in which the action of one biomolecule
is enhanced by another unrelated chemical has been the hallmark of herbal bioenhancers. The concept for bioenhancers
of herbal origin can be tracked from the ancient knowledge of Ayurveda.‘Trikatu’ is a traditional Ayurvedic herbal
formulation consisting of three herbs in equal ratio. It includes Long Pepper (Piper longum), Black pepper
(Piper nigrum), and Ginger (Zingiber officinale). Active phytomolecule in both Piper longum and Piper nigrum, which is
responsible for bioenhancing effect, is piperine. Herb ingredients are effective bioenhancer at very low doses. They are
safer compounds than synthetic one, cost effective and easily available.Nutritional deficiency due to poor gastrointesti-
nal absorption is an increasing problem worldwide. Nutritional herbal bioenhancers provide an alternative method for
improving nutritional status by increasing bioavailability of nutrients due to better GIT absorption. They can be used as
animal and bird feed supplement.Herbal bioenhancers have several mechanisms of action. These include mainly,
increase in gastrointestinal blood supply, decrease in gastric emptying and gastrointestinal transit time, non competitive
inhibition of drug metabolizing enzymes, increase in bioenergetic processes, suppression of first pass metabolism and
elimination of drugs.Herbal bioenhancers are effective for number of drug classes such as antibiotics, anti-tuberculous,
antiviral, antifungal, anticancerous drugs etc. Combinations which have potential application in veterinary therapeutics
include rifampicin plus piperine, oxytetracycline plus piperine, ciprofloxacin plus piperine, ampicillin plus niaziridin and
taxol plus glycyrrhizin. Newer herbal bioenhancers includes Niaziridin (Moringa oleifera), Glycyrrhizin (Glycyrrhiza glabra),
Cuminum cyminum extracts, Carum carvi extracts, Allicin (Allium sativum), Lysergol (Ipomoea muricata), Aloe vera, and
Rosewater. Their development is to be targeted for drugs which are poorly bioavailable, given for longer period of time,
highly toxic and expensive. For example, formulation with Rifampicin in reduced dose plus Piperine has gone through
clinical trials up to phase III under anti-TB drug development. Further, research should be carried out to evaluate clinical
application of herbal bioenhancers in modern veterinary therapeutics.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER - 18
BIO-ENHANCER
Bioenhancers are molecules, which do not possess drug activity of their own but promote and augment
the biological activity and/or bioavailability when used in combination therapy. Synergism in which the
action of one biomolecule is enhanced by another unrelated chemical has been the hallmark of herbal
bioenhancers.

The concept for bioenhancers of herbal origin can be tracked from the ancient knowledge of Ayurveda.
‘Trikatu’ is a traditional Ayurvedic herbal formulation consisting of three herbs in equal ratio. It includes
Long Pepper (Piper longum), Black pepper (Piper nigrum), and Ginger (Zingiber officinale). Active
phytomolecule in both Piper longum and Piper nigrum, which is responsible for bioenhancing effect,
is piperine. Herb ingredients are effective bioenhancer at very low doses. They are safer compounds
than synthetic one, cost effective and easily available.

Nutritional deficiency due to poor gastrointestinal absorption is an increasing problem worldwide.

Nutritional herbal bioenhancers provide an alternative method for improving nutritional status by
increasing bioavailability of nutrients due to better GIT absorption. They can be used as animal and
bird feed supplement.

Herbal bioenhancers have several mechanisms of action. These include mainly, increase in
gastrointestinal blood supply, decrease in gastric emptying and gastrointestinal transit time, non
competitive inhibition of drug metabolizing enzymes, increase in bioenergetic processes, suppression
of first pass metabolism and elimination of drugs.

Herbal bioenhancers are effective for number of drug classes such as antibiotics, anti-tuberculous,
antiviral, antifungal, anticancerous drugs etc. Combinations which have potential application in
veterinary therapeutics include rifampicin plus piperine, oxytetracycline plus piperine, ciprofloxacin
plus piperine, ampicillin plus niaziridin and taxol plus glycyrrhizin.

Newer herbal bioenhancers includes Niaziridin (Moringa oleifera), Glycyrrhizin (Glycyrrhiza glabra),
Cuminum cyminum extracts, Carum carvi extracts, Allicin (Allium sativum), Lysergol (Ipomoea
muricata), Aloe vera, and Rosewater. Their development is to be targeted for drugs which are poorly
bioavailable, given for longer period of time, highly toxic and expensive. For example, formulation
with Rifampicin in reduced dose plus Piperine has gone through clinical trials up to phase III under
anti-TB drug development. Further, research should be carried out to evaluate clinical application of
herbal bioenhancers in modern veterinary therapeutics.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER-26
CNS STIMULANTS
CNS STIMULANTS
These are the drugs which stimulates the CNS.They are classified in threencategories:
(1) Cortical stimulator
(2) Medullary stimulator / Direct CNS stimulator
(3) Spinal stimulator : Nicotine, ammonia and lobelin are indirect or reflexly CNS stimulator
(clinically not used)
(1) Cortical stimulator
A.Xanthine derivatives: These are alkaloid obtained from tea & coffee. Basically, there are
three alkaloids.
Caffeine: It is chemically 1,3,7-trimethylxanthine, obtained from coffee seed (Coffee arabica)
It affects CNS & cardiovascular system.
Mechanism: It acts via four mechanisms as given bellow.
(1) It releases Ca+2 from the sarcoplasmic reticulum (skeletal and cardiac muscle). It also blocks
the adenosine receptors.
(2) Phosphodiestrase inhibition and release of Ca+2. This is probably observed at concentrations
much higher than the therapeutic plasma concentration, while adenosine receptors blockade.
(3) cAMP is metabolized by enzyme phosphodiestrase, it causes inhibition of phosphodiestrase
enzyme. More cAMP is available. So there is more steroid synthesis and release of hormones.
(4) This caffeine causes stimulation of â-adrenergic receptors so it causes cardiac stimulation.
Caffeine acts on adenosine receptors and block them & due to this blockage there is inhibition
of depression of cardiac pacemaker.
Clinical uses:
l Given orally or I/M, when given I/M sodium-benzoate is added in caffeine which increases
solubility of it.
l It is generally used in severe case of narcotic depression or sedation.
l Dose:
Horse and cattle : Total dose 4 mg
Sheep and goat : Total dose 1 - 1.5 mg
Cat and dog :
Total dose 100 - 500 mg
l In general, there is wide margin of safety but in heavy dose lead to convulsion.
Theobromine: It is 3,7-dimethylxanthine, obtained from cocoa seeds (Theobroma cacao)
it produces mild effect on CNS, mainly affect cardiovascular system & diuresis.
Theophylline:
l 1,3-dimethylxanthine, obtained from tea leaves (Thea sinensis).
l Aminophylline is a semisynthetic derivative and used clinically.
l It has less CNS stimulant activity but more bronchodialator activity.
l It increases cardiac activity and has diuretic effect.
l It is more commonly used in respiratory depression like “asthma” etc.
l It is used in congestive heart failure.
l It is commonly used in condition in horses called as “Broken wind”
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 l Dose:
Dog : Total dose, 50mg
Horse/other species : 1-2mg/kg, orally or I/M or I/V
l In human it is used as spray (Asthalin spray contains aminophylline/salbutamol)
l Out of above three, theobromine is not used clinically.
B. Sympathomimetics:
l Commonly used drugs are amphetamine andephedrine
l They are powerful pressure drugs and increase B.P as well as cardiac output.
l Amphetamine occurs as dextrorotatory (CNS stimulation) & leavorotatory (cardiovascular
drug) form.
l Dextrorotatory form causes temporary stimulation of nervous system which increases mental
and physical activity. So it is drug of abuse for dopping (in horses)
l It has got effects like anorexigenic effect which causes anorexia (loss of appetite), so it is
used as anti-obesity effect.
l Dose: 3-4mg/kg, S/C or I/M
l Ephedrine? similar to amphetamine, given orally, 3-4mg/kg
(2) Medullary stimulator : These are mainly respiratory stimulant & also called analeptics.
Clinical uses:
1) They are used in post anaesthetic depression and asphyxia
3) Also employed in neonate asphyxia.
4) They are also used to stimulate respiration in case of drowning
5) They also stimulate depressed respiration in barbiturate poisoning
6) They are used as tretment for heat and electric shock.
7) They are used in chronic hypoventilation with CO2 retention.
Doxapram:
l It stimulates medullary respiratory centre and it acts on chemo-receptors present in carotid
arteries and aortic arch.
l It stimulates respiration and also increase the B.P.
l It is considered as most superior respiratory stimulant, it has got very short duration of action.
l It is used as an antidote of thiopentone toxicity.
l Dose:
Dog : 1 - 2 mg/kg, I/V
Cattle and buffalo : 0.5 mg/kg, I/V
Leptazol, metrazol:
l It causes stimulation of medullary respiratory centre.
l It also causes stimulation of vasomotor centre leading to increased blood supply.
l It causes Inhibition of GABA and there by leads to stimulation.
l It acts very rapidly but is has very low margin of safety.
l Dose:
Dogs and cats : Total dose, 50 -100 mg, I/M
Horse and cattle : Total dose, 0.5 -1mg, I/M
l It is also given in case of extensive barbiturate depression.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 Nikethamide: (Coramine)
l It is derivative of the nicotinic acid and action is similar to doxapram.
l It initially causes stimulation and lately depression.
l It is commonly used in barbiturate and morphine depression.
l It is available oral formulation and mainly given in small animals
l Dose:
Dog and cat : 22mg/kg, orally or I/V or I/M or S/C
Picrotoxin: (cocculin)
l Natural compound obtained by seeds of plant Anamirta cocculus.
l It cause effect on medulla as well as spinal cord.
l It is non-competitive antagonist of GABA.
l Margin of safety is less.
l As it stimulates spinal cord, it causes convulsion. Clnically not used.
Bemigride: (antagonist of barbiturate)
l Clinically used in barbiturate poisoning.
l Dose: 20mg/kg, I/V
CO2: (physiological analeptic)
l When CO2 concentration increase in blood? it stimulate respiratory centre.
l CO2 can be given eternally & causes respiratory stimulation.
l It causes severe acidosis when given externally.

(3) Spinal stimulants

Strychnine
l It is alkaloid derived from seed of plant Strychnos nux-vomica.
l It is commonly available as”nux vomica powder”.
l It basically acts on spinal cord.
l In brain “reinshow cells” are present. It does not allow impulse to pass continuously (motor
impulse). This strychnine blocks reinshow cells and give exaggrated response. This leads to
continous discharge of motor impulses.
l Strychnine causes inhibition of these GABA (brain) and Glycine (spinal cord). This will cause
exaggrated response and lead to condition “hyperaesthesia”
l It causes severe convulsion and muscular spasm.
l Clinically, it is used very rarely. It used as nervine tonic to stimulate ruminal motility.
Dose:
Horse and cattle : 15-16mg
Sheep and goat : 10 -15mg
Pig : 5.0 - 8.0 mg always orally
Dogs : 0.5 -1.0 mg
Cats : 0.1- 0.5mg
Strychnine is available as powder. It is dissolved and solution is used orally.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER-27
LOCAL ANAESTHETICS
Local anaesthetics
l Drugs on topical / local aaplication causes reversible loss of sensations in a restricted area of
body is termed as local anaesthetics.
l Agents applied locally to skin / mucosa for reversible blockade of the nerve impulses – they
effectively block the somatic sensory, somatic motor and autonomic nervous system.
l Initially, in 1860 cocaine was isolated from Erythroxylum coca – numbing of tongue (Niemann).
l Koller introduced it into surgery (1884).
l It is not used now because of known toxicity and addictive potential.
Ideal properties of a LA
l It should produce reversible paralysis.
l It should be non addictive.
l It should be readily soluble and stable in water.
l It is non irritant to the skin.
l It is compatible with epinephrine.
l It is slowly absorbed to have long duration of action.
l It is inexpensive.
l It does not induce hyperesthesia.

Common mechanism of actions? basically 3 mechanisms

1) They act as membrane stabilizing agent: They reduce the permeability of membrane. The local
anaesthetic has amino group which combines with polar group of cell membrane, it affects Na+-K+
pump. The transmission of nerve impulse is impeded.
2) Effect on membrane Ca+2: The calcium whenever present decreases threshold potential, so local
anaesthetic act on Ca+2 in such a manner that threshold potential gets increase.
3) Local anaesthetics bring deformities in Na+ channels: Sometime Na+ channels get closed & Na+-K+
exchange do not take place. This blocks the impulse transmission.
Absorption pattern & systemic effects of local anaesthetics
l Absorption: The minimum absorption in to blood circulation is desired. For this purpose, adrenaline is
added along with local anaesthetics. Epinephrine cause local vasoconstriction leading to lesser
absorption and longer persistence of local anaesthesia at site. The adreanline is used at ratio of 1:
100000 or 1: 50000 along with local anaesthetics.
l Addition of hylouronidase with local anaesthesia increases the penetration of local anaesthetics into
surrounding tissues. Whenever given S/C, it cause diffusion of local anaesthesia over large area and
increase area of desensitization. Adverse effects; If local anaesthesia is absorbed into systemic circulation
due to over dose or faulty injection site, It may precipitate nervous and cardiovascular reactions.
(1) CNS – It causes initially stimulation, tremor, restlessness, convulsions and death. Higher doses
may lead to depression. Low non-seizure dose is used for euphoria in man and to enhance
performance in horses
(2) CVS: It decreases myocardial contractility, rate and force of conduction. It causes dilatation of the
arterioles. Renal and hepatic blood flow is reduced. This lower the metabolism and excretion of
local anaesthetics and cocurrently admnistered drugs.
Different compounds used as local anaesthesia
Cocaine: Cocaine is alkaloid obtained from plant Erythroxylon cocoa. This cocaine is first local anaesthesia to
be used and is regarded as or mother of all local anaesttics. It does not affect intact skin (not topically used) o If
given orally than destroyed in gastric pH. It is potent local anaesthetic, given through sub cutaenous injection.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
Mechanism
l It reduces/blocks the uptake of catecholamines, so epinephrine remain at the site, it itself cause the
vasoconstriction. So epinephrine is not required in addition with cocaine as vasoconstriction. Cocaine
causes pupil dilatation, so very good anaesthesia for ophthalmic observation.
l It is mainly used for observation of eyes.
l It cause of dilation of pupil & constriction of blood vessels locally, so very good for conjunctivitis.
l It is very good anaesthetic for nasal, buccal cavity, larynx & pharynx.
Procaine
l It is first synthetic local anaesthetic introduced by Einhorn in 1905.
l It has an added advantage over coccaine that it is not addictive in nature.
l It is not potent as cocaine, but less toxic.
l It has got very short half-life of 25 minutes, so It increase its life (duration of action) epinephrine is
added & decrease absorption.
l It is metabolized to PABA, so it cannot be used along with sulfonamides.
l It cause severe vasodilatation & it is commonly used as antihypertensive drug. In this procaine is not
used but procaine amide is used.
l It is not used in shock.
l Dose: 1-2% for infiltration, 3-4% for nerve block.
Lignocaine (lidocaine)
l Most commonly used local anaesthetic.
l It is twice potent than than procaine & not cause tissue irritation.
l Quick onset of action & duration of action is twice longer than procaine.
l It is quickly absorbed, hence epinephrine is added.
l Also used as surface anaesthetic/topical.
l Dose:0.5-1% for infiltration, 2-5% for nerve block
Lignocaine like compounds newer compounds
i) Bupivacaine
ii) Mepivacaine
iii) Prilocaine
iv) Cinchocaine
l Among these bupivacaine is most potent (7 times) having 1-12 hours duration of action.
l Mepivacaine is 2-3 times more potent than procaine. The duration of action is 2 hours. It is
commonly used in horses.
Some rarely used local Anaesthetics:
i) Ethanol
ii) Phenol
iii) Chlorbutol
iv) Menthol
v) Benzyl alcohol
Surface anaesthesia:
Ethyl chloride (spray): It has freezing effect locally, so it causes numbness. It is also used as inhalant
anaesthesia.
Amethocaine (tetracaine): It is used for ophthalmic purpose, also for infiltration. It is 10 times potent than
cocaine. For topical purpose, 0.5-1% and for infiltration, 1-2%. Other surface anaesthetics are lidocaine,
dibucaine, benzocaine and oxythazine. Repeated application of surface anaesthetics can cause skin allergy.

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 CHAPTER-28
MUSCLE RELAXANTS AND ANTIDEPRESSANTS
MUSCLE RELAXANTS
All these agents cause muscle paralysis, so used in convulsion and extreme contration. They either
cause flaccid or spastic paralysis. These terminology more used for neuromuscular blockage. These
are divided into two main groups; (1) Centrally acting and (2) peripherally acting.

(1) Centrally acting:

They act on brain, but not cause anaesthesia.
They expected to control muscle contraction.
They are known as skeletal muscle spsmolytics.
E.g., Diazepam, mephensin, guiafenensin, baclofen,

Diazepam:
It acts via GABA receptors. It antagonizes convulsions induced by picrotoxin and nikethamide.
It is used commonly to control muscle spasm, muscle stiffnees and convulsions.
Dose:
Dog : 0.5 - 1.0 mg/kg IV or IM
Cat : 2.5 - 5.0 mg/kg PO TID

Mephenesin:
l It is specific centrally acting muscle relaxant and least effect on CNS.It is a gycine agonist.
So antagonise strychnine or tetanus convulsions, but not of picrotoxins.
l It is not used clinically, due to various adverse reactions (it causes thrombosis & haemolysis).
l It acts on both skeletal and smooth muscle.

Guaifenesin:
l Commonly used muscle relaxant.
l Common irritant added in cough syrup.
l It causes flaccid type of paralysis.
l It acts as glycine agonist
l It acts on monosynaptic & polysynaptic motor nerve.
l It has got wide margin of safety.
l It is used as cough syrup.
l It can control convulsion due to strychnine poisoning and tetanus convulsion.
l But not used against GABA induced convulsions.
l If given via I/V route, it causes haemolysis, so lways gaiven orally mostly.
Dose:
Dog : 45-90 mg IV
Large animal : 60 - 120 mg IV

Baclofen:
l It has GABA like activity, so it can be used in reduce spasticity in neurological disorders.

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 Methocarbamol:
l Its mechanism is not clear.
l It is used in dog, cat and horse as muscle relaxant.
l Dose:
Dog and cat : 40 mg/kg, orally
l Horse : 5 - 20 mg/kg, I/V

Dantrolene:
l It is directly acting skeletal muscle relaxant.
l It inhibits release of Ca+2 from sarcoplasmic reticulum.
l It has also some effect on brain.
l It is only specific and effective treatment for malignant hyperthermia, a life-threatening disorder
triggered by general anaesthesia.
l Dose:
Dog : 2.5 mg/kg, I/V
Horse and pig :1 -3 mg/kg, I/V

(2) Peripherally Acting/Skeletal Muscle Relaxant/Neuromuscular Blockers

They are act on neuromuscular end plate and so called as neuromuscular blockade.
They are given by IV route only.
They are categorised into two groups namely (1) Competitive neuromuscular blockers and
(2) Non competitive neuro muscular blockers.
The comparison of both types of neuromuscular blockers
COMPETITIVE BLOCKER NON-COMPETITIVE BLOCKER
(1) Non-depolarizing (1) Depolarizing
(2) Reversible blocker (2) Irreversible blocker
(3) Flaccid paralysis (Curariform effects) (3) Tonic / Spastic paralysis
(4) Antagonised by AchE inhibitors (4) Produces synergistic effecst with AchE inhibitors

Competitive neuromuscular blockers

I. Natural compounds : eg. d-tubocurarine (obtained from plant, Chondrodendron tomentosum)
á-toxin present in venom of poisonous snake like cobra
II. Synthetic compounds : eg., gallamine, pancuronium, alcuronium, atracuronium, They acts by
competitive antagonism of acetylcholine for nicotinic receptors at neuromuscular junction. They
do not allow acetylcholine to cause depolarisation of muscle cells. They are thus known as Non
depolarising blockers.They produce curariform effects characterised by flacid paralysis.
Following drugs potentiate the curariform effecst of non competitive neuromuscular blockers.
(1) Quinidine,
(2) Ananesthetics (baribiturates, halothane, methoxy furane, ether),
(3) Aantibiotics (aminoglycoside, oxytetracycline, polymixin, lincosamide).

Following drugs antagonises the curariform effecst of non competitive neuromuscular blockers.
(1) Anti AchE compound like physostigmine, neostigmine and edrophonium.
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Non competitive neuromuscular blockers: E.g., Succinylcholine (suxamethonium),
decamethonium They acts through persistant depolarisation of post syneptic muscle fibers. Muscle
fibers becomes non responsive to acetylcholine. They do not competete for nicotinic receptors at
motar end plate. Organophosphate compounds potentiate the action of non competitive
neuromuscular blockers.Both of these groups have antagonistic effect, if given together so
combination has no effect at all.

Pharmacological effects of neuromuscular blockers:

Effect on Cardiovascular system:-
it causes severer vasodilatation and fall in B.P.
Most of these agents when given rapid I/V injection, release histamine which causes
anaphylactic reaction, severe bronchoconstriction leads to shock and death.
They are always given slowley in diluted form.

Clinical uses:
1) As preanaesthesia for inducing skeletal muscle relaxation.
2) As anti convulsant.
3) Capturing the wild animals (Curariform drugs)
4) For orthopedic surgical manipulation (Diazepams and methocarbamol)
5) Adjunct therapy in acute muscle injury (centrally acting drugs are used)
6) Prevention or treatment of malignant hyperthermia or rhabdomyolysis in horse

Dose:
1) d–tubocurarine: Cat, dog and pig : 0.4 - 0.5 mg/kg Small ruminants? 0.06mg/kg
2) Gallamine: Dog and cat: 0.1 mg/kg, Other:0.5 mg/kg
3) Succinylcholine: Dog & cat :0.5 -1 mg/kg, Cattle, buffalo and horse: 0.04 - 0.05 mg/kg

ANTIDEPRESSANT (MOOD ELEVATORS)

Used in human in case of depression. Also called as thymoleptics/antidepressant.

Types of antidepressents:
1) Selective serotonin reuptake inhibitors (SSRIs) : E.g. citalopram, fluoxetine, fluvoxamine
etc.
2) Selective serotonin reuptake enhancers (SSREs) : e.g. tianeptine
3) Serotonin-norepinephrine reuptake inhibitors (SNRIs): e.g. duloxetine, milnacipran,
venlafexine
4) Tricyclic antidepressant (TCAs) : e.g. imipramine, desimipramine, trimipramine,
amitriptyline, clomipramine
5) Monoamine Oxidase inhibitors (MAO-inhibitors)/MAOIs : e.g. selegiline, iproniazid,
isocarboxazid, moclobemide, mitheum chloride Moclobemide? reversible inhibitor of
monoamine Oxidase A (RIMA).

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 SECTION III : EXERCISE FOR OBJECTIVE QUESTIONS
Q-I. Fill in the blanks appropriately:
1. __________________ deals with post marketing surveillance and reporting of ADR of drug.
2. Decreasing response to a drug on repeated or prolong administration is termed as
______________________.
3. __________________ is the medicinal system based on the principle of “Like Cures Like”.
4. ___________________ is the medicinal system based on principle “Equilibrium among three elements
of Vatt, Kapha, and Pitta”.
5. CDRI is abbreviation for _____________________________________________________.
6. NIPER is abbreviation for _________________________________________________.
7. _____________ is worshiped as a God of Medicine or Health in Indian System of Medicine.
8. _____________ founded the first pharmacology laboratory at Estonia, University of Dorpet.
9. First pharmaceutical company established in Gujarat is _____________________________.
10. _________ name of drug gives the precise information regarding chemical structure of drug.
11. Drug included in Pharmacopoeias is termed as ______________________ drug.
12. ________________________________ is an anti malarial drug obtained from plant source.
13. ______________________________ is an example of alkaloid drug obtained from plants.
14. The oldest known source of drug is ______________________.
15. _______________________________ is an example of drug obtained from animal sources.
16. ____________________________ is an example of drug obtained from microbial origin.
17. DCGI stands for ________________________________________________________.
18. _______________________________ is an example of drug obtained from soil.
19. An agent, which stimulates gastric acid secretion and digestion, is known as ____________.
20. An agent, which induces vomiting, is termed ____________________________________.
21. An unethical use of drug to increase physical endurance during sport events is known as
__________________.
22. ___________________ form of drug is lipophili C.
23. ___________________ form of drug is hydrophili C.
24. If pH > pK then Ionized fraction of drug __________________ unionized fraction of drug.
25. If pH = pK then Ionized fraction of drug _________________ unionized fraction of drug.
26. An agent, which induces deep sleep, is termed as ________________________________.
27. An agent, which promotes growth of rumen microbes and digestion, is known as
______________________________.
28. If pH < pK then Ionized fraction of drug _________________ unionized fraction of drug.
29. The time taken by the drug to enter in to the solution phase is known as ______________.
30. ________________ is a saturable process of drug transport across the biological membrane.
31. Higher the value of Volume of distribution, longer is ____________________________.
32. _______________________________is an example of drug obtained by biosynthetic tool.
33. Higher the plasma protein binding, lesser is ___________________________.
34. Enzyme assembly responsible for drug metabolism is known as _____________________.
35. _______________________ is the science that deals with genetic variation of drug response in
individuals.
36. Agent which is pharmacologically inert but, sometimes given to simulate impact of medication in
patients is known as _______________.
37. Atropine is used for pre-anaesthetic medication for its __________________ property.

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38. Barbiturates are derivatives of ___________________.
39. Basic drugs bind to_______________ fraction of plasma proteins.
40. All substances are poison, there is none, which is not poison. The right dose differentiates poison and
remedy. This famous quotation was given by _____________________.
41. ___________________________ is regarded as the Father of Indian Pharmacology.
42. Pethidine in U.K. is same as _____________________ in U.S. A.
43. _____________ is an agent, which stimulates sexual urge and desire.
44. _____________ is an agent, which induces sleep.
45. _____________ is an agent which promotes growth of ruminal microbes.
46. The time taken by the drug to enter in to the solution phase is known as _____________ .
47. Paracetamol and ________________ has the tendency to accumulate in the liver.
48. An unusual response to drug is known as ___________________.
49. _____________________ consists of testing of drug in small group of healthy volunteers.
50. ___________________________deals with study of economics of drug used and derived benefits /
effects.
51. Dosage regimen includes ____________, _____________ & _____________________.
52. __________________________________is roman god of health for whom Rx is use D.
53. Captopril act by inhibiting ____________________ enzyme.
54. Norepinephrine is metabolized by ______________ and _____________enzymes.
55. H2 antagonists are used in the treatment of _______________________.
56. Dobutamine is a selective _____________ receptor agonist.
57. Screening of drug for one or two pharmacological properties is known as _____________.
58. Full form of NF is______________________.
59. Bioavailability is 100% following _____________ administration.
60. Succinylcholine is a ________________________ type of muscle relaxant.
61. The inert substance administered to satisfy the patient psychologically is referred
as_________________.
62. Pigs are deficient in _________________ metabolic pathway.
63. Cats are deficient in _______________ synthetic phase of metabolism.
64. The pharmacokinetic parameter that describes the extent of distribution of a drug
is____________________.
65. ________________was the first alkaloid to have been isolated from the plant source.
66. Excretion of acidic drugs is promoted in __________________ urine.
67. _______________ was the first Professor of Pharmacology in Indi A.
68. Dose- Response curve shifts to ___________________ in presence of antagonist.
69. Non-responsiveness of the previously responsive tissue following repeated drug administration is
called as ______________________.
70. _______________ is the most potent among all cardiac glycosides.
71. Omeprazole inhibits gastric acid secretion by inhibiting ______________________.
72. Ondansetron acts on ______________________ to produce antiemetic effect.
73. International Pharmacopoeia (Ph.I.) is published by _______________________________.
74. The drugs that are neglected for inclusion in the drug development program owing to their limited use
are termed as _______________________.
75. Drug induced diseases are termed as _______________________ diseases.
76. Therapeutic index = ______________
77. Study of drug in relation to dose and dosages is termed as __________________.
78. The structural components of glycosides are _________________ & ________________.

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79. Apomorphine is _____________________ acting emeti C.
80. Tyramine is _________________________ acting sympathomimeti C.
81. Aminophylline and theophyliline increases intracellular concentration of __________________ while
inducing bronchodilatation.
82. eCG ( PMSG) is the source primarily of ____________________________.
83. Bromhexine is classified as ____________________ expectorant.
84. __________________ is a cholinergic alkaloid obtained from a mushroom.
85. Two main types of adrenergic receptors are _________ and ________, while that of cholinergic
receptors are ______________ and ____________.
86. Higher the potency of a drug, _________ will be its dose required for treatment.
87. __________________ is a bacterial toxin of which diminishes release of Acetylcholine.
88. ________________ is the neurotransmitter at the post-ganglionic parasympathetic fiber.
89. ____________________ is an intraneuronal enzyme oxidizing catecholamines.
90. ____________________ is an anticoagulant used in vitro and in vivo.
91. _____________________ is also referred as antiarrythmic of intensive cardiac care units.
92. The agent that increases bile secretion from hepatocytes is called as _____________.
93. The agents that contract uterus are termed as _______________________.
94. _______________________________ purgatives are the fastest acting purgatives.
95. Deficiency of vitamin ______________ produces ‘curled toe paralysis’ in chicken.
96. ________________ is drug of choice in toxicity of d-tubocurarine.
97. _________________ agents are used for painless killing of animals.
98. __________________ is the active metabolite of chloral hydrate.
99. Acetazolamide inhibits_________________ enzyme.
100. Metformin is used as ______________ agent.
101. Insulin is secreted by _________________ cells of Islets of Langerhans.
102. Hexamine exerts antiseptic effect in ____________________________ urine.
103. Aspirin used in treatment of coagulopathies due to its _________________ effect.
104. The agents inhibiting bacterial fermentation in stomach are referred as ________________.
105. ____________ is the most potent vasoconstrictor agent formed from renin.
106. ____________ is used in angina pectoris and is administered by ________________route to avoid
first pass effect and it releases ______________________in body.
107. Drugs which increase force of heart contractions are termed as __________.
108. Nikethamide has ____________ action on CNS.
109. Non-steroidal anti-inflammatory drugs act by inhibiting ___________ enzyme.
110. Nystagmus is noticed in the horse in stage ______ of anaesthesi A.
111. Organophosphate insecticides act by irreversible inhibition of __________ enzyme.
112. Phenobarbital is ________________ of hepatic microsomal enzyme system.
113. Shape of curve in graded log-dose response plot is ______________________.
114. Study of qualitative and quantitative evaluation of drugs is known as ___________________.
115. ___________________and ___________________are used to dissolve extravascular and
intravascular clots, respectively.
116. ______________________, produced in spoiled sweet clover, has _____________________ action
by inhibiting _______________.
117. It is advisable to give __________ to piglets before iron therapy.
118. ________________ and ______________ are bitter principles present in Nux vomica and they act
as ____________________.
119. Excess of ______________ in food decreases absorption of copper.
120. Histamine and Dopamine are synthesized from amino acids ___________________ and
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 ________________ respectively.
121. _____________________________ is a direct acting emeti C.
122. Xylazine is a _________________________ acting emetics.
123. _______________ are drugs which promote gastric motility and facilitate gastric emptying.
124. Cardiac gylcosides __________________ heart rate and increases force of contraction.
125. _________________________________ is an example of calcium channel blockers.
126. ________________________ is an antagonist of heparine.
127. __________________________ is an anticoagulant from leech and it can be used in vivo.
128. Terburtaline is ____________________________ agonist.
129. _______________________ causes mainly water diuresis with low degree of natriuresis.
130. ____________________________ are the drugs which relax the uterine myomatrium.
131. White muscle disease in sheep occurs due to deficiency of _______________________.
132. __________________________ is an enzyme associated with destruction of acetylcholine.
133. ____________________________________ is an alkaloid from Nicotiana tabacum.
134. Syrup of ipecae contains _____________ alkaloid, which has _____________action.
135. Dilatation of bronchi is medicated by ________________type of adrenoceptors.
136. Source of pilocarpine and arecoline are _________________and __________________, respectively.
137. _______________________ is an example of ganglionic blocker agent.
138. GABA stands for _____________________________________________________.
139. Sympathomimetic drugs causes _________________________ of bronchial smooth muscle.
140. _______________ is a histaminergic receptors involved in regulation of gastric acid secretion.
141. _________________________________ is a precursor of 5-hydroxytryptamine
142. Amphetamine is ______________________________ acting adrenomimetics.
143. ____________________ decreases the fluidity and volume of saliv A.
144. _______________ is a synthetic analogue of Prostaglandin (PGE1) used in gastric ulcers.
145. ____________________ is a non buffering antacid suitable for IV use.
146. Cardiac glycosides produce positive inotropic effects by inhibiting _______________.
147. ____________________ releases nitrous oxide and produces powerful vasodilatation.
148. ____________________ is an antagonist of leukotrine receptors.
149. Salbutamol is____________________ agonist.
150. Drug which decreases viscosity of naso-pulmonary secretion to facilitate expectoration is known as
____________________.
151. Hexamine in acidic urine liberates ammonia and ___________________ which produces antiseptic
effects.
152. Site of action of loop diuretics is ____________________.
153. ______________ is an alkaloid from Claviceps purpurea, having uterine stimulant effects.
154. ____________________ are the agents which dissolve keratinized layers of skin.
155. ____________________ is a diuretic which induces hyperglycemia in patients.
156. ____________________ is an anticoagulant known as physiological anticoagulant.
157. Dopamine is synthesized from amino acids____________________.
158. _____________ are solutions or suspensions of soothing substances to be applied to the skin without
friction.
159. _____________ is an active metabolite of phenylbutazone.
160. _____________ is term for inactive drug which is convertible to pharmacologically active form in vivo.
161. ________________ administration of drug is subjected to first pass effect.
162. ______________ is drug which has both local anesthetic and anti-arrhythmic action.
163. _______________ is drug which has both antiepileptic and antiarrythmic action.
164. Reserpine causes depletion of ____________________ levels in adrenergic neurons.
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165. ________________________ is an example of nasal decongestant.
166. Adrenaline is the drug of choice for the treatment of type _____ hypersensitivity reactions.
167. ____________________ is an example of fish derived toxin which block axonal action potential by
inhibiting voltage gated sodium ion channel.
168. ___________________________ is an example of mast cell stabilizers.
169. Major pre-ganglionic neurotransmitter in both sympathetic as well as parasympathetic nervous
system is __________________.
170. Gastric and pancreatic glands receive supply of _________________ nervous system only.
171. Estimation of drug concentration or potency by measuring its biological response in intact animals or
isolated preparations is known as _______________.
172. ______________ isolated morphine from opium.
173. _______________ are the drugs that cause expulsion of gases from stomach.
174. ___________________ is most important means by which drugs enter the body and their distribution
occurs across cell boundaries.
175. _______________________ is the study of physiologic and biochemical effects of drugs and how
these effects relate to the drugs mechanism of action.
176. A drug that has both affinity as well as efficacy is termed as ________________.
177. Aspirin affects prostaglandin synthesis by inhibiting _____________ enzyme.
178. Atropine has ______________ effect on pupil of eye.
179. Diazepam produces anticonvulsant effect by antagonizing _______________ in CNS.
180. Drug that produce profound sleep with marked depression are termed as _____________.
181. Drugs which have ability to induce parturition before full term are known as _______________.
182. Surgical operations are performed generally in stage_________ of general anesthesi A.
183. ________________________________ is regarded as Father of Modern Pharmacology.
184. Tannins have _____________________ action on the mucous membrane.
185. All conjugative reactions are catalyzed by non-microsomal enzymes except ____________.
186. In ______________ order kinetics, constant fraction of drug is eliminated per unit time.
187. Half life of the drug is not constant and depends on drug concentration in ___________ order kinetics.
188. A __________________ is the macromolecule component of body tissues with which a drug interacts
to produce pharmacological effects.
189. ______________________ is an example of inverse agonist or negative antagonist.
190. Receptors remained unoccupied (free) by agonists are known as _____________ receptors.
191. Four variables of dose-response curve are ______________, ________________, ___________,
and _______________.
192. Ratio of LD1 and ED99 is known as __________________________________.
193. Pirenzepine and telenzepine are selective antagonists of ____________ receptor.
194. Type of muscarinic receptors which predominant in heart is __________.
195. Interaction, in which a drug with no effect of its own but increases effect of another drug, is known as
_____________________________.
196. ______________ is a non-selective â antagonist which undergo significant first-pass effect.
197. ________________, a reversible anticholinesterase, is used for differential diagnosis of myasthenia
gravis and cholinergic crisis.
198. Dantrolene sodium, a direct acting muscle relaxant, interferes with release of _____________ from
sarcoplasmic reticulum of voluntary muscles.
199. Species like _______________ can tolerate large dose of atropine without any toxic effects.
200. Zafirlukast and montelukast are ______________________ receptor antagonists used to treat allergic
respiratory disease.

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Q-II: Select the most appropriate answer:
1. Following is a H2 blockers:
A. Omeprazole
B. Ondansetron
C. Domperidol
D. Ranitidine
2. Asafoetida (heeng) is:
A. Oleoresin
B. Gum-resins
C. Waxes
D. Plant derived fixed oil
3. Order of duration of action for a drug given by different routes will be:
A. SC > IM > IV
B. IM > SC > IV
C. IM > IV > SC
D. SC > IV > IM
4. Following are non-pharmacological or type B adverse drug effect except:
A. Hypersensitivity
B. Intolerance
C. Idiosyncrasy
D. Photosensitization
5. Acetazolamide acts on:
A. Loop of Hinle
B. Glomerulus
C. PCT
D. DCT
6. Which is true for misoprostol?
A. Induces ulcers
B. Stimulates gastric acid secretion
C. Reduces mucus secretion
D. Synthetic prostaglandin (PGE1) analogue
7. Pharmacologically inert substance which does not produce any therapeutic effect:
A. Placebo
B. Psychotropic agent
C. Anti-psychotic drug
D. Psychosomatic drug
8. Which one is an in vivo as well as in vitro anti-coagulant?
A. Sodium citrate
B. Heparine
C. Sodium chloride
D. EDTA
9. Following cause primarily water diuresis:
A. Mannitol
B. Acetazoalmide
C. Amiloride
D. Hydrochlorthiazide

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10. Drug which helps propelling mucus secretion in respiratory tract:
A. Mucokinetics
B. Mucolytics
C. Prokinetics
D. Gastrokinetics
11. Dose of drug that produces mortality or lethality in 50% of exposed population is:
A. LD50
B. ED50
C. Toxic dose
D. Lethal dose
12. Following drug is obtained from soil:
A. Atropine
B. Caffeine
C. Morphine
D. Magnesium
13. Science that deals with study of mechanism of action of drug is known as:
A. Pharmacokinetics
B. Pharmacodynamics
C. Pharmacometrics
D. Pharmacovigilance
14. “Pen Tsao” is a material medica written in the language of:
A. English
B. Chinese
C. Arabic
D. Urdu
15. Following drug acts by blocking calcium channel and causes fall in blood pressure:
A. Phentolamine
B. Propanol
C. Amlodipine
D. Labetalol
16. Caffeine acts on which part of CNS?
A. Medulla
B. Cortex
C. Spinal cord
D. All of above
17. Following is a naturally occurring alkaloid obtained from Chinese shrub Ephedra vulga:
A. Atropine
B. Ephedrine
C. Digitalis
D. Digitoxin
18. Which is the competitive neuromuscular blocker?
A. d-tubocurarine
B. Pancuronium
C. Gallamine
D. All of above
19. Which is true for balanced anaesthesia?
A. Irreversible loss of consciniousness.
B. Irrevesible loss of sensation.
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 C. Muscle relaxant
D. Both (A) and (C)
20. Adrenaline does not have the following effect:
A. Increase heart rate
B. Increases blood glucose
C. Increase cardiac output
D. Miosis
21. The antagonist of diazepam is:
A. Lorezapam
B. Flumazenil
C. Atropine
D. Thiophenate
22. Which of following is most potent inhalant anaesthetic?
A. Ether
B. Halothane
C. Methoxyfurane
D. Isofurane
23. Which of the following inhibits uptake of acetylcholine into vesicles?
A. Vesamicol
B. Cobra toxin
C. Bungarotoxin
D. Botulinum toxin
24. Which of following is used in the treatment of myasthenia gravis:
A. Dopamine
B. Neostigmine
C. Atropine
D. Benzodiazepam
25. Which of following is used for relief of heaves in horse?
A. Oxytocin
B. Atropine
C. Methanol
D. Frusamide
26. Which of following drug increases blood pressure, heart rate and force of contractions?
A. Epinephrine
B. Atropine
C. Labetolol
D. Pindalol
27. Post operative urinary bladder atony can be treated with:
A. Atropine sulphate
B. Dopamine
C. Bethanechol
D. Pilocarpine
28. Following is not a pharmacokinetics process:
A. Absorption
B. Distribution
C. Metabolism
D. Dissolution

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29. Pharmacovigilance does not include:
A. Screening
B. Adverse drug reaction
C. Drug toxicity in patients
D. Extra label use of drug
30. Which drug is metabolized by sulphoxidation:
A. Malathion
B. Phenylbutazone
C. Albendazole
D. Quinidine
31. Drug which reduces viscosity of mucus secretion in respiratory tract:
A. Mucokinetics
B. Mucolytics
C. Prokinetics
D. Gastrokinetics
32. Dose of drug that produces mortality or lethality is:
A. LD50
B. ED50
C. Toxic dose
D. Lethal dose
33. Following drug is not obtained from soil:
A. Atropine
B. Caffeine
C. Morphine
D. All of above
34. ‘All or none’ response is related to:
A. Quantal dose response curve
B. Graded dose response curve
C. Drug excretion
D. Drug metabolism
35. The recommended route of administration for oxytocin is:
A. IV and Oral
B. IM and Oral
C. IV and IM
D. IV and Local
36. Conversion of nicotinic acid to nicotinamide leads to:
A. Increases toxicity
B. Decreased toxicity
C. No change in toxicity
D. None of above
37. Which is a sign of digitalization:
A. Dyspnoea
B. Nausea
C. Relief in coughing
D. Palpitation
38. Science that deals with drug dosage determination is known as:
A. Posology

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 B. Pharmacy
C. Pharmacometrics
D. Metrology
39. Following is not a dissociative anaesthetics:
A. Ketamine
B. Tiletamine
C. Phencyclidine
D. None of above
40. Chlorpent anaesthesia include:
A. Chloral hydrate
B. Magnesium sulphate
C. Phenobarbitone
D. All of above
41. Following is a beta receptor blocker which is used as bronchodilator:
A. Terbutaline
B. Salbutamol
C. Caffeine
D. Both (A) and (B)
42. Propanolol blocks:
A. â1
B. â2
C. â3
D. â1 and â2
43. Verapamil acts by:
A. blocking potassium channel
B. blocking L type calcium channel
C. blocking sodium channel
D. blocking ATPase
44. Following is an action of H1 blockers:
A. CNS sedatives
B. Anti-emetics
C. Local anaesthetics
D. All of above
45. Following is an anti-cholinergic pre-anaesthetic:
A. Atropine
B. Sumatropine
C. Promethazine
D. Chloral hydrate
46. Chloral hydrate is converted to:
A. Diethyl ether
B. Trichloromethane
C. Trochloroethanol
D. Dichloromethane
47. Which is not true for aspirin:
A. It is NSAIDs
B. It has strong analgesic and antipyretic activity
C. Prolong use leads to gastric bleeding

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 D. It inhibits phospholipase
48. The source of opium alkaloids is:
A. Papaver somniferum
B. Digitalis purpurea
C. Claviceps purpurea
D. Urgenia maritime
49. Paracetamol has following characteristics:
A. Strong analgesic
B. Strong anti-inflammatory
C. Sedative
D. Selective COX-2 inhibitor
50. Following is an á1 blocker:
A. Pentazocin
B. Pentaprazole
C. Prazocin
D. Penylephrine
51. All of following except one is not a NOT a natural drug:
A. Atropine
B. Quinine
C. Digitalis
D. Paracetamol
52. Which is true for ondansetron?
A. 5 HT3 analogue
B. 5 HT3 agonist
C. 5 HT3 antagonist
D. 5 HT3 reactivator
53. Which one is an in vivo as well as in vitro anti-coagulant?
A. Sodium citrate
B. Heparine
C. Sodium chloride
D. EDTA
54. Following is a tocolytic drugs?
A. Emodine
B. Naloxane
C. Oxytocin
D. Acetycholine
55. Physostigmine acts on which receptors?
A. Alpha
B. Beta
C. Muscarinic
D. Dopamine
56. Which of following has no action on nicotinic receptors?
A. Acetylcholine
B. Carbachol
C. Methacholine
D. Muscurine
57. Which of following represents parasympathetic part of ANS?

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 A. Lumbo-sacral
B. None of above
C. Thoraco-lumber
D. Cranio-sacral
58. Acetylcholine is metabolized by following enzyme:
A. Ach-e
B. ACE
C. Adenyl cyclase
D. ATPase
59. Following is NOT a â2 receptor agonist:
A. Salbutamol
B. Salmetrol
C. Terbutaline
D. Dobutamine
60. Which of following is á-2 adrenoceptor antagonist?
A. Yohimbine
B. Atropine
C. Atenolol
D. Clenbuterol
61. Following is an precursor of histamine:
A. Tyrosine
B. Tyrptophane
C. Histidine
D. Renitidine
62. Metoserpate is an synthetic analogue of:
A. Xylocaine
B. Tetracaine
C. Reserpine
D. Lidocaine
63. Following is an MAO inhibitor:
A. Imipramine
B. Desipramine
C. Amitriptyline
D. All of above
64. Which of following is major process responsible for termination of action of thiopentone?
A. Metabolism
B. Redistribution
C. Excretion
D. Absorption.
65. Stage IV of general anesthesia is also known as:
A. Delirium
B. Analgesia
C. Surgical anaesthesia
D. Medullary paralysis
66. Alkalization of urine promotes action of following antibacterials:
A. Fluoroquinolones
B. Penicillins

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 C. Aminoglycosides
D. Macrocyclics
67. Following is an example of caustics:
A. Copper sulfate
B. Zinc sulfate
C. Salicylic acid
D. Bentonite
68. The pharmacological activity of cardiac glycoside is a function of:
A. Aglycon
B. Gylcon
C. Both (A) & (B)
D. None of above
69. Drug(s) which gets inactivated in rumen:
A. Chloramphenicol
B. Digitalis
C. Trimethoprim
D. All of above
70. Action of cholinergic agonist on GIT smooth muscle is:
A. Increased motility
B. Decreased motility
C. Causes no effects
D. Induces paralysis
71. Following is a precursor of histamine:
A. Tryptophan
B. Histidine
C. Tyrosine
D. Dopamine
72. Fluoride has a tendency to accumulate in which of following tissues:
A. Kidneys
B. Liver
C. Teeth of young animals
D. Spleen
73. Hypoprotinaemia has direct impact on:
A. Drug solubility
B. Drug disintegration
C. Drug distribution
D. None of above
74. Following is NOT an in vitro anticoagulant:
A. Sodium oxalate
B. Sodium citrate
C. K2 EDTA
D. Dicoumarol
75. Amphetamine acts by:
A. Releasing noradrenaline
B. Releasing dopamine
C. Both (A) & (B)
D. None of above

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76. Caffeine acts on which part of CNS via:
A. Blocking adenosine action in cortex
B. Blocking adenosine action in medulla
C. Blocking adenosine action in spinal cord
D. All of above
77. Strychnine causes one of following:
A. CNS stimulantation
B. Severe spinal convulsion
C. Inhibition of gylcine
D. All of above
78. Which of following synthetic opioid has anti-diarrhoeal activities?
A. Dicyclomine
B. Loperaminde
C. Domperidole
D. Hydroxycodeine.
79. Which is not a phenothiazine tranquilizer?
A. Acepromezine
B. Chlorpromezine
C. Triflupromezine
D. Cetrizine
80. Following is angiotensin receptor blocker:
A. Losartan
B. Enalapril
C. Ketanserin
D. Ondansetron
81. Following is an example of endogenous opioid:
A. Endorphins
B. Epinephrine
C. Ephedrine
D. All of above
82. All opioid receptors belong to following type of receptors:
A. G protein coupled
B. Ligand gated ion channels
C. Enzymes linked
D. None of above
83. What determines the degree of movement of a drug between body compartments?
A. Partition constant
B. Degree of ionization
C. pH
D. All of the above
84. Which of the following is considered the brand name?
A. Paracetamol
B. Crocin
C. Acetaminophen
D. Antipyretics
85. Pharmacokinetics is the effect of the ____ & pharmacodynamics is the effect of the _____.
A. Drug on other drug; Body on the drug

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 B. Body on the drug; Drug on other drug
C. Drug on the body; Body on the drug
D. Body on the drug; Drug on the body
86. Which of the following process is NOT an action of the body on a drug?
A. Distribution
B. Target binding
C. Synthetic conjugations
D. Biliary excretion
87. Which of the following is the amount of a drug absorbed per the amount administered?
A. Bioavailability
B. Bioequivalence
C. Drug absorption
D. None of above
88. For intravenous (IV) dosages, what is the bioavailability assumed to be?
A. 0%
B. 1%
C. 50 %
D. 100 %
89. Which of the following is NOT a pharmacokinetic process?
A. Alteration of the drug by liver enzymes
B. The drug is readily deposited in fat tissue
C. Movement of drug from the gut into general circulation
D. The drug causes dilation of coronary vessels
90. Which of the following has least side effects?
A. Paracetamol
B. Aspirin
C. Meloxicam
D. Nimesulide
91. Most drugs are either _______ acids or _______ bases.
A. Strong; Strong
B. Strong; Weak
C. Weak; Weak
D. Weak; Strong
92. Weak acids and bases are excreted faster in ________ and ________urine, respectively.
A. Acidic; Alkaline
B. Alkaline; Acidic
C. Neutral; Neutral
D. Neutral; Alkaline
93. Organ responsible “first pass effect” is:
A. Brain
B. Heart
C. Kidney
D. Liver
94. Which of the following enteral administration routes has the largest first-pass effect?
A. Sublingual
B. Buccal
C. Rectal

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 D. Oral
95. Which of the following would receive drug slowly?
A. Brain
B. Fat
C. Muscle
D. Kidney
96. What type of drugs can cross the blood-brain barrier (BBB)?
A. Large and lipid-soluble
B. Large and lipid-insoluble
C. Small and lipid-soluble
D. Small and lipid-insoluble
97. Which of the following is NOT a phase II substrate?
A. Glucuronic acid
B. Sulfuric acid
C. Acetic acid
D. Alcohol
98. Which of the following reactions is phase II and NOT phase I?
A. Reductions
B. Conjugations
C. Deaminations
D. Hydrolyses
99. The goal of the Cytochrome - P450 system is:
A. Metabolism of xenobiotics
B. Detoxification of xenobiotics
C. Absorption of xenobiotics
D. (A) & (B)
100. Generally, following is in the correct order regarding doses:
A. ED50 < LD50 < TD50
B. ED50 < TD50 < LD50
C. LD50 < TD50 < ED50
D. LD50 < ED50 < TD50
101. Which of the following is considered the therapeutic index?
A. T.I. = LD25 / ED75
B. T.I. = LD50 / ED50
C. T.I. = ED25 / LD75
D. T.I. = ED50 / LD50
102. Following causes inhibition of aggregation of platelets
A. Aspirine
B. Urokinase
C. Thromboxane A2
D. Streptokinase
103. Most appropriate anticoagulant used for collection of blood for blood glucose estimation:
A. Sodium EDTA
B. Sodium fluoride
C. Heparin
D. Sodium oxalate
104. Agar acts as:

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 A. Cathartics
B. Emollient purgative
C. Bulk purgative
D. Osmotic purgative
105. Acid rebound effect is observed with:
A. Sodium bicarbonate
B. Sodium citrate
C. Sodium chloride
D. Potassium iodide
106. An antagonist has:
A. Efficacy only
B. Affinity only
C. Both efficacy and affinity
D. Neither efficacy nor affinity
107. Isaphgula husk acts as:
A. Bulk purgative
B. Osmotic purgative
C. Emollient purgative
D. Cathartics
108. The stage(s) of anaesthesia which is induced by ketamin is:
A. Stage I only
B. Stage II only
C. Stage I and II only
D. Stage II and III only
109. Antiemetic action of domperidone is mediated by inhibition of receptors:
A. Opoid receptor
B. Muscarinic receptor
C. Dopamine receptor
D. 5-HT receptor
110. Pharmacological effects of oxytocin:
A. Contraction of myoepithelium of mammary alveoli
B. Contraction of uterus
C. Both (A) & (B)
D. None of the above
111. High plasma protein binding of drugs results in increased:
A. Volume of distribution
B. Plasma half-life
C. Clearance
D. Rate of metabolism
112. The therapeutic index of the drug indicates:
A. Potency
B. Efficacy
C. Safety
D. Toxicity
113. In hepatocytes, the seat of drug-metabolizing enzymes is:
A. Cell membrane
B. Ribosomes

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 C. Smooth endoplasmic reticulum
D. Rough endoplasmic reticulum
114. Bioavailabilty of a drug is calculated by formula:
A. 0.693/â
B. Dose/AUC x â
C. AUC (extravascular)/ AUC (intravenous)
D. AUC (intravenous)/ AUC (extravascular)
115. Most potent local anaesthetic among the following
A. Lignocaine
B. Mepivacaine
C. Bupivacaine
D. Procaine
116. Most potent inhalant anaesthetic having lowest MAC:
A. Methoxyflurane
B. Halothane
C. Isoflurane
D. Enflurane
117. Which one of the following is a rate limiting step in adrenaline synthesis?
A. Tyrosine to DOPA
B. DOPA to Dopamine
C. Dopamine to Nor-adrenaline
D. None of the above
118. Magnesium sulphate has following properties EXCEPT:
A. Euthanizing agent
B. Purgative
C. Muscle relaxant
D. Analeptic
119. Which one of the following has maximum natriuretic effect?
A. Spironolactone
B. Frusemide
C. Mannitol
D. Acetazolamide
120. Which one of the following is an example of physical antagonism?
A. Use of activated charcoal in poisoning cases
B. Use of antacids to neutralize gastric acidity
C. Use of atropine in organophosphate poisoning
D. Use of yohimbine in xylazine overdose
121. In simple terms, pharmacokinetics is study of effect of:
A. Drug on another drug
B. Drug on body
C. Body on drug
D. All of the above
122. Reserpine, an anti-hypertensive alkaloid is obtained from medicinal plant:
A. Ocimum sanctum
B. Adhatoda vasica
C. Leptadenia reticulate
D. Rauwolfia serpentina

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123. Half-life of a drug is calculated by formula:
A. 0.693 / â
B. AUC (P.O.) / AUC (I.V.)
C. Dose / AUC x â
D. F x dose / AUC
124. Drug metabolism involving conjugation through acetylation is absent in:
A. Horse
B. Dog
C. Cat
D. Pig
125. Drug reducing anxiety with little sedation without affecting consciousness is:
A. Narcotics
B. Ataratics
C. Soporifics
D. Sedatives
126. An injection of local anaesthetic into CSF within subarachnoid space is called:
A. Topical anaesthesia
B. Nerve block anaesthesia
C. Infiltration anaesthesia
D. Spinal anaesthesia
127. Replacement of oxygen by =NH group at carbon 2 of barbituric acid:
A. Increase potency
B. Increase duration of action
C. Decrease potency
D. Destroy activity
128. Antagonism between heparin and protamine is an example of:
A. Functional antagonism
B. Competitive antagonism
C. Chemical antagonism
D. Physiological antagonism
129. Most effective drug for induction of sedation in ruminants:
A. Diazepam
B. Medetomidine
C. Triflupromazine
D. Xylazine
130. Potentiation of local anesthesia can be achieved by co-administration of:
A. Atropine
B. Adrenaline
C. Acetylcholine
D. All of the above
131. Irritant and non-isotonic drug solutions are injected by:
A. Intravenous route
B. Intramuscular route
C. Subcutaneous
D. Intraperitoneal route
132. Sudden death due to chloral hydrate anesthesia in horses occurs due to:
A. Cardiac failure

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 B. Renal failure
C. Respiratory failure
D. Hepatic failure
133. Death in chloroform anesthesia occurs due to:
A. Respiratory failure in acute over dosage.
B. Cardiac arrest during induction.
C. Hepatotoxicity
D. All of the above.
134. Following has ultra-short duration of anesthetic action:
A. Phenobarbital sodium
B. Thiopentol sodium
C. Amobabbital sodium
D. Pentobarbital sodium
135. Terms related to drugs acting on digestive system except:
A. Antacids
B. Anticarminative
C. Analeptics
D. Antizymotics
136. Species which is most sensitive to sedative action of xylazine:
A. Dog
B. Cat
C. Horse
D. Cow
137. Droperidol – fentanyl citrate is combined in the ratio of:
A. 1:5
B. 5:1
C. 1:50
D. 50:1
138. More selective COX-2 inhibitor is:
A. Meloxicam
B. Aspirin
C. Paracetamol
D. Phenylbutazone.
139. Most potent mu, kappa, and delta opioid receptor agonist is:
A. Morphine
B. Etorphine
C. Naltrexone
D. Fentanyl
140. Drug which interfere with uptake and binding of norepinephrine in storage vesicles:
A. Reserpine
B. Gaunethidine
C. 6-hydroxydopamine
D. Bretylium
141. A selective â2 agonist is:
A. Tyramine
B. Dobutamine
C. Salbutamol

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 D. Clonidine
142. Immediate precursor of Norepinephrine is:
A. Tyrosine
B. Dopamine
C. Adrenaline
D. DOPA
143. A selective á-1 receptor antagonist is:
A. Yohimbine
B. Atenolol
C. Pindolol
D. Prazosin
144. Effects of stimulation of muscarinic receptors on cardiovascular system:
A. Vasodilation
B. Positive chronotropic and ionotropic
C. Decrease in cardiac output
D. All of the above
145. Drug of choice in Anaphylactic shock:
A. Isoproterenol
B. Norepinephrine
C. Carbidopa
D. Epinephrine
146. Followings are pharmacological effects of Atropine EXCEPT:
A. Decrease GIT motility
B. Miosis
C. Relaxation of bronchial smooth muscles
D. Reduce salivary secretions
147. A proton pump inhibitor used to treat gastroesophageal reflux disease (GERD) is:
A. Ondansetron
B. Fomatidine
C. Domperidone
D. Omeprazole
148. Antagonist of Nm receptor is:
A. Tubocurarine
B. Hexamethonium
C. Trimethaphan
D. All of the above
149. Following drug produces prokinetic effect:
A. Cimetidine
B. Metaclopramide
C. Prochlorperazine
D. Ameprazole
150. The drug of choice to treat status epilepticus in dogs is:
A. Acepromazine
B. Phenobarbitone
C. Diazepam
D. Potassium bromide

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Class Notes- VPT 321

ANS PHARMACOLOGY
Brain
Central Nervous
System
Spinal Cord

Nervous System
Sympathetic
Nervous System
Autonomic
Nervous System
Peripheral Parasympathetic
Nervous System Nervous System
Somatic Nervous
System

Term ANS given by LANGLEY (1908) as ANS supplies nerve fibres to visceral organs
which have some autonomicity.
Autonomic Nervous System: (Autonomic=Visceral=vegetative)
Controls involuntary functions of the body.
It supplies it’s fibres to all organs except skeletal muscles
[Auto= self, Nomos= Governing]
So self regulating the functions of visceral organs thereby maintains the homeostasis or vital
functions of the body like thermoregulation, blood pressure, cardiac function, digestion,
urination, defecation.
Comparison of autonomic and somatic nervous system:

Particular Autonomic Nervous System Somatic Nervous System

Supply All peripheral structures except Skeletal system
1
skeletal muscles
2 Synapse Outside CNS Within CNS
3 Ganglion Contain Ganglion No any Ganglion
Formation of Many Autonomic fibres form Absent
4
plexus plexus/network
Type/nature of Preganglionic Myelinated All are Non-myelinated
5
fibre Postganglionic Nonmyelinated
Nerve Organs does not undergo Complete paralysis & atrophy
6
degeneration atrophy of skeletal muscle
7 Neurotransmitters Acetylcholine or adrenaline Acetylcholine
8 Nature of work Involuntary Voluntary

Divisions of Autonomic Nervous System:

Divided into 2 main divisions: sympathetic & parasympathetic.
Two divisions differ from each other: Anatomically, physiologically,
pharmacologically.

By Dr. H. B. Patel & Satyajeet Singh ~2~

Class Notes- VPT 321

Organs with both Sympathetic & Heart, Intestinal smooth muscles

Parasympathetic supply
Organs with only Sympathetic supply Many Blood vessels, sweat gland, Haair
follicles
Organs with only Parasympathetic supply Ciliary muscle, Gastric & Pancreatic gland

General considerations about ANS:

All Autonomic fibres have 2 neurons. I.e. Preganglionic & Postganglionic.

Cell body (cyton) of Preganglionic fibres are located within CNS i.e. Cerebrospinal
Axis.
Axon of Preganglionic neurons forms synapse with cell body of Postganglionic nerve
fibres outside CNS within Autonomic Ganglions.
Autonomic ganglion is specialised nodular structure comprising neurons (>1,00,000).
It occurs outside the Cerebrospinal Axis.
Neurons that are before the autonomic ganglion are called as Preganglionic Neurons
and which are after autonomic ganglion are called as Postganglionic Neurons.
After forming synapse with Preganglionic neurons, the Postganglionic neurons travels
and innervates effector organs (e.g. smooth muscles, heart) called effectors.
Junction of pre and postganglionic nerve fibres is called as Synapse. There is always a
gap of 200-400A° between two neurons. This gap is known as Syneptic Cleft.
Junction of Postganglionic nerve fibres to its effector organ is known as Neuroeffector
Junction/Neuromuscular Junction.
Nerve membrane/terminal prior to the synapse is known as Pre Synaptic Membrane.
Nerve membrane after synapse is known as Post Synaptic Membrane/Post Junctional
Membrane.
Passage of nerve impulse along the axon is electrical in nature, called as Conduction.
Passage of nerve impulse across the synapse is known as Neurotransmission.
Nerves that release the Acetylcholine (Ach) as a neurotransmitter are called as
Cholinergic Nerves.
Nerves that release the Nor-adrenaline or Adrenaline are called as Nor-adrenergic or
Adrenergic Nerves.

General functions of Autonomic Nervous System:

Sr. Sympathetic Nervous System Parasympathetic Nervous System

No
1 Functions mainly for:
Not essential for life under
laboratory conditions. Organised/localised discharge
But in case of stress condition the Not for mass response
function of Sympathetic Nervous Conservation/restoration of energy.
System is essential.

By Dr. H. B. Patel & Satyajeet Singh ~3~

Class Notes- VPT 321

2
Absorption of nutrients.

3
This occurs in conditions whenever In Rest & Digest conditions
there is a threat to life/stress. Prepare
body for fight or flight response

4 Anabolic function (Conservation of

Catabolic function (Expenditure of energy)
energy)
5 Heart Rate
Heart Rate
6 Blood pressure
Blood Pressure
7 Constriction of pupil.
Dilatation of Pupil
8 Constriction of Bronchi.
Dilatation of Bronchi.
9
Peristalsis & Tone (so Constipation) Peristalsis & Tone (so Diarrhoea)

10
Salivation (so Dryness in Mouth) Salivation

11
Sweat secretion Sweat secretion

12
Respiration Respiration

13
Urinary Output Urinary Output

14
Blood supply to skeletal muscle Blood supply to skeletal muscle

15
Blood supply to visceral organs Blood supply to visceral organs

16
It has Ganglion close to spinal cord. The Ganglia are far away from the
spinal cord & close to or within the
effectors.

17
Blood supply shifted from peripheral
organs to heart, brain, lung, skeletal
muscle.

By Dr. H. B. Patel & Satyajeet Singh ~4~

Class Notes- VPT 321

18
More blood supply/RBCs to general
circulation from spleen.

19. Release of glucose

(Hyperglycaemia).

The neurotransmitter of the

Preganglionic sympathetic neurons
is Acetylcholine (ACh) Neurotransmitter is only the
The neurotransmitter released by the Acetylcholine on both pre and
20.
Postganglionic sympathetic neurons postsynaptic parasympathetic
is Noradrenaline. there is one ganglion.
exception: the sympathetic post-
ganglionic neurons of the sweat
glands release acetylcholine
In general the functions of sympathetic and parasympathetic nervous system are viewed as
Antagonist but there are some exceptions:
1) Independent & different
2) Interdependent & integrated
3) Complementary
o Antagonist: e.g. Heart/pupil
Sympathetic------ Heart Rate, Dilates Pupil
Parasympathetic--- Heart Rate, Constricts Pupil

o Complementary/Interdependent: e.g. Male sex organ

Parasympathetic----- Erection of penis
Sympathetic--------- Ejaculation

o Independent: e.g. Blood Vessels

Control of Blood Pressure Peripheral Vasoconstriction is through Sympathetic
system (No Parasympathetic system)

Neurotransmitter: Chemical substance that releases in synapse and carry the impulses.
Depending upon receptors and transmitters there may excitation or inhibition of post synaptic
neuron. If receptors are excitatory then excitation and if receptors are inhibitory then
inhibition of post synaptic neuron will occur. Two important NTs of Autonomic Nervous
System are Acetylcholine (Ach) & Nor-adrenaline.

Conduction Neurotransmission

Require physical media for propagation Propagation without any physical media

No requirement of nerves, requirement of

Require nerves
chemical

By Dr. H. B. Patel & Satyajeet Singh ~5~

Class Notes- VPT 321

Neuromodulators Neurotransmitter
Chemical substances transmit nerve
Nerves participate in the transmission of
impulses across the synapse.
nerve impulses.
Chemical substance on reaching post
synaptic membrane excites or inhibits
They control the release of
post synaptic membrane and cause
Neurotransmitters.
transmission of nerve impulses.
Process is very fast.
Process is slow.
E.g. acetylcholine, adrenaline.
E.g. prostaglandins.

Neuromodulators: Chemical substances produced by cells but

Not participate into Neurotransmission directly.
Control release of NTs.
Produced by non-synaptic site.
Process is slow & involves cascade of intercellular processes and messengers.
E.g. Prostaglandins (PGs), peptides, Adenosine, Arachidonic acid

Neuromediators: Enhance the postsynaptic response of specific NTs. E.g. cAMP, cGMP,
DAG

Co-Transmitters: when neuron releases more than one Neurotransmitters/Neuromodulators,

both are required to produce effects, then NTs are called as co-Transmitters.

----------------------------------------------------------------------------------------------------------------

Neurotransmissions:

Passage of nerve impulse across the synapse is known as Neurotransmission.

Steps in Neurotransmission (6 steps in sequences)

1. Axonal conduction
2. NT release
3. Receptor events
4. Post synaptic Response
5. Destruction of NTs.
6. Non electrogenic activities.

By Dr. H. B. Patel & Satyajeet Singh ~6~

Class Notes- VPT 321

1. Axonal Conduction: passage of impulse along on Axon is known as Axonal

Conduction.
Steps in Axonal Conduction:
a) Resting Membrane Potential= -70mV
b) Due to stimuli RMP become zero due to movement of Na+ inside.
(positivity/Depolarization)
c) Rapidly K+ move out followed by Na+ move out so again negativity (-ve) so
Hyperpolarization.
d) Gradually K+ re-enters in cells & re-established RMP.

In this way Action Potential is generated at the point of stimulus

So local part of Neuron /nerves get excited

This excited part conducts the Action Potential to adjacent parts

In this way impulse conduction occurs.

Tetradotoxin:(Puffer fish poison) it will cause blockage of Axonal conduction by blocking

the Voltage sensitive Na channels, so blocks entry of Na+ thus inhibit generation of Action
Potential.

Bratrachotoxin :(an alkaloid toxin from south American frog) it causes increase Na+ entry
into the nerve causing persistant Depolarization and Axonal conduction.

2. Neurotransmitter Release:
o Action Potential arrives at nerve terminals
o Depolarization of nerve membrane at terminals
o Ca++ enter into cell from ECF
o Ca++ causes fusion of vesicles to Axoplasmic Membrane.
o Release of contents of vesicles (NTs/Enzymes/proteins) into Synaptic Cleft by
process of exocytosis.

NTs are synthesized by cells using enzymes and stored in Granules or Vesicles inside the
cells/neurons in inactive or bound forms. This process is Ultrafast/Supersensitive.

3. Receptor Events:
Once NT released, it diffuse across the Synaptic Cleft/junctional Tissues and combines
with receptors located on Post synaptic membrane.
This interaction of NT & Receptor may initiates two types of effects i.e. Excitatory
[Excitatory Post Synaptic Potential (EPSP)] and Inhibitory [Inhibitory Post Synaptic
Potential (IPSP)].

4. Post Synaptic Response: Depending upon EPSP & IPSP (Receptor-NT interaction), it
may produce excitation or inhibition on cells/effector organs.

By Dr. H. B. Patel & Satyajeet Singh ~7~

Class Notes- VPT 321

If EPSP-- reaches Post Synaptic Membrane in neurons or skeletal muscle or cardiac

muscle (Effector organ) there is muscle contraction, muscle tone, secretion of glands
in periphery.
If IPSP-- no initiation of Action Potential, so no excitation in effector organs and
inhibitory effect is observed

5. Destruction of Neurotransmitter: For rapid action of NT, its action must be

terminated.
3 ways to terminate the action of NT:
I. Metabolic Degradation: Some specific enzymes inactivate the NTs. These
enzymes are produced by Pre synaptic membranes or by synaptic tissues. For
e.g.
o Ach hydrolysed by Acetylcholinesterase (AchE).
o Nor-adrenaline hydrolysed by COMT & MAO.
COMT= Catecholamine o-methyl transferase (causes extraneural hydrolysis)
MAO= Monoamine Oxidase (causes intraneural hydrolysis)
End product of Nor-adrenaline oxidation by MAO is VMA (Vanillylmandelic Acid).

II. Reuptake: Certain NTs after their release are taken back into Pre Synaptic
Membrane by specific carrier. E.g. Nor-adrenaline reuptake by nerve cells
terminates its action at synapse.
III. Diffusion: Small amount of NTs are diffused by surrounding tissues &
metabolised locally. E.g. Peptide NTs & Peptidase enzyme.

6. Non Electrogenic function: During resting stage small quantity of NTs is released
continuously but not sufficient to initiate the EPSP & IPSP but require maintaining the
physiological responsiveness of cell/stimuli.
-------------------------------------------------------------------------------------------------------

Cholinergic Transmission

Neurons that release the Ach are known as cholinergic transmission. Or

Neurotransmission by Ach is known as cholinergic transmission.

Sites where Ach acts as NT:

Autonomic ganglion both Sympathetic & Parasympathetic.

Adrenal medulla
Somatic nerves of skeletal muscles.
CNS
Preganglionic Sympathetic Nerve Fibres
Pre & Postganglionic Parasympathetic Nerve Fibres

By Dr. H. B. Patel & Satyajeet Singh ~8~

Class Notes- VPT 321

Biosysnthesis/Storage/Release of Ach:

Acetic acid + ATP Acetyl AMP

Acetyl AMP + CoA Acetyl CoA

Choline Acetyltransferase (CAT or ChAT)
Acetyl CoA + Choline Acetylcholine + CoA

Choline is supplied from Vitamine-B complex from extraneural sources.

ATP is derived from Carbohydrate.
CoA is derived from minerals & proteins.

Ach synthesis occurs in axon.

Acetyl CoA is synthesized in Neurons. (Hemicholium & Triethylcholine blocks
Choline transferse)
After synthesis, Ach is stored into storage vesicles.
When Action Potential/Nerve Impulse arrives at the nerve terminals

Ca++ Channels Open

Increase Influx of Ca++

Increased concentration of Ca++ causes fusion of vesicles with cell membrane

Exocytosis of vesicles occurs

Discharge of Ach into synapse

Vesamicol: inhibit uptake of Ach into vesicle leading to empty vesicles fusing with neuron
membrane. It is Cholinergic Antagonist. It does not act at Post synaptic Ach Receptors.

Botulinum & Bungarotoxin: it inhibits release of Ach into synaptic cleft. Bungarotoxin is a
snake venom of krait(Bungarus multicinctus).
α-Bungarotoxin: Binds irreversibly & competitively to Ach Receptor.
β-Bungarotoxin: Target is Pre Syneptical Terminal where it cause exhaustion of Ach stores
by binding to actin protein.

Black widow spider & Ciguatoxin: initially increase release of Ach and later
decrease release of Ach. Black widow spider is the common name of some spiders in
the Genus latrodactus. Ciguatoxin is fish poison which causes Ciguatera.

Receptor Events:

By Dr. H. B. Patel & Satyajeet Singh ~9~

Class Notes- VPT 321

Released Ach diffuse across synapse & combines with receptors located on Post
Synaptic Membrans/Pre Synaptic Membrane.
Interaction with receptors initiates the biological events depending upon the nature of
receptors.
After their action with receptors (Action of Ach with Receptor lasts only for 2
mSecond.), dissociated or hydrolysed into Choline & Acetyl CoA by enzyme
Acetylcholinesterase.
Acetylcholinesterase (AchE)
Acetylcholine (Ach) Acetyl CoA + Choline

Two types of AchE enzyme: (on Enzyme Specificity)

Pseudo/Non Specific /Butyryl
True/Acetylcholinesterase cholinesterase
Enzyme
All body tissues, RBCs. Blood, Plasma, Liver, Urine.
1.
AchE hydrolyses Ach at faster BchE hydrolyses Bch & Benzylcholine
2. rate. at faster rate.
Not hydrolyses Bch & Slowly hydrolyses Ach.
3. Benzylcholine.

Organophosphorus compounds: inhibits AchE & BchE enzyme.

Neostigmine/Physostigmine: inhibits AchE enzyme

Cholinergic transmission

Acetylcholine (ACh) synthesis:

o Requires choline, which enters the neuron via carrier-mediated transport
o Requires acetylation of choline, utilising acetyl coenzyme A as source of acetyl groups, and
involves choline acetyl transferase, a cytosolic enzyme found only in cholinergic neurons.
ACh is packaged into synaptic vesicles at high concentration by carrier-mediated transport.
ACh release occurs by Ca2+-mediated exocytosis. At the neuromuscular junction, one presynaptic nerve
impulse releases 100-500 vesicles.
At the neuromuscular junction, ACh acts on nicotinic receptors to open cation channels, producing a
rapid depolarisation (endplate potential), which normally initiates an action potential in the muscle
fibre. Transmission at other 'fast' cholinergic synapses (e.g. ganglionic) is similar.
At 'fast' cholinergic synapses, ACh is hydrolysed within about 1 ms by acetylcholinesterase, so a
presynaptic action potential produces only one postsynaptic action potential.
Transmission mediated by muscarinic receptors is much slower in its time course, and synaptic
structures are less clearly defined. In many situations, ACh functions as a modulator rather than as a
direct transmitter.

Main mechanisms of pharmacological block: inhibition of choline uptake, inhibition of ACh release,
block of postsynaptic receptors or ion channels, persistent postsynaptic depolarisation

By Dr. H. B. Patel & Satyajeet Singh ~ 10 ~

Class Notes- VPT 321

Adrenergic Transmission

Transmission mediated by Nor-adrenaline or Nor-epinephrine at Postganglionic

Sympathetic Nerve Terminals (except Sweat gland in mare & dogs) is known as
Adrenergic Transmission.
Or
Transmission mediated by Nor-adrenaline & Dopamine is known as Adrenergic
Transmission.

Site of action is Postganglionic Sympathetic Nerve Fibres.

3 Steps:
1) Synthesis of Nor-adrenaline.
2) Storage & Release of Nor-adrenaline.
3) Disposition/Destruction of Nor-adrenaline.

1) Synthesis of Nor-adrenaline:
Site: Adrenergic nerves
Precursor: Phenylalanine (Taken up from ECF)
Phenylalanine

Phenylalanine hydroxylase

Tyrosine

In Axoplasm (Rate limiting step) Tyrosine hydroxylase

DOPA (Dihydroxy Phenylalanine)

Dopa decarboxylase

Dopamine

Dopamine β-hydroxylase

In synaptic vesicle Nor-epinephrine

Phenylethanolamine N-methyl transferase

Epinephrine

o Phenylalanine essential amino acid- converted into tyrosine in LIVER

o DOPA decaboxylase- Histamine, 5-HT synthesis also require

By Dr. H. B. Patel & Satyajeet Singh ~ 11 ~

Class Notes- VPT 321

o Synthesis upto Dopamine occur in Axoplasm.

o Dopamaine enter into vesicles & converted into Nor-adrenaline by Dopamine
β-hydroxylase.
o α-methyl tyrosine inhibits tyrosine hydroxylase & block Epinephrine/Nor-
epinephrine synthesis.
o Carbidopa Dopa decrboxylase inhibited- used in the treatment of
Parkinson disease.
o α-methyldopa analogue to Dopa forming methylnephrine which is
false transmitter of Nor-epinephrine so loss of functions.

2) Storage & release of Nor-adrenaline:

o In nerve cells, Nor-epinephrine is stored in Synaptic Vesicles along with ATP.
(in Adrenal medulla Chromaffin Cells)
o Action potential arrives, Ca+2 inflow is enhanced so granules release Nor-
epinephrine by exocytosis in synaptic cleft.
o There is a self regulatory/Feed Back mechanism in Nor-epinephrine release.
o Other Neuromodulators, Ach, Nor-epinephrine (NE), Epinephrine, 5-HT, PGE,
Histamine, Dopamine, & ATP decreases Nor-epinphrine release through
various specific responses.

Autoregulation how it occurs?

NE released in Synapse combines with Presynaptic α-2 Receptor no formation of
cAMP closing of Ca+2 gated channels & resultant failure of exocytosis.

3) Destruction/Disposition of Nor-adrenaline:
Enzymes:
In mitochondria Liver & Intestinal epithelium

MAO (intracellular)
Axoplasmic degradation in Adrenergic Nerve Terminal

COMT (extracellular) neural and Non-neural tissues (circulatory degradation)

Pheocytochroma:- Tumour of Adrenal gland

MAO Antidepressent action

Termination of action of NE is mainly by reuptake of NE into Presynaptic Vesicles. From

where
a. 60% reuptake into vesicles (as it was)
b. 20% reuptake into Extraneural tissues & enzymatic breakdown by COMT
c. 5% bind with receptors
d. 15% metabolised by MAO.

By Dr. H. B. Patel & Satyajeet Singh ~ 12 ~

Class Notes- VPT 321

Noradrenergic transmission

Transmitter synthesis involves the following.

o L-tyrosine is converted to dihydroxyphenylalanine (dopa) by tyrosine hydroxylase
(rate-limiting step). Tyrosine hydroxylase occurs only in catecholaminergic neurons.
o Dopa is converted to dopamine by dopa decarboxylase.
o Dopamine is converted to noradrenaline by dopamine β-hydroxylase (DBH), located
in synaptic vesicles.
o In the adrenal medulla, noradrenaline is converted to adrenaline by
phenylethanolamine N-methyl transferase.
Transmitter storage: noradrenaline is stored at high concentration in synaptic vesicles,
together with ATP, chromogranin and DBH, all of which are released by exocytosis.
Transport of noradrenaline into vesicles occurs by a reserpine -sensitive transporter.
Noradrenaline content of cytosol is normally low due to monoamine oxidase in nerve
terminals.
Transmitter release occurs normally by Ca2+-mediated exocytosis from varicosities on the
terminal network. Non-exocytotic release occurs in response to indirectly acting
sympathomimetic drugs (e.g. amphetamine), which displace noradrenaline from vesicles.
Noradrenaline escapes via uptake 1 (reverse transport).
Transmitter action is terminated mainly by transporter-mediated reuptake of noradrenaline
into nerve terminals (uptake 1). Uptake 1 is blocked by tricyclic antidepressant drugs and
cocaine.
Noradrenaline release is controlled by autoinhibitory feedback mediated by α2 receptors.
Cotransmission occurs at many noradrenergic nerve terminals, ATP and neuropeptide Y
being frequently coreleased with NA. ATP mediates the early phase of smooth muscle
contraction in response to sympathetic nerve activity

Receptors of ANS

1. Cholinergic Receptor (Cholinoreceptor)

2. Adrenergic Receptor (Adrenoreceptor/sympathetic Receptor)

By Dr. H. B. Patel & Satyajeet Singh ~ 13 ~

Class Notes- VPT 321

1. Cholinergic Receptors

Cholinergic
Receptor

Muscarinic Nicotinic

Muscle
M1 M2 M3 M4 M5 Type (Nm) Neuronal
Type (Nn)
-on
Skeletal - on
muscle Neuronal
tissues

o Muscarinic Muscarine (alkaloid obtained from mushroom Amontia

muscaria)
o Nicotinic Nicotine (alkaloid obtained from leaves of Nicotiana tabacum)
o Muscarinic receptors (mAChR) are G-protein Coupled Receptors (M1. M3,
M5 activates Gs while M2, M4 activates Gi)
o Nicotinic receptors (nAChR) are Ligand Gated Ion Channels, activation of
which results in depolarization & excitation.
o G-protein coupled receptors (GPCRs) also called 7TM (7 Transmembrane
receptor) is the family of Transmembrane Receptors.

I. Nicotinic Receptors: (nAChR)

Mechanism of action of Nicotinic Receptors:

Nicotinic Receptors combine with Ligand Gated Ion Channels

Ach binding induces conformational changes in Receptor proteins

Pore is created

Na+ enters via pores

Depolarization

Contraction of skeletal muscle

Stimulation of Postganglionic Nerve
Secretion of Adrenaline from adrenal medulla
Usually these Nicotinic Receptors do not respond to low dose of Ach.
Nicotinic Receptor produces effect exactly like consumption of Nicotine.

By Dr. H. B. Patel & Satyajeet Singh ~ 14 ~

Class Notes- VPT 321

Nicotinic Receptor
Agonist Antagonist
type
d- Tubocurarine
Acetylcholine
Pancuronium
Carbachol
Nm
Atracuronium
Suxamethonium
α-Bungarotoxin
Decamethonium
Trimethaphan
Acetylcholine
Mecamylamine
Carbachol
Nn
Hexamethonium
Cobeline

Cytisine(Baphitoxin/Sophorine)

II. Muscarinic Receptors: (mAChR)

Five types:
Nature
of Location Effect
Receptor
o Autonomic ganglion,
M1 o Gastric glands, Adrenaline & HCl secretion
excitatory
o CNS
o Heart, Heart rate,
M2 o GIT, Force of contraction,
inhibitory
o CNS NE release
o contraction of
bronchiole & GIT but
o Smooth muscles of viscera exception in blood
(Bronchi, GIT, Urinary vessels where relaxation
M3 excitatory tract & Blood vessels) i.e. dilatation
o Glands o stimulate salivary,
bronchial, lacrimal &
sweat gland
o Lungs
M4 inhibitory o CNS
o Eyes
M5 o Salivary glands
excitatory
o CNS

Mechanism of Action of M1, M3, M5:

By Dr. H. B. Patel & Satyajeet Singh ~ 15 ~

Class Notes- VPT 321

M1, M3, M5 stimulate the GPCRs (Gs)

Activation of Phospholipase C

Increase in the concentration of

Inositoltriphophate (IP3)

Increase in the concentration of Diacyl Glycerol (DAG)

( Conc. Of DAG Ca+2 concentration contraction of smooth muscles
secretion of gland)

Activation of Protein Kinase C

Further biological response

Mechanism of Action of M2, M4:

M2 & M4 stimulate the GPCRs (Gi)

Inhibit Adenylcyclase

K+ channels become activated

Ca+2 channels blocked

Negative effect on the heart rate & contraction

G-Protein Coupled Receptors
Agonist + Receptor ------ Binding

Phospholipase C

Phospholipids Phospholipase C IP3 + DAG

( Ca+2 releases from ER) (Stimulate protein
Kinase C)

Agonist Antagonist

Acetylcholine
Pirenzepine
M1 Oxotremorine

By Dr. H. B. Patel & Satyajeet Singh ~ 16 ~

Class Notes- VPT 321

Gallamine
M2 methacholine
Himbacine
M3 Bethanechol

Acetylcholine receptors

Main subdivision is into nicotinic (nAChR) and muscarinic (mAChR) subtypes.

nAChRs are directly coupled to cation channels, and mediate fast excitatory synaptic
transmission at the neuromuscular junction, autonomic ganglia, and various sites in the
central nervous system (CNS). Muscle and neuronal nAChRs differ in their molecular
structure and pharmacology.

mAChRs and nAChRs occur presynaptically as well as postsynaptically, and function to

regulate transmitter release.

mAChRs are G-protein-coupled receptors causing:

o activation of phospholipase C (hence formation of inositol trisphosphate and

diacylglycerol as second messengers)

o inhibition of adenylyl cyclase

o Activation of potassium channels or inhibition of calcium channels.

mAChRs mediate acetylcholine effects at postganglionic parasympathetic synapses (mainly

heart, smooth muscle, glands), and contribute to ganglionic excitation. They occur in many
parts of the CNS.

Three main types of mAChR occur.

o M1 receptors ('neural') producing slow excitation of ganglia. They are selectively

blocked by pirenzepine.

o M2 receptors ('cardiac') causing decrease in cardiac rate and force of contraction

(mainly of atria). They are selectively blocked by gallamine. M2 receptors also
mediate presynaptic inhibition.

o M3 receptors ('glandular') causing secretion, contraction of visceral smooth muscle,

vascular relaxation.

M4 and M5, occur mainly in the CNS.

All mAChRs are activated by acetylcholine and blocked by atropine.

2. Adrenergic Receptors

2 types and many subtypes

By Dr. H. B. Patel & Satyajeet Singh ~ 17 ~

Class Notes- VPT 321

Adrenergic Receptor

α β

α1 α2 β1 β2 β3

α2-inhibits Adenylcyclase
all β subtypes stimulates Adenylcyclase (producing cAMP & protein kinase- A)

Recept
Agonist antagonist Location Effect
or

Smooth
Vasoconstriction
muscles of
Blood vessels, Constriction of
Uterus
Bronchi,
Uterus Relaxation of GIT
muscle
α1 Phenylephrine Prazosin Sphincter
muscle of GIT Constriction of
Urinary Bladder
Sphincter
muscle of Secretion of Gland
urinary system Constriction of Iris
Iris Radial Radial muscle
muscle
Relaxation of GIT
muscle
Constriction of
GIT smooth vascular smooth
muscles muscle
Blood vessels Decrease insulin
α2 Clonidine Yohimbine secretion from β-
β cells of
cells of pancrease.
pancrease
Inhibition of NT
Brain stem
release
Platelets
Produce platelet
aggregation

Heart
Increase Heart Rate
Salivary
β1 Dobutamine Metoprolol Increase Rennin
glands
secretion.
JG cells of
kidney

By Dr. H. B. Patel & Satyajeet Singh ~ 18 ~

Class Notes- VPT 321

Bronchodialation
Vasodilation
Bronchi Relaxation of GIT
Blood vessels Relaxation of uterus
β2 Terbutaline Butoxamine GIT & urinary bladder
Uterus Hepatic
Urinary glycogenolysis
bladder Inhibition of
Histamine release
β3 Lipolysis
Adipose tissue

Note: β-blockers are used to reduce performance related anxiety. E.g. Diazepam (β-
blocker)

All α-Receptors are : Excitatory (except in GIT)

All β-Receptors are : Inhibitory (except in Heart)

Classification of adrenoceptors

Main pharmacological classification into α and β subtypes, based originally on order of

potency among agonists, later on selective antagonists.
Adrenoceptor subtypes:
o two main α-receptor subtypes, α1 and α2, each divided into three further subtypes
o three β-adrenoceptor subtypes (β1, β2, β3)
o All belong to the superfamily of G-protein-coupled receptors.
Second messengers:
o α1-receptors activate phospholipase C, producing inositol trisphosphate and
diacylglycerol as second messengers
o α2-receptors inhibit adenylate cyclase, decreasing cAMP formation
o All types of β-receptor stimulate adenylyl cyclase.
The main effects of receptor activation are as follows.
o α1-receptors: vasoconstriction, relaxation of gastrointestinal smooth muscle, salivary
secretion and hepatic glycogenolysis
o α2-receptors: inhibition of transmitter release (including noradrenaline and
acetylcholine release from autonomic nerves), platelet aggregation, contraction of
vascular smooth muscle, inhibition of insulin release
o β1-receptors: increased cardiac rate and force
o β2-receptors: bronchodilatation, vasodilatation, relaxation of visceral smooth muscle,
hepatic glycogenolysis and muscle tremor

o β3-receptors: lipolysis

By Dr. H. B. Patel & Satyajeet Singh ~ 19 ~

Class Notes- VPT 321

Non-peptide Mediators: 5-Hydroxytryptamine, Dopamine, GABA, NO

Peptide Mediators: Neuropeptide, VAP (Vaso active peptides), GnRH, substance-P,

CGRPb (Calcitonin Gene Related Peptide beta), Opoid peptides.

----------------------------@@@@@@-------------------

Some Toxins act Ion Channels.

Channel Types Mode of Toxin Action Source

Voltage-gated
Sodium channels
Tetrodotoxin (TTX) Blocks channel from outside Puffer fish
Batrachotoxin (BTX) Slows inactivation, shifts activation Colombian frog
Potassium channels
Apamin Blocks "small Ca-activated" K Honeybee
channel
Charybdotoxin Blocks "big Ca-activated" K channel Scorpion
Calcium channels
Omega conotoxin ( -CTX- Blocks N-type channel Pacific cone snail
GVIA)
Agatoxin ( -AGA-IVA) Blocks P-type channel Funnel web spider
Ligand-gated
Nicotinic ACh receptor
α-Bungarotoxin Irreversible antagonist Marine snake
GABAA receptor

Picrotoxin Blocks channel South Pacific

plant
Glycine receptor
Strychnine Competitive antagonist Indian plant
AMPA receptor
Philanthotoxin Blocks channel Wasp

By Dr. H. B. Patel & Satyajeet Singh ~ 20 ~

Class Notes- VPT 321

Autonomic drugs

Sympathetic Nervous Parasympathetic

System Drugs Nervous System Drugs

Sympathomimetic Sympatholytic
Drugs Drugs
or or
Adrenomimetic Antiadrenergic
Drugs Drugs
or or
Adrenergic Drugs Adrenoreceptor
antagonist Drugs
or
or
Adrenergic agonist
Drugs Adrenergic
antagonist Drugs
or
or
Sympathoplegic
drugs

Parasympathomimetic
Drugs Parasympatholytic
or Drugs
Cholinomimetic Drugs or
or Cholinolytic
Cholinergic agonist Drugs
Drugs or
or Cholinergic
Cholinergic Drugs antagonist Drugs
or or
Cholinoreceptor agonist Anticholinergic
Drugs Drugs

By Dr. H. B. Patel & Satyajeet Singh ~ 21 ~

Class Notes- VPT 321

Sympathomimetic Drugs

Drugs which mimic the action of sympathetic nervous system are called as
sympathomimetics.
They produce effect similar to epinephrine or norepinephrine on animal body.
These drugs mediate their action through adrenoreceptors (α & β) so they are called
as adrenergic drugs.
These adrenergic drugs are classified into 3 categories:
1. Direct acting
2. Indirect acting
3. Mixed acting

1. Direct acting
Drugs which directly act on α & β receptors. These are classified as
1) α- Agonist
2) β- Agonist
3) Mixed Agonist

1) α- Agonist: Drugs which selectively act on α- Receptor.

It includes:

a) α1 Agonist:
E.g. Phenylephrine
Methoxamine
Cirazoline
Xylometazoline
Noradrenaline
Phenylephrine & Methoxamine produce constriction of bronchiole. So used
in nasal decongestant (in cold, allergy, inflammation, pain in nasal tract) and
hypotensive crisis (severe fall in B.P).

b) α2 Agonist:
E.g. Clonidine
Xylazine
Guanafacine
Guanabenz
Detomidine
Remifidine
Oxymetazoline
These drugs are used in chronic diarrhoea to reduce frequency of diarrhoea
because in chronic diarrhoea nerves get damage so motility of GIT increases.
These drugs reduce tone and motility of GIT due to relaxation of GI smooth
muscles & constriction of sphincter.

By Dr. H. B. Patel & Satyajeet Singh ~ 22 ~

Class Notes- VPT 321

2) β- Agonist: Drugs which selectively act on β- Receptor.

It includes:

a) β1 Agonist:
E.g. Dobutamine
Isoproterenol
These stimulate heart so used in cardiac failure.

b) β2 Agonist:
E.g. Terbutaline
Salbutamol
Retodrine
Metaproterenol
Terbutaline & Salbutamol act in bronchiole & produce inhibitory effect so,
bronchiole dialates & animal get relief from cough, asthma etc. So they are
common in cough syrup.
Retodrine is used in females in premature labour. (as Tocolytic drug)

c) Mixed agonist: drugs which non selectively act on α & β receptor.

2. Indirect acting:
They act indirectly on α & β receptors.
E.g. Amphetamine
Tyramine
Amphetamine is used in hypotensive crisis.
Amphetamine is misused to reduce body weight in humans.
Amphetamine and tyramine are used in ADHD (Attention Deficit Hyperactivity
Disorder.) E.g. DYSLAXIA in which person know everything but not able to
express.

3. Mixed acting:
They can act both directly and indirectly.
E.g. Ephedrine
Mephetramine
Metraminol
Mephetramine is used in hypotensive crisis.
Relative Selectivity of Adrenoceptor Agonists

Relative Receptor Affinities

Alpha agonists

By Dr. H. B. Patel & Satyajeet Singh ~ 23 ~

Class Notes- VPT 321

Phenylephrine, methoxamine α1 > α2 >>>>> β

Clonidine, methylnorepinephrine α2 > α1 >>>>> β

Mixed alpha and beta agonists

Norepinephrine α1 = α2; β1 >>β2

Epinephrine α 1 = α 2; β 1 = β 2

Beta agonists

Dobutamine1 β1 > β2 >>>> α

Isoproterenol β1 = β2 >>>> α

Terbutaline, metaproterenol, albuterol, ritodrine β2 >> β1 >>>> α

Dopamine agonists

Dopamine D1 = D2 >> β>> α

Fenoldopam D1 >> D2

Distribution of Adrenoceptor Subtypes & Their Action

Type Tissue Actions

Most vascular smooth muscle (innervated) Contraction
Pupillary dilator muscle Contraction (dilates pupil)
α1
Pilomotor smooth muscle Erects hair
Prostate Contraction
Heart Increases force of contraction
Postsynaptic CNS adrenoceptors Probably multiple
α2
Platelets Aggregation
Adrenergic and cholinergic nerve terminals Inhibition of transmitter release

By Dr. H. B. Patel & Satyajeet Singh ~ 24 ~

Class Notes- VPT 321

Some vascular smooth muscle Contraction

Fat cells Inhibition of lipolysis
β1 Heart Increases force and rate of
contraction
Respiratory, uterine, and vascular smooth Promotes smooth muscle relaxation
muscle
β2
Skeletal muscle Promotes potassium uptake
Liver Activates glycogenolysis
β3 Fat cells Activates lipolysis

D1 Smooth muscle Dilates renal blood vessels

D2 Nerve endings Modulates transmitter release

Effect of Sympathomimetic Drugs on various systems:

1. Cardio Vascular system:

Heart rate (Positive Chronotropic effect)
Cardiac Output
Force of Contraction (Positive Inotropic effect)

2. Blood pressure:
At lower dose or slow infusion B.P

At higher dose or rapid infusion B.P

Lower dose B.P

Higher dose B.P

Above phenomenon is called as “Dale Re e al Phe e ” or

“Epinephrine Reversal”. (Epinephrine causes increase in B.P, which is followed
by decrease in B.P)
Reason of this phenomenon:
There are 2 types of receptor for the epinephrine-α & β.
α are excitatory for B.P (B.P )
β are inhibitory for B.P (B.P )
Numbers of receptors α >β
By Dr. H. B. Patel & Satyajeet Singh ~ 25 ~
Class Notes- VPT 321

Affinity of epinephrine α <β

The rise in the B.P is mediated by α-receptors as these are more in number than more
powerful & sensitive β-receptors in blood vessels. Here though β-receptors are
occupied by the drug, there effect is suppressed by activation of large number of α-
receptors.
As concentration of epinephrine is decreased by metabolism or elimination, it
dissociates first from less sensitive α-receptors. So at later stage, the numbers of
activated β-receptors remain more than activated α-receptors which causes decrease in
B.P.

If α-receptors are blocked, than B.P decreases on giving epinephrine

3. Respiratory system:
Bronchodialation by β2 receptors

4. Uterus:
By α1 & β2 receptors
Effect on uterus depends on species and stage of pregnancy.
In non pregnant uterus, it will produce the contraction.
In the last trimester of pregnancy, it will produce the relaxation of uterine muscles
that’s why it used in the treatment of premature labour. (Post partum
complication).

5. Gastrointestinal tract:
By α2 & β2 receptors
More prominent is α2
Relaxes GIT smooth muscles.
Reduces GIT motility.
Reduces gland secretion.
Facilitates contraction of sphincters.

6. Urinary bladder:
Decreases secretion due to relaxation of smooth muscles of bladder.
By Dr. H. B. Patel & Satyajeet Singh ~ 26 ~
Class Notes- VPT 321

7. Eye:
By α1 receptors
Produce dilation of pupil (mydriasis) due to contraction of radial iris muscles.
Decreases intraocular pressure especially in glaucoma

Iris Radial muscle

Iris Circular muscle

8. Effect on metabolism:
Hyperglycaemia
Hyperlipaemia
Decrease insulin secretion (α2)

9. Effect on skeletal muscles:

Increase force of contraction.
Increase thermogenesis

10. Central Nervous System:

Stimulate PNS
Restlessness
Headache
Tremor

11. Effect on other glands:

Contraction of spleen release of RBCs in circulation
Contraction of pilomotor muscle of hair follicle

Pharmacokinetics:
Though epinephrine is absorbed from the GIT, but its bioavailability is poor because it
is rapidly degraded in the intestinal wall & liver. (By MAO & COMT)

Clinical uses of adrenergic drugs:

1) For prolongation of action of local anaesthesia.
2) Used in local haemostasis.
3) Used in allergy (α1)
4) Cardiac stimulant

By Dr. H. B. Patel & Satyajeet Singh ~ 27 ~

Class Notes- VPT 321

5) Nasal decongestant. E.g. Oxymetazoline (α1)

6) In cardiac arrest. E.g. Adrenaline (β1)
7) Cardiogenic shock. E.g. Dobutamine (β1)
8) In the treatment of asthma and cough (as bronchodialator) (β2) E.g. salbutamol,
terbutaline.
9) Decrease histamine release from mast cells & help in the treatment of anaphylaxis.
E.g. sting bite
--------------------------------------------------------------------------------------------

Sympatholytic Drugs
Drugs which inhibit the effect of sympathetic neurotransmitters.
Also called adrenoreceptor blockers.
Generally known as antiadrenergic drugs.

Classification:
Mixed α1 & α2 blockers:
Phenoxybenzamine
Phentalomine
Tolazosin
Mixed β1 & β2 blockers:
Propranolol
Nadolol
Timolol
Phenbutolol

Effects:

α1 receptor blocker : B.P

α2 receptor blocker: insulin secretion
β1 receptor blocker: Heart rate
β2 receptor blocker: dilate coronary artery

By Dr. H. B. Patel & Satyajeet Singh ~ 28 ~

Class Notes- VPT 321

sympatholytics

Adrenergic Inhibition of Drug which

receptor norepinephrine Drug which interfere with
antagonist synthesis interfere with nor
nor epinephrine
e.g. epinephrine release
Metyhyldopa storage
Carbidopa
e.g. Bretylium
α-Methyltyrosine e.g. Reserpine
Guanethidine

α Blocker β Blocker

α1 antagonist
β1 antagonist

e.g.
e.g.
Prazosin
Atenolol
Terazosin
Doxazosin Esmolol
Trimazosin Metoprolol
Proctolol

α2 antagonist
β2 antagonist
e.g.
Yohimbine e.g.
Atipamezole Butoxamine

Relative Selectivity of Antagonists for Adrenoceptors

Receptor Affinity
α Antagonists
α1 >>>> α2
Prazosin, terazosin, doxazosin

α1 > α2
Phenoxybenzamine

By Dr. H. B. Patel & Satyajeet Singh ~ 29 ~

Class Notes- VPT 321

α1 = α2
Phentolamine

α2 >> α1
Yohimbine, tolazoline

Mixed antagonists
β1 = β2 ≥ α1 > α2
Labetalol

β Antagonists
β1 >>> β2
Metoprololol, atenolol, esmolol

β1 = β2
Propranolol, pindolol, timolol

β2 >>> β1
Butoxamine

Use of α receptor blockers:

Diagnosis and treatment of pheochromocytoma.

E.g. Phenoxybenzamine
Phentalomine
Tolazosin
Used in high B.P.
Use of β receptor blocker:

In hypertension, angina, cardiac arrhythmia, anxiety, tremor and glaucoma.

In treatment of hyperthyroidism.

Labetalol:

Mixed α & β receptor antagonist.

Used in hypertensive crisis

Propranolol:

Mixed β blocker
Used in ventricular fibrillation
In performance related anxiety
Dose in dog is @ 1mg/kg/day.

Methyldopa:

By Dr. H. B. Patel & Satyajeet Singh ~ 30 ~

Class Notes- VPT 321

It inhibits the conversion of dopamine to adrenaline by combining with the enzyme,

which is involving in converting dopamine to adrenaline.
Methy ldopa is used in the treatment of parkinson’s disease.

Reserpine:
It is an alkaloid obtained from Rauwolfia serpentina.
Reserpine block the uptake of catecholamines (epinephrine and norepinephrine) ,
serotonin & dopamine into synaptic vesicle by blocking the VMAT(Vesicular
Membrane-Associated Transporter) in the both CNS & PNS.
It inhibit uptake of noradrenaline or adrenaline into vesicles so, norepinephrine
remain in cytosol where it degraded by MAO.

Effects of reserpine:
It initially increases B.P then follow decrease in B.P
Used in hypertension (antihypertensive drug)
Antiserotonin, antidopamine
May cause sedation by depleting storage of catecholamines & serotonin.

Action:
Reserpine enter into neuron & break the vesicle so, no adrenaline is stored in the
vesicles.
-----------------------------------------------------------------------------
-------

By Dr. H. B. Patel & Satyajeet Singh ~ 31 ~

Class Notes- VPT 321

Parasympathomimetic Drugs
Drugs which produce Ach like action.
Generally known as cholinergic drugs

Out of two cholinergic receptors, nicotinic receptors are activated at very higher dose
while muscarinic receptors are activated at very lower dose.
Due to this reason anticholinergic drugs are often called as antimuscarinic drugs.
Antinicotinic drugs are often not used.

Cholinergic drugs

Indirect acting
Direct acting
(Act via inhibition of
(Act on N and M receptor) AChE)

Natural Reversible Agent

e.g. e.g.
Muscarine
Neostigmine
Arecoline
Physostigmine
Pilocarpine
Pyridostigmine
Nicotine
Edrophonium

Synthetic Irreversible Agent

e.g. e.g.
Acetylcholine Organophosphate
Methacholine
compounds
Bethanechol
Carbamates (malathion,
Carbachol parathion)

By Dr. H. B. Patel & Satyajeet Singh ~ 32 ~

Class Notes- VPT 321

Effect of Directly acting cholinomimetic drugs on various systems:

A. Muscarinic effect:

1. Heart/CVS:
Heart rate
Cardiac output
Blood pressure (Hypertension)
Vasodialation

2. Gastrointestinal tract:
GIT motility
Secretion

3. Respiratory system:
Bronchoconstriction
Tracheobronchial secretion

4. Urinary tract:
Contract urinary bladder & uterus & facilitate micturition.

5. Endocrine system:
Sweating
Salivation
Lacrimation

6. Eye:
Produce contraction of pupil (miosis) due to contraction in iris circular
muscles.

7. Male sex organ:

Erection of penis

8. CNS:
Muscular tremor/ fasciculations
Hypothermia
Effects of Direct-Acting Cholinoceptor Stimulants
Organ Response
Eye
Sphincter muscle of iris Contraction (miosis)

By Dr. H. B. Patel & Satyajeet Singh ~ 33 ~

Class Notes- VPT 321

Ciliary muscle Contraction for near vision

Heart
Sinoatrial node Decrease in rate (negative chronotropy)
Atria Decrease in contractile strength (negative inotropy).
Decrease in refractory period
Atrioventricular node Decrease in conduction velocity (negative dromotropy).
Increase in refractory period
Ventricles Small decrease in contractile strength
Blood vessels
Arteries Dilation (via EDRF)
Veins Dilation (via EDRF
Lung
Bronchial muscle Contraction (bronchoconstriction)
Bronchial glands Stimulation
Gastrointestinal tract
Motility Increase
Sphincters Relaxation
Secretion Stimulation
Urinary bladder
Detrusor Contraction
Trigone and sphincter Relaxation
Glands
Sweat, salivary, lacrimal, Secretion
nasopharyngeal

EDRF: endothelium-derived relaxing factor

B. Nicotinic effect:
At higher dose of acetylcholine
Stimulation of autonomic ganglia.
Stimulation of adrenaline secretion.
Increase in B.P (Hypertension)
Skeletal muscle fasciculation.
If drug persist for long time, paralysis occur.

Note: due rapid destruction & hydrolysis of Ach by endogenous esterases, it is not
used therapeutically.

By Dr. H. B. Patel & Satyajeet Singh ~ 34 ~

Class Notes- VPT 321

Behtanechol:
Structurally related to Ach.
Very little nicotinic effect.
Strong Muscarinic effect.
Not hydrolysed by AchE but not by other esterases enzymes.
Uses:
Measure effect on smooth muscle & GIT producing contraction.
Promote micturition & defaecation.

Carbachol:
Structurally related Ach.
Both Muscarinic & nicotinic effect.
Poorly hydrolysed by AchE but slowly hydrolysed by other esterase enzyme.
Uses:
It has open effect on CVS & GIT.
Produce miosis. Sometime used as ophthalmic solution (0.01%) to reduce
intraocular pressure in glaucoma.
In Intestinal colic, ruminal colic & impaction.
Note: Carbachol is very rarely used for therapeutic purpose because of high potency
& longer duration of action.

Pilocarpine:
Obtained from plant Pilocarpus microphyllus.
It has only Muscarinic effect.
It is used in treatment of wide angle glaucoma to reduce intraocular pressure
producing contraction of cilliary muscle.

Arecholine:
Obtained from seeds of Areca catechu (Beetle nut).
Both Muscarinic & nicotinic effect.
Used in the treatment of taeniasis in dog.

Muscarine:
Obtained from mushroom Amanita muscaria.
It has only muscarinic effect.

Indirectly acting cholinomimetic drugs / indirectly acting

Antiacetylcholinesterase agents:
These are indirectly acting parasympathomimetic agents.
They inhibit AchE enzyme resulting acculation of Ach at cholinergic effector site.
All of the cholinesterase inhibitors increase the concentration of endogenous
acetylcholine at cholinoceptors by inhibiting acetylcholinesterase.

By Dr. H. B. Patel & Satyajeet Singh ~ 35 ~

Class Notes- VPT 321

Indirectly acting drugs are of two types:

I.Reversible inhibitors:
They bind to the active site of the AchE enzyme reversibly to act as an alternate
substrate for AchE enzyme, this result in inhibition of hydrolysis of Ach.
E.g. Neostigmine
Physostigmine
Pyridostigmine
Edrophonium
II.Irreversible inhibitors:
They bind to the esteratic site of the AchE enzyme resulting in formation of an
irreversible (or very highly stable) complex which cannot hydrolyse Ach.
E.g. Organophosphate compounds.
Carbamates (Malathion, Parathion)
Aging of Ach:
Aging" is due to the loss of one alkoxy group, leaving a much more stable monoalkyl-
or monoalkoxy-phosphoryl-AchE & AchE enzyme become totally resistant to
hydrolysis.
This produces more stable form of AchE enzyme.
The rate of aging varies with the particular organophosphate compound. If given
before aging has occurred, strong nucleophiles like pralidoxime are able to break the
phosphorus-enzyme bond and can be used as "cholinesterase regenerator" drugs for
organophosphate insecticide poisoning. Once aging has occurred, the enzyme-
inhibitor complex become more stable and is more difficult to break, even with oxime
regenerator compounds.
Clinical uses of Anticholinesterase Agents:
1. To antagonize curare. (e.g edrophonium, pyridostigmine)
This increases strength of contraction, especially in muscles weakened by
curare-like neuromuscular blocking agents or by myasthenia gravis.
Curare:
It is a plant alkaloid which blocks Neuromuscular Junction and produce
muscular relaxation.
Earlier time used as arrow poison.

2. To treat Glaucoma:
To reduce intraocular pressure
E.g. Physostigmine (0.5-1.0% solution)
3. In Ruminal impaction:
E.g. Physostigmine (cattle= 30-45 mg S/C inj.)
4. In Myasthenia gravis:
It is muscular weakness of nervous origin
E.g. Physostigmine or Neostigmine

By Dr. H. B. Patel & Satyajeet Singh ~ 36 ~

Class Notes- VPT 321

5. In snake Bite: (especially in cobra bite)

Venom has curare like effect.
[Neostigmine+Atropine] is given to prevent respiratory paralysis.

Malicious poisoning/Organophosphate poisoning:

1. Poisoning which is performed as an act of malafied intension.
2. In this poisoning Muscarinic & Nicotinic receptors are destroyed.
Treatment:
1. Atropine sulphate
It has Antimuscarinic effect.
2. Cholinesterase Regenerator Compounds
Capable of regenerating active enzyme from the organophosphorus-
cholinesterase complex, is also available to treat organophosphorus poisoning.
These oxime agents include:
Pralidoxime (PAM),
Diacetylmonoxime (DAM),
Mono Iso Nitro Amide (MINA)

The oxime group (=NOH) has a very high affinity for the phosphorus atom,
and these drugs can hydrolyze the phosphorylated enzyme if the complex has
not "aged".
PAM is most effective in regenerating the cholinesterase associated with
skeletal muscle neuromuscular junctions. Pralidoxime is ineffective in
reversing the central effects of organophosphate poisoning because its positive
charge prevents entry into the central nervous system.
DAM, on the other hand, crosses the blood-brain barrier and, can regenerate
some of the central nervous system cholinesterase.
Monoxime are not recommended in carbamate poisoning because
carbamide inhibitor act on AchE enzyme irreversibly & are contraindicated
Dose of PAM:
Dog: 10-20 mg/kg
Horse: 20 mg/kg
Sheep & Goat: 25 mg/kg

By Dr. H. B. Patel & Satyajeet Singh ~ 37 ~

Class Notes- VPT 321

Parasympatholytics

Agents which prevent Ach from producing its characteristic effect.

These drugs inhibit the effect of Ach, mainly the Muscarinic action & other
cholinomimetic drugs.
These parasympatholytic drugs are also called muscarinolytic or
antimuscarinic drugs because they produce selective effect on Muscarinic
receptor at therapeutic dose.
Nicotinic receptor antagonist also blocks the certain action of Ach. They are
generally referred to as ganglionic blocker or neuromuscular blocker.

Parasympatholytics

Synthetic
e.g.
Natural alkaloid Glycopyrolate
Semi-synthetic
e.g. Dicyclomin
E.g.
Atropine Cyclopentamine
Homatropine
Scopolamine Isopropamide
Oxyphencyclimine
Propanetheline

Source & Chemistry:

1. Atropine (hyoscyamine) is found in the plant Atropa belladonna, or deadly

nightshade, and in Datura stramonium, also known as jimsonweed (Jamestown
weed), sacred Datura, or thorn apple.
2. Scopolamine (hyoscine) occurs in shrub Hyoscyamus niger, or henbane, as the l(-)
stereoisomer. Naturally occurring atropine is l(-)-hyoscyamine, but the commercial
material is racemic d,l-hyoscyamine.
3. The l(-) isomers of both alkaloids are at least 100 times more potent (Antimuscarinic
activity) than the d(+) isomers.

Pharmacological effects of Muscarinic receptor blocking drugs on various

systems:

By Dr. H. B. Patel & Satyajeet Singh ~ 38 ~

Class Notes- VPT 321

1. Cardio Vascular System:

At low dose of atropine decrease heart rate followed by increase heart rate.
Rapid injection of atropine increase heart rate followed by sudden fall in Heart rate
(or B.P)

2. Gastrointestinal tract:
Atropine produces sooth uscle relaxation.
Dercreases ruminal activity.
Atropine is used as antihypermitilitic drug.

3. Glands:
Decrease salivary secretion
Decrease lacrimal secretion

4. Respiratory system:
Atropine decreases bronchial secretion. Antimuscarinic drugs are
frequently used prior to administration of inhalant anesthetics to reduce the
accumulation of secretions in the trachea and the possibility of laryngospasm.
Atropine dialate bronchioles.

5. Eye:
Produce dilation of pupil (mydriasis) & cycloplegia (paralysis of ciliary muscles)
due to relaxation of circular iris muscles.

6. Urinary tract:
Atropine is used in relaxation of urinary tract muscle & slows voiding of
urine.
Useful for urinary/renal spasmolytic colic.

7. Central Nervous System:

In toxic doses, scopolamine and to a lesser degree atropine can cause
excitement (stimulatory effect), agitation, hallucinations, and coma.
Atropine at therapeutic dose, produce minimal stimulant effects on the
central nervous system & sedative effect on the brain.

8. Sweat glands:
Atropine suppresses thermoregulatory sweating. So produce anhydrotic effect
(loss of sweating) and produce hyperthermia.
These effects are not observed in horse.
In human, in adults, body temperature is elevated by this effect only if large
doses are administered, but in infants and children even ordinary doses may
cause "atropine fever."

9. Other effects:
By Dr. H. B. Patel & Satyajeet Singh ~ 39 ~
Class Notes- VPT 321

Atropine produces hyperpyrexia particularly at higher dose.

These effects are not observed in horse.

Clinical Pharmacology of the Muscarinic Receptor-Blocking Drugs:

1. Central nervous system disorders:

In parkinson’s disease
In motion sickness

2. Opthalmic examination:
Accurate measurement of refractive error requires ciliary paralysis. Also,
ophthalmoscopic examination of the retina is greatly facilitated by mydriasis.
Therefore, antimuscarinic agents, administered topically as eye drops or
ointment, are very helpful in doing a complete examination
Antimuscarinic drugs should never be used for mydriasis unless cycloplegia
or prolonged action is required. Alpha-adrenoceptor stimulant drugs, eg,
phenylephrine, produce a short-lasting mydriasis that is usually sufficient for
funduscopic examination
Homatropine is 10 times less potent than atropine sulphate and used as
mydriatic agent.

3. Respiratory disorder:
In asthma (e.g. Ipratropium, a synthetic analogue of atropine)
In COPD (Chronic Obstructive Pulmonary Disorder)

4. Gastrointestinal disorders:
Antidiarrhoeal agent in ruminants

5. Cardiovascular disorder:
In myocardial infarction

6. Urinary disorders:
In urinary colic

7. Atropine is used as preanaesthetic medication (antisialogogue)

8. In cholinergic poisoning:
Antimuscarinic therapy
Cholinesterase Regenerator Compound: capable of regenerating active
enzyme from the organophosphorus-cholinesterase complex, is also available
to treat organophosphorus poisoning. These oxime agents include
pralidoxime (PAM), diacetylmonoxime (DAM), and Mono Iso Nitro Amide
(MINA).

By Dr. H. B. Patel & Satyajeet Singh ~ 40 ~

Class Notes- VPT 321

The oxime group (=NOH) has a very high affinity for the phosphorus atom,
and these drugs can hydrolyze the phosphorylated enzyme if the complex has
not "aged".
Pralidoxime is most effective in regenerating the cholinesterase associated
with skeletal muscle neuromuscular junctions. Pralidoxime is ineffective in
reversing the central effects of organophosphate poisoning because its positive
charge prevents entry into the central nervous system. Diacetylmonoxime, on
the other hand, crosses the blood-brain barrier and, in experimental animals,
can regenerate some of the central nervous system cholinesterase.
In excessive doses, pralidoxime can induce neuromuscular weakness and other
adverse effects. Pralidoxime is not recommended for the reversal of inhibition
of acetylcholinesterase by carbamate inhibitors.

Mushroom poisoning has traditionally been divided into rapid-onset and

delayed-onset types.
Rapid-onset type is appear within 15-30 minutes following ingestion
of the mushrooms. It is often characterized by signs of muscarinic excess:
nausea, vomiting, diarrhea, urinary urgency, vasodilation, tachycardia,
sweating, salivation, and sometimes bronchoconstriction. Although Amanita
muscaria contains muscarine, numerous other alkaloids, including
antimuscarinic agents, are found in this fungus. In fact, ingestion of A.
muscaria may produce signs of atropine poisoning, not muscarine excess.

Delayed-onset type mushroom poisoning, usually caused by

Amanita phalloides, A. virosa, Galerina autumnalis, or G marginata,
manifests its first symptoms 6-12 hours after ingestion. Although the initial
symptoms usually include nausea and vomiting, the major toxicity involves
hepatic and renal cellular injury by amatoxins that inhibit RNA polymerase.
Atropine is of no value in this form of mushroom poisoning.

By Dr. H. B. Patel & Satyajeet Singh ~ 41 ~

VPT 311

CNS PHARMACOLOGY
Brain
Central Nervous
System
Spinal Cord

Nervous System
Sympathetic
Nervous System
Autonomic
Nervous System
Peripheral Parasympathetic
Nervous System Nervous System
Somatic Nervous
System

o Sympathetic neurotransmitters are epinephrine & Norepinephrine, & in parasympathetic

acetylcholine.
o Resting stage is called as polarized stage, in this stage -70 mV (internal –ve & outer +ve). It is
maintained by sodium-pump.
o Stimulation disrupts sodium-pump & inner potential is +50 mV& called depolarization.
o After sometime bring back to normal is called repolarization.

Impulse transmission through nerve junction: 4 steps

1) Release of neurotransmitter: by Ca+2
2) Combination of neurotransmitter with post junctional receptor: whenever act on receptor,
there is 2 possibility
a) Increase permeability of Na+& Ca+2, so depolarization of muscle & positive response
(contraction)
EPSP: Excitatory Post Synaptic Potential
b) May be increase permeability of K+ &Cl- ions, so there is hyperpolarization, so
negative response or inhibitory response.
IPSP: Inhibitory Post Synaptic Potential
3) Post junctional activity: 2 types
a) Depolarization of neurotransmitter (EPSP)
b) Hyperpolarization (IPSP)
4) Destruction of neurotransmitter: neurotransmitter destructed within fraction of second.
Prolonged effect of neurotransmitter may lead to nerve fatigue or paralysis.
Ways of neurotransmitter destruction:
a) Local metabolism: by detoxification by enzyme
b) Absorbed in circulation & it is taken by liver & detoxified.
c) Diluted or dissipated in adjoining area& then taken into circulation.
Dr. H. B. Patel & Satyajeet singh
~ 45 ~
VPT 311

CNS Depressent
Lowest from to highest form of depressant is
1) Tranquilization mild
2) Sedation drowsiness
3) Hypnosis sleep
4) Narcosis deep sleep
5) Anaesthesia loss of sensation
6) Death

ANAESTHESIA
1) General anesthesia: induce amnesia (loss of memory) & analgesia (loss of pain)
2) Regional anesthesia: it is reversible loss of sensation over a large restricted area. E.g. epidural
anesthesia, paravertebral block
3) Local anesthesia: reversible loss of sensation over a very small area.
4) Basal anesthesia: it refers to very light level of anesthesia for minor surgery. E.g. removal of teeth.
5) Balanced anesthesia: combination of different drugs to get all ideal effect of anesthesia.
6) Dissociative anesthesia: patient feel dissociation from surrounding & which brought by stimulation
of brain & suppression of other parts & leads to state called as catalepsy or cataleptic stage.
Catalepsy: waxy muscular relaxation/wax like rigid muscle. Commonly used in cats.

History of anaesthesia:
In two parts, before 1846 & after 1846
o 1846: landmark of anesthesia, before 1846 surgery was not common (no aseptic condition, no
anesthesia)
o In Greek period: pressing of carotid artery, leads to unconsciousness & surgery perform.
o 1776: Priestley synthesized gaseous anesthesia nitrous oxide.
o 1776: Priestley & dewin anaesthetic property of nitrous oxide.
o 1816: Michael faraday states that diethyl ether can use as anaesthetic.
o 1821: Benzamine
o 1842: croford long: under ether removed tumor.
o 1844: Hoveswalter use nitrous oxide on his own & remove own tooth.
o 1846: William T. G. morton he was 2nd year medical student & first time demonstrated ether
anesthesia, patient was Edward Gilbert& surgeon was Dr. John Collins Warren.
o 1847: Dr. Edward mayhem used ether in veterinary practice in dog.
o 1847: James Simpson chloroform
o 1903: Barbiturate was used parental anaesthesia for first time
o 1956: Halothane as inhalant anaesthesia
o 1965: Ketamine was first dissociative anaesthesia
o 1972: Althesin was first steroid anaesthesia.
o 1990: Propafol is now used as infusion anaesthesia.

Dr. H. B. Patel & Satyajeet singh

~ 46 ~
VPT 311

Mechanism of action in general: different theories

1. Lipid theory: by mayer & overton in 1899
Action of general anaesthsia depends upon lipid solubility.
High solubility high action
Efficacy depends on lipid-water partition coefficient i.e. it is comparative solubility as compare
to water in lipid.

2. Feg n inci le: this theory states that the efficacy of anasesthesia depend upon
thermodynamic property.

3. Colloidal theory: by Claude Bernard

The anaesthesia molecule form colloid inside brain which depress consciousness of brain.

4. Surface tension theory: by Trop (adsorption theory)

Anaesthetic cause reduction in surface tension in neuron which leads to outflow & inflow of
ions are hindered.

5. Cell permeability theory:

Anaesthesia reduces cell permeability towards certain ions so reduce activity.

6. Biochemical theory: by Quantal

There is reduction in O2 utilization & uptake therefore energy production reduce.

7. Clatheratepanding theory:
Anaesthetic form miro-crystals inside neurons, which reduce conductivity.

8. Iceberg theory: by Miller

Anaesthetic form iceberg i.e. crystal of water form in neurons which prevent conductivity by
plugging the ion channels.

9. Protein theory: by Frank & Zip

Anaesthetic target certain protein which are responsible for movement or control of ions due to
ionic interference leads to anaesthesia.

10. Concentration of neurotransmitter:

GABA (inhibitory neurotransmitter), so anaesthetic which stimulate potential
Certain anaesthetic cause inhibition of glutamate (glutamate is excitatory neurotransmitter)

Different stages of anaesthesia:

They are generally observed in case of gaseous anaesthesia or inhalant anaesthesia. In parenteral
anaesthesia are stages are not observed.
Dr. H. B. Patel & Satyajeet singh
~ 47 ~
VPT 311

G del classification of anaesthesia stages:

Four stages
I. Stage- (stage of voluntary excitemrnt/stage of analgesia)
II. Stage- (stage of involuntary excitement/stage of delirium)
III. Stage- (stage of surgical Anaesthesia)
1) Plane-1
2) Plane-2
3) Plane-3
4) Plane-4
IV. Stage- V (stage of medullary paralysis/stage of toxicity/toxic stage)

Stage- & stage- combinely called as stage of induction.

All operations performed in stage- in plane-2 & 3.
Different reflexes are observed to know the which stage is going on, these reflexes are
i) Corneal reflex: by touching cornea with the help of finger, if blinking present than reflex
present otherwise not.
ii) Eyelid/palpebral reflex: medial canthus of eyelid, if eyelid blinks than reflex present.
iii) Skin reflex: tested by fine needle by touching skin, if reflex present than severing
iv) Swallowing reflex: done by gentle massage on lower jaw, if there is swallowing than reflex
present.
v) Cough reflex: put slight pressure on tracheal cartilage
vi) Pedal reflex: pinching interdigital skin, if reflex present, response takes place.
Observe color of mucous membrane, respiratory pattern, pulse rate & blood pressure.

I. Stage- (stage of voluntary excitement/stage of analgesia)

o Basically sensory cortex get depressed, but before that animal try to run away from
anaesthesia.
o There is lacrimation, salivation, urination etc.
o Blood pressure, pulse rate & respiratory rate high.
o All reflexes are present in this stage.
o At the end of this stage animal starts losing consciousness &cambing effect.

II. Stage- (stage of involuntary excitement/stage of delirium)

o Sensory cortex is totally depressed & motor cortex yet to be depress so only motor
activity/involuntary activity takes place& at the end of this stage motor activity also stop &
animal unconscious totally.
Motor activity paddling of limbs, rolloing of eyeballs, abnormal vocalization etc.
o Blood pressure, respiratory rate, pulse rate are high & reflexes are present.

Ideally speaking, anaesthetic should have rapid induction or both stage- & are very
rapid.
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In parenteral anaesthesia, stage- & are not observed.

III. Stage- (stage of surgical Anaesthesia)

o In this stage depression proceed from cortex to mid brain&to spinal cord.
o Entry into stage- is marked by respiratory pulse, blood pressure become normal.
This stage divided into 4 planes:
1) Plane-1
o Mid brain get depressed.
o All the reflexes except corneal & eyelid reflex lost.
Exception: pedal reflex in dog is also present.
o In this plane pulse & pressure are normal.
o Respiratory rate slow but regular.
o Pupils are normal.
2) Plane-2
o Depression starts to spinal cord.
o In this plane eyelid reflex abolish but corneal reflex persist & in dog pedal reflex also
present.
o Pulse & blood pressure normal.
o Mucous membrane starts to turning pale.
o Pupils are slightly dialated.
3) Plane-3
o All reflexes are abolished including pedal reflex in dog.
o Eyeball fixed
o Respiration starts to abdominal respiration (i.e. both thoracic & abdominal)
o Pupils get dialated
o Blood pressure start falling down
o Mucous membrane starts to turning pale blue in color.
This is stage when stop administration of anaesthesia.
4) Plane-4
o Spinal cord is completely depressed& depression starts over the medulla.
o Respiration is completely abdominal.
o Blood pressure & body temperature goes down.
o Mucous membrane is completely cyanotic.
o Pupils are dilated to maximum strength.
o Pulse is very weak & cannot feel it.

IV. Stage- V (stage of medullary paralysis/stage of toxicity/toxic stage)

o It is overdose stage.
o Medulla is completely depressed.
o Heart rate, blood pressure drastically goes down.
o Complete cyanosis
o Respiratory paralysis & death.
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Stage- & plane-2, muscle tone is very less or muscle is relaxed, so easily performed operations.
The recovery is exactly in opposite direction
During recovery, also there is voluntary & involuntary excitement.

General Anaesthesia
There are 2 types of general anaesthesia:

1. Inhalant anaesthesia
a) Volatile anaesthesia (e.g. ether, chloroform, halothane)
b) Gaseous anaesthesia (N2O, cyclopropane)
2. Parenteral anaesthesia

1. INHALANT ANAESTHESIA:
o This is vapor.
o They will go to lung, alveoli, blood, brain & part of this anaesthesia circulate, metabolize &
excrete, but majority of inhalant excreted in expiration.
In this two laws:
Dalton law: higher the concentration, higher the partial pressure.
Hennery law: higher the partial pressure, higher the solubility.
So higher the concentration of anaesthesia, higher the solubility in blood.

Factors affecting inhalant anaesthesia:

o Concentration of anaesthesia
o Rate of respiration
o Depth of respiration & permeability of alveolar capillary
o Blood supply to lungs
o Permeability of alveolar capillary
MAC:
o MAC is the parameter to know the potency of inhalant anaesthesia.
o It is minimum concentration of inhalant anaesthetic which should be present in alveoli for
abolition of response to standard stimuli in 50% of exposed population/animal.
Two standard stimuli:
i) Skin incision
ii) Tail clamping
o If lower concentration is required to get effect than more potency of anaesthetic.
o Methoxyfurane (MAC=0.23%) is more potent than Ether (MAC=3%).

Properties of ideal inhalant anaesthetic:

1) There should be rapid induction.
2) It should cause smooth recovery

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3) Should not cause any post anaesthetic complication

4) Should have high potency
5) It should cause fair amount of muscle relaxation
6) Should have pleasant odour (sweet smell).
7) Non-inflammatory
8) Non-irritant
9) Economic

Volatile liquids:
1) Ether
2) Chloroform Older
3) Halothane
4) Methoxyflurane
5) Enflurane
6) Isoflurane Newer
7) Desflurane
8) Sevoflurane

Property Ether Chloroform Halothane

1 Boiling point 35 °C 60 °C 50 °C
2 Solubility 10% in H2O 0.5% in H2O 0.5% in H2O
Most in organic Totally in organic Totally in
organic
3 Inflammable property Highly Non-inflammable Non-
inflammable
4 Irritant property Highly Moderate Very less
5 Induction Prolonged & Short & pleasant Short & pleasant
unpleasant
6 Capillary bleeding Yes No No
7 Effect on heart & B.P Not depress Depress from 2nd Depress from 2nd
stage stage
8 Myocardial No Yes Yes
sensitization
9 Muscle relaxation Fair Excellent Good
10 Potentiation of neuro Increase Slight effect Slight effect
blocking effect
11 Post anaesthetic No Delayed hepato& Lesser extent of
complication nephrotoxicity hepato&
nephrotoxicity
12 Dose Induction 10% 2-5% 2-4%
Maintenance 5% 1% 1%
13 MAC 3% 0.77% 0.87%

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Older drugs:

1) Ether/diethyl ether (C2H5-O-C2H5)

Advantages:
(1) Cheapest one/very economic
(2) Safest one
(3) All the stages seen, so better control over anaesthesia
(4) Preferred in small animals, not commonly used in large animals and ruminants because difficult
to restrain the animal. Also general anaesthesia is not used in large animal & ruminant because
difficult to calculate precise dose (because weight of rumen is excluded )& in large animal
surgery performed in standing position.
(5) Good relaxation of muscle.
(6) No effect on cardiac & respiratory function.
Disadvantages:
(1) Highly inflammable, cannot performed any operation which involve dithermy because it
cause spasm & they catch fire.
(2) Highly irritant
(3) Less potent
(4) Whenever it is exposed to air it converted into peroxide.
(5) Hypoglycaemia& hyperthermia

2) Chloroform (CHCl3)
o It is stored in dark colored bottle+ 1% ethyl alcohol added because in presence of sunlight &
air chloroform produce phosgene (COCl2) gas which is irritant & highly toxic, so ethyl
alcohol act as cleansing agent.
NOTE: Anesthesia containing halogen atom, cause myocardial sensitization
Advantages:

(1) Smooth induction due to pleasant smell.

(2) Non irritant
(3) Non inflammable.
(4) Good muscle relaxer.
(5) Economic

Disadvantages:

(1) Cause myocardial sensitization

(2) Direct get myocardial toxicity
(3) Direct vagal arrest
(4) Delayed hepatotoxicity
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3) Halothane (trifluoro-bromo-chloroethane)
Advantage:
(1) Used in small & large animals
(2) Non-inflammable
(3) Non-irritant
(4) Very potent
Disadvantage:
(1) Maximum sensitization of myocardium
(2) Hepatotoxicity
(3) Poor muscle relaxer
(4) When enter in plane-3, sudden drop blood pressure & it may be fatal. In this case adrenaline is
not given to normal the blood pressure.
o Combination of chloroform & ether in 1:2 is advisable to safety & reduce toxicity.

Newer drugs:

1) Methoxyflurane:
o Most potent inhalant anaesthetic
o MAC = 0.23%
o Non-inflammable, non-irritant, non-explosive
o Used in both small & large animals.
o It bypasses stage- & stage- , so there is no excitement.
o Good analgesic effect, also after operation.
o Good muscle relaxer
o No delayed toxicity.
Disadvantage:
Slow onset & slow recovery because it is highly soluble in blood, higher solubility slower the
induction because achieve saturation point larger duration. So longer duration for action.

2) Enflurane:
o Most potent
o MAC = 0.0212%
o Boiling point = 67°C
o Chemically derived from methoxyflurane.
o Non-inflammable, non-explosive
o Very pungent smell, so induction is not smooth.
o It is dissociative type of anaesthesia, if slight higher dose than it cause convulsion. So this is called
convulsion anaesthesia . So to prevent convulsion diazepam is given before anaesthesia.
o Causes sensitization of myocardium
o Fatal nephrotoxic effect in cat if tetracyclin is used in vicinity of this anaesthesia.
o Hypothermia

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3) Isoflurane:
o It is isomer of enflurane.
o MAC = 1.3-1.5%
o Boiling point = 43°C
o Non-inflammable, non-explosive
o Does not any convulsion or lesion.
o Very-very less soluble in blood so fast induction & fast recovery.
o In body metabolism: 1/10th part into enflurane, 1/100th get converted into halothane.

4) Desflurane:
o Very less potent
o MAC = 7.2%
o It is latest anaesthetic.
o Very low solubility in blood, so fast induction & recovery.
o Very good muscle relaxation.
o It causes very less myocardial sensitization.

5) Sevoflurane:
o Very latest but very low LD50 value, so it is toxic.
o Easily degradation

Gaseous anaesthesia
Two inhalant anaesthetics which are gaseous

1) N2O (nitrous oxide/laughing gas)

2) Cyclopropane

1) N2O:
o Always in blue colored bottles.
o Commonly used in veterinary practice.
o Non-inflammable
o Very low solubility in blood, so rapid induction & recovery.
o No sensitization of myocardial muscle.
o N2O is not used as sole agent, later on maintenance obtained by halothane & methoxyflurane.
o N2O never given as single gas, it given along with O2. [N2O (80%) + O2 (20%)]
At this stage it is good anaesthesia up to stage- , but not goes beyond. That is limit, if N2O
percentage increases than toxic effect occurs.
o Muscle relaxation is very poor.
o N2O is least potent.
o MAC = 105% in human
188% in dog
205% in cat

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2) Cyclopropane:
o Orange colored cylinder to avoid confusion.
o Mostly used in human being
o Almost insoluble in blood
o Less irritant
o No myocardial sensitization
o No renal & hepatotoxicity
o Lower potency but more than N2O
o MAC = 17.5%
o Induce capillary bleeding
o No adequate muscle relaxant
o Very costly
o Clinically cyclopropane (20%) given with O2 (80%).

MAC orders:
N2O (105%-in man, 188%-in dog, 205%-in cat) > Cyclopropane(17.5%) > Desflurane(7.2%) > Ether(3%)
> Isoflurane(1.3-1.5%) > Halothane(0.87%) > Chloroform(0.77%) > Methoxyflurnae(0.23%) >
Enflurane(0.0212%)

Disadvantages of inhalant anaesthesia:

(1) Induction is slow & sometime unpleasant, so there is lot of excitation during induction.
(2) Many inhalants are inflammable, irritant & explosive.
(3) Halogenated anaesthesia sensitizes myocardium.
(4) Poor muscle relaxer
(5) Control over anaesthesia is poor or not proper control, so not get uniform anaesthesia.
(6) Level of anaesthesia is varying person to person.

2. PARENTERAL ANAESTHESIA
I. Barbiturates
II. Chloral hydrate
i) Chloromag
ii) Chloropent
iii) Chloralose
III. Urethane
IV. Althesin
V. Imidazole derivatives
VI. Propofol

Advantages of parenteral anaesthesia:

1) Non-inflammable, non-irritant & non-explosive
2) Rapid & pleasant induction, smooth recovery
3) No capillary bleeding & no myocardial sensitization
4) Easily administered & proper control over anaesthesia

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I. Barbiturates:
group of anaesthesia, very commonly used.
Chemistry: it is derivative of barbituric acid. This acid is formed by combination of two compounds
urea &malonic acid. They give compound malonyl urea.
Derivative of this barbituric acid are different barbiturates, which are commonly used.

Classification: substitution made at N1, C2, R1, R2.

Barbiturates are divided into 4 categories:
Long acting
Intermediate acting
Short acting
Ultrashort acting

N1 C2 R1 R2
Long acting Phenobarbitone H O C2H5/CH3 C6H5
(6 Hours)
Methyl barbitone
CH3 O C2H5/CH3 C6H5
Intermediate Butobarbitone H O C2H5 C4H9
acting (3-6
Hours) pentobarbitone H O C2H5 CH3(C4H7)
Short acting pentobarbitone H O C2H5 CH3(C4H7)
(1-3 Hours) Secobarbitone H O C3H5 CH3(C4H7)
Thiopentone
H S C3H5 CH3(C4H7)
Ultrashort (pentothal)
V acting (20-30 Thiamylal H S CH3(C4H7)
min.)
Methohexital CH3 O C3H5 CH3(C4H7)

Structural activity relationship (SAR) of barbiturates:

Barbituric acid does not have any anaesthetic property, to have CNS depression property, there has to
be substitution, add at R1, R2, N1, N2 or C2 either alkyl, aryl or thio group.
More the number of double bond (unsaturated) metabolize easily, so the compound is short acting.
If there is long chain substitution, so chain is easily break & metabolize & short acting.
If there is branching, they again break easily & compound is short acting.
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Short chain substitution, stable compound & become long acting compound.
Whenever there is substitution of sulfur at 2nd position, compound becomes ultrashort acting.
Any substitution at N1 or N3 with alkyl group the product becomes CNS stimulant.

Chemical property:
Na-salt is used as they are water soluble & given in injection but compound become alkaline&
alkali give irritant property, so most of these compounds are givenI/V.
Na-salt is water soluble, but as dissolve in water, it loses its property of anaesthesia after
dissolution, so freshly prepared water is used.
These are hygroscopic in nature so placed in dark place in water shield.
If solution keeps at room temperature for 2 days or in refrigeration for 5 days, it loses its
anaesthetic property.
While administering there should not be leakage outside the veins, because it is irritant. So in case
of small animals 2.5% solution is used, in large animals 10% solution is used.
Once start given anaesthesia, don t take out needle during anaesthesia because all veins get
collapsed & unable to raise, so after compete administration, needle will be remove.

Mechanism of action of barbiturates:

1) It reduces calcium accumulation of nerve terminals, release of neurotransmitter also reduces.
2) Most of barbiturate gets action like GABA & GABA is inhibitory neurotransmitter.
3) They reduce the sensitivity of post-synaptic receptor & this reduction is more in Ach receptor, Ach
not act properly on receptor.
4) These agents reduce oxygen uptake to brain, so this reduces brain activity in general.
5) Some of agents inhibit glutamate receptor & these glutamate receptors are excitatory receptor.

Kinetics of barbiturate in general:

1) All the barbiturates absorbed through I/V, I/M or Oral but sodium solution must be given I/V.
2) Highly soluble barbiturates absorb, distributed & excreted rapidly.
3) Due to this high solubility they have shortest duration of action i.e. ultrashort acting.
4) Thiopentone, pentobarbitone&phenobarbitone most commonly used.
5) Lipid solubility Thiopentone >Pentobarbitone>Phenobarbitone

Metabolism:
Microsomal oxidation, these are enzyme inducers.
Ultrashort acting barbiturates when given orally they are detoxified in gut, so never given orally.
Ultrashort acting barbiturates have tendency to get stored in tissues.
Glucose saline increases the permeability of barbiturate (mostly thiopentone) inside the cell, so
along with glucose they increase the depth of anaesthesia, so recovery time increases.
All these are excreted through urine.

Pharmacological property:
1) Effect on CNS: in case of nervous system, it is able to depress both motor & sensory cortex, but
motor cortex get depress at low dose & sensory cortex require higher dose to get depress, which

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may mild toxic. So barbiturates are good anticonvulsant & muscle relaxant but poor in
analgesic.
2) Effect on respiratory system: particularly thiopentone causes temporary cessation of respiration
because it is highly lipid soluble. Entire drug is taken to brain; due to high concentration in brain
respiratory centre get depress so respiration stop & at this point administration of thiopentone stop.
So thiopentone get redistributed to other organs & due to redistribution concentration fall down &
respiration start again.
3) Effect on CVS: causes depression of vasomotor Centre& peripheral vasodilation, so blood pressure
fall down, so loss of heat from the body & due to heat loss shivering observe in animal. That s why
during recovery animal shivering takes place.
4) Effect on uterus & foetus: barbiturates cross the placental barrier& affect the respiratory Centre
of foetus & lead to foetus death. It causes uterine contraction so not given in pregnancy.
5) Effect on skeletal muscle: it acts on neuromuscular end plate (NMEP) & reduces the effect of
acetyl choline & this can causes muscle relaxation. In some cases post anaesthetic lameness.
6) Toxic effect: it causes phlebitis. High dose & rapid injection causes respiratory arrest & death. In
case of long acting barbiturates repeated administration cause incoordination.

Clinical uses of barbiturates:

1) Induction of anaesthesia
2) As a general anaesthesia
3) Some of agents show anticonvulsion activity, mostly long acting barbiturates are used.
4) When used for epilepsy, given for prolonged period & repeated administration.
5) Lower dose as sedative, hypnotic.
6) Ultrashort acting barbiturates are used for euthanising animals.

Doses of barbiturates:
Thiopentone:
In dog 15-17 mg/kg
In cats 9-12 mg/kg
Route I/V 2.5% solution or 5% solution
In sheep, goat & calves 5-10 mg/kg 2.5% solution I/V
These all doses are for general anaesthesia.
Duration 35-40 minutes

Pentobarbitone:
In dog & cat 24-33 mg/kg (6% solution, I/V)
In large animals 15-20 mg/kg (10% solution, I/V)
Pentobarbitone also used as sedative & hypnotic (dose: 2-4 mg/kg BW, I/V)
Duration 3 hours

Phenobarbitone:
Mainly used for an anticonvulsion or control epilepsy.
Dose: 7.5-15 mg/kg, orally
For long acting period is 6 to 7 hours.
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II. Chloral hydrate [CHCl3(OH)2]

o Always used for large animals basically horses.
o White crystalline powder having pungent odour& completely water soluble.
o It enters in body, and thenmetabolize to form product trichlorethanol & this trichlorethanol have
anaesthetic effect, sochloral hydrate is prodrug.
o Trichlorethanol gets combine with glucuronic acid to form urochloralose, this urochloralose
excreted in urine.
o It causes depression of motor cortex, so it depresses motor activity, but sensory cortex is not
depressed. So it does not produce good analgesic effect, so to get analgesic effect high dose is
given, as dose increases severely affect respiratory system & vasomotor centre& it is mildly toxic
or may be fatal. So chloral hydrate always administered at hypnotic level i.e. just below
anaesthetic level, operation is performed under local anaesthesia.
o Chloral hydrate is having activity called as physostigmine like activity&physostigmine is
cholinergic drug (Ach like) & due to this activity it causes cardiac arrest. So avoid that atropine
is given as preanaesthetic.
o Finally chloral hydrate is poor muscle relaxant.

Clinical uses of chloral hydrate:

o Chloral hydrate is given orally or I/V.
o If orally given it causes vomition & nausea hence it diluted & then given.
o When diluted form given, it only have sedative effect, never anaesthetic.
o Maximum used in horse only (in case of colic pain)
o It is used as narcotic agent, it induces sleep.
o Used as general anaesthetic (I/V)
o In cattle & buffalo, it is used as sedative, commonly used in prolapse of rectum & vagina.
o In cattle & buffalo, in case of acetonemia, nervous excitement prevented.

Doses of chloral hydrate:

o 5 gm/45kg of body weight, orally in horse & cattle
o Maximum total dose 30gm, not to be exceeding then 30gm, at this dose get dose narcotic effect.
o In sheep, goat & pig total dose 3-4gm, orally
o 6 gm/45 kg body weight, I/V, of 10% solution & this dose for general anaesthesia for horse &
cattle.

Different combinations:
i) Chloromag:[chloral hydrate (12gm) + MgSO4 (6gm), both dissolved in 100 ml of water] (Da k
formulation*)
o MgSO4 causes muscle relaxation by neuromuscular blocking activity.
o This combination increases the depth & rapid induction of anaesthesia.
o Horse 200-300 ml, I/V (30ml/ minute)
o In camel [ chloromag 12gm chloral hydrate + 12gm MgSO4] and given 6gm/100 kg BW, I/V

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ii) Chloropent (Equithesin): [Chloral hydrate (30gm) + MgSO4 (15gm) + pentobarbitone (6.6gm)
dissolve in 1000 ml of water]
o Dose: 30-70ml/45kg, I/V, in horse & cattle. It is enough for 30 minute anaesthesia.
Advantages: good muscle relxation, excitement reduce, combination increases the safety.
o It is also useful in birds, but combination is 20gm, 5gm, 10gm respectively & given 2.2ml/kg,
I/M. This formulation is known as millerbruck & walling formulation* .

iii) Chloralose: [Chloral hydrate + glucose]

o This combination gives prolonged effect but slow induction.
o Dose: 100mg/kg of 1% solution, I/V or I/P
o More commonly used as rodenticide.

III. Urethane:
o Usedfor lab animals only*.
o Chemically it is ethyl ether of carbonic acid.
o In this case, onset is slow, prolonged duration of action, there is no recovery of anaesthesia that
is terminal anaesthesia*
o It has no effect on heart rate, respiration & blood pressure etc.
o Dose: 25% solution, 6ml/kg, I/P or I/V

IV. Althesin:
o It is steroid anaesthetic.
o It is combination of 2 steroids. Steroid-1 is alphaxalone& steroid-2 is alphadalone.
o Alphaxalone (9mg/ml) + alphadalone (3mg/ml), both are dissolved in ionic detergent.
o As they dissolve in ionic detergent not used in dog, because in dog ionic detergent release
histamine, which cause anaphylactic reaction& death.
o Use in cat: 9mg/kg, I/V, give short duration anaesthetic effect (10-15 minute). If again give
anaesthesia, after 15 minute, then no cumulative effect.
o In birds: 10mg/kg, I/V
o In pigs: 2mg/kg, I/V
o In rabbit: 6-9mg/kg, I/V

V. Imidazole derivatives: mainly 2 compounds used- etomidate, metomidate

o Both are poor analgesic
o Etomidate used in dog, give rapid induction, there are no side effect like respiration & blood
pressure, so it has wide margin of safety. Dose in dog: 1.5mg/kg, I/V
o Metomidate used in birds, pigs, dogs & cats. Dose in birds: 3-4mg/kg, I/V. dose in dog, cat &
pigs: 15-20mg/kg, I/V

VI. Propofol:
o It is latest parenteral general anaesthesia.
o It is infusion anaesthesia.

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o At room temperature, it is oily solution but, it is exception that it is given I/V because
formulation in such a way that oil molecule not exposed.
o It is given as continuous, as stop recovery within 1-2 minutes.
o It potentiate on GABA
o No effect on respiration, heart rate & blood pressure.
o It does not cross the placenta, hence does not affect the foetus.
o It diluted in 5% dextrose solution.
o Dose: dog 0.5-2mg/kg, cat 5-8mg/kg, horse 4mg/kg
o Infusion rate: 0.4mg/kg/minute
o Very short half-life (4-5 minutes)

3. DISSOCIATIVE ANAESTHESIA:
o Anaesthesia in which person feels dissociative from surrounding, due to some part gets stimulated
& some part get depressed. It leads to cataleptic stage or catalepsy.
o Catalepsy is muscular rigidity like wax.
o There are mainly three compounds- 1) Phencyclidine, 2) Tiletamine, 3) Ketamine
o Out of these three phencyclidine is most potent & it is longest duration of anaesthesia, but now a
days it is banned due to abuse.
o Tiletamine is less potent, so not used
o Ketamine mainly used, each gram sold is accounted because it is abuse for amnesia (=loss of
memmory)
o Use of ketamine started from 1965 in human, but now not used in human.
o In veterinary used 1972 & still commonly used in cats.
o Ketamine causes anaesthesia, it capable of inducing stage- & stage- only. It is capable of
inducing amnesia & dissociative with catalepsy.

Mechanism of action:
o It causes inhibition of binding of GABA to its receptor, it stimulate certain parts of brain.
o It blocks the transport of 5-HT (serotonin)
o It prevents the uptake of nor-epinephrine & dopamine leads to stimulation of cardiovascular
functions.
o It causes depression of cortical centre so net effect is depression of cortical centre& stimulation of
limbic system.

Pharmacological effects:
1) Effect on nervous system: there is functional disturbance of nervous system leading to
stimulation & depression, due to this it can induce stage- & anaesthesia but not i.e. go upto
unconsciousness.
It causes muscular rigidity, so excitement not seen clinically due to rigid muscle so animal
become unconscious without showing sign of excitement.
2) Effect on cardiovascular system: due to effect on dopamine & nor-epinephrine there is increase
in B.P.

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3) Effect on respiratory system: as stage- not arrive hence respiration is normal & ventilation is
excellent.

Pharyngeal, laryngeal & swallowing reflex persist.

Ketamine induces lot of salivation but swallowing reflex present, hence swallow all saliva.
On the other hand, Pharyngeal, laryngeal reflex present, if endoscopy perform it cause
laryngospasm & it may be fatal.
Other reflexes are present & eyes are wide open.
Pedal reflex & skin reflex also not affected.
In case of ruminants, regurgitation is not affected & eructation of gas is also not affected, so it is
advantage & suitable for ruminants.
Ketamine anaesthesia is very safe & margin of safety is 5. Even if give repeated dose, there is no
cumulative effect.

Disadvantages:
1) As there is not complete anaesthesia, animal may recover in between & stand & walk.
2) Very poor muscle relaxation & muscle is tensed & contracted.

Difference between ketamine & other anaesthesia:

Ketamine Other anaesthesia
Only 2 stages All stages
Maximum reflex present No reflex
Cardiovascular & respiratory system not Affected
affected
Muscular rigidity Muscular relaxation

Clinical uses of ketamine:

Note: Always better to give atropine (0.05mg/kg, S/C) before given ketamine to reduce salivation.
1) It can give I/V or I/M
2) Normal dose @ 11 to 44mg/kg body weight.
3) As increase dose depth of anaesthesia increase.
11mg restrain animal
22mg minor operation
33-44mg major operation
4) Duration of anaesthesia 45minutes to 1 hour
5) Complete recovery 4-5 hours after given highest dose
6) Need some muscle relaxant, if want to perform operation under ketamine anaesthesia. For
muscle relaxation best drug is Xylazine.
7) Ketamine &Xylazine is best combination& recover all the side effects of both drugs & it is
suitable for all species & all operations.
Xylazine: sedative, muscle relaxant & analgesic& these properties lacking in ketamine.

Uses: restraining purpose, minor surgery, orthopedic manipulation, castration, laparotomy & caesarian.

In dog, if ketamine singly given then cause severe convulsion & jerking movement, so in dog ketamine +

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xylazine or diazepam is given

Ketamine = 11mg/kg, I/M xylazine = 0.1-0.2mg/kg
This is used in dog, cat, sheep, goat & horse

In dog: ketamine = 10mg/kg, I/V

Xylazine = 0.5mg/kg, I/M
Combination = I/M

Preanaesthetic:
Drugs which are given before administration of anaesthesia for muscle relaxation etc.
Objectives:
1) To reduce the excitement, to calm down the animal
2) To reduce dose of anaesthetic
3) For rapid induction
4) To reduce the secretions like salivation, vomition etc.
5) To have proper muscle relaxation
6) To control cardiac & respiratory side effects
7) To have proper analgesic effect
Drugs used as preanaesthetic:
1) Tranquilizers: e.g chlorpromazine = 1-2mg/kg, I/
It reduces the excitement, dose of anaesthesia, secretion & vomition.
2) Sedatives: e.g. diazepam = 1mg/kg, I/M or I/V
It induces the sleep, reduces dose, reduce excitement & muscle relaxant.
3) Anticholinergic compounds: e.g. atropine = 0.05-0.5mg/kg, S/C
It reduces all secretions
4) Analgesics: e.g. analgine&novalgine = 5-10mg/kg, I/M
To control pain
5) Muscle relaxant: e.g ketamine & inhalant anaesthesia
a) Xylazine: 0.5-1.0mg/kg
It is sedative, analgesic & muscle relaxant.
b) Diazepam
c) Gallamine: 0.25mg/kg, slow I/V or I/M
If rapid then respiratory paralysis & death

Postanaesthetics:
Given after recovery of anaesthesia & surgery.
Objective:
1) To control the pain (analgesic drug)
2) Blood & fluid replacement by fluid therapy (5% dextrose saline or blood transfusion)
3) For fast recovery vitamin A, B-complex, C, D etc
4) Antibiotic to avoid secondary infection
5) Tranquilizers because recovery stage is opposite stage, so voluntary excitement avoid.
Chlorpromazine = 1-2mg/kg, I/M
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4. LOCAL ANAESTHESIA :
Common mechanism of actions basically 3 mechanisms
1) They act as membrane stabilizing agent: they reduce the permeability of membrane. The local
anaesthetic got amino group, combine with polar group of cell membrane, it affects Na +-K+ pump
& nerve impulse is disturbed.
2) Effect on membrane Ca+2: this calcium whenever present, decreases threshold potential, so local
anaesthetic act on Ca+2 in such a manner that threshold potential gets increase.
3) Local anaesthetics bring deformities in Na+ channels: sometime Na+ channels get closed &
Na+-K+ exchange not takes place & impulse transmission not takes place.

Absorption pattern & systemic effects of local anaesthetics:

o Absorption: as far as possible, absorption must be minimum. 1st way epinephrine combines
with local anaesthesia, because epinephrine got direct effect on B.P by severe constriction
after administration. Epinephrine cause local vasoconstriction, due to this, local anaesthesia
absorb in very low amount & most of part remain at the site of injection.
1 : 10,000 or 1:20,000
Epinephrine local anaesthesia

o Addition of hyaluronidase& local anaesthesia:hyaluronidase increases the spreading of

local anaesthesia, so whenever given S/C, it cause diffusion of local anaesthesia over large
area & it is given during epidural anaesthesia.
o If it is given as such, then some part gets absorb & show systemic effect.
o After absorption of local anaesthesia, there will be CNS stimulation, due to which
excitement, convulsion.
o In cardiovascular system: vasodilatation, decreased B.P, decrease in heart rate.
o In GIT: reduction of peristalsis i.e. constipation effect

Different compounds used as local anaesthesia:

I. Cocaine: cocaine hydrochloride is used.
o Cocaine is alkaloid obtained from plant erythroxyloncocoa.
o This cocaine is 1st local anaesthesia to be used or mother of all local anaesthesia.
Characteristics:
o Does not effect on intact skin (not topically used)
o If given orally than destroyed in gastric pH.
o It is potent local anaesthetic, given S/C.

Mechanism:
It reduces/blocks the uptake of catecholamines, so epinephrine remain at the site, it itself cause the
vasoconstriction. So epinephrine is not required in addition with cocaine as vasoconstriction.
o Cocaine causes pupil dilatation, so very good anaesthesia for ophthalmic observation.
o Clinical uses: it is mainly used for observation of eyes.
o Dose: expressed in %

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o It cause of dilation of pupil & constriction of blood vessels locally, so very good for
conjunctivitis.
o It is very good anaesthetic for nasal, buccal cavity, larynx & pharynx.
o Toxic effect is same as absorbed in systemic effect.
o When given with prolonged period cause addiction.

II. Procaine:
o 1st synthetic local anaesthetic.
o To reduce the addiction property of cocaine, it was synthesized.
o It is not potent as cocaine, but less toxic.
o It has got very short half-life. Half-life is 25 minutes, so to increase its life (duration of action)
epinephrine is added & decrease absorption.
o It is metabolized to PABA, so it cannot be used along with sulfonamides.
o It cause severe vasodilatation & it is commonly used as antihypertensive drug. In this procaine is
not used but procaine amide is used.
o Procaine is contraindicated as it is require in large dose.
o Not used in shock.
o Dose: 1-2% for infiltration, 3-4% for nerve block

III. Lignocaine (lidocaine)

o Most commonly used local anaesthetic.
o Potency 2 times than procaine & not cause tissue irritation.
o Quick onset of action & duration of action is twice than procaine.
o It is quickly absorbed, hence epinephrine is added.
o Also used as surface anaesthetic/topical 5% concentration use
o Dose:0.5-1% for infiltration, 2-5% for nerve block

Lignocaine like compounds recent compounds

i) Bupivacaine
ii) Mepivacaine
iii) Prilocaine
iv) cinchocaine
o Among these bupivacaine is most potent (7 times) & 11-12 hours duration of action
o mepivacaine is 2-3 times more potent than procaine. In horse commonly used (2 hours duration of
action)
Some rarely used local Anaesthetics:
i) ethanol
ii) phenol
iii) chlorbutol
iv) menthol
v) benzyl alcohol
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Surface anaesthesia:
Ethyl chloride (spray):
o It has freezing effect locally, so it causes numbness.
o Also used as inhalant anaesthesia.
Amethocaine (tetracaine):
o Used for ophthalmic purpose, also for infiltration.
o It is 10 times potent than cocaine.
o For topical purpose 0.5-1%, For infiltration 1-2%

TRANQUILIZERS
o Tranquilization: calmness or peace of mind.
o Tranquilizers are the drugs which calm down or unaware to surrounding.
o It is also called as psychotropic/neurotropic/ataractic drugs.
o Ataractic because they produce ataraxia & ataraxia means calmness or undisturbed stage & it is
mildest form of CNS depression, quieting, reduction in excitement & control over aggressiveness.

Tranquilizers are divided into 5 categories:

I. Phenothiazine derivatives
II. Butyrophenones
III. Benzodiazepenes
IV. Thioxanthenes
V. Rauwolfia derivatives

I. Phenothiazine derivatives:
Substitution at 2nd& 10th position gives different derivatives with different efficacy.
Common derivatives:
1) Promazine, 2) chlorpromazine, 3) acepromazine, 4) triflupromazine, 5) prochlorpromazine, 6)
trimeperazine
All of these have same property & chlorpromazine is representative of all of them.
Chlorpromazine:
They are absorbed orally, I/M & I/V all three routes & get effect depending upon route of
administration.
All these agents are metabolized in liver by sulfoxidation & they are excreted through urine.
Action & effects:
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1) Sedative action: chlorpromazine causes depression in brain stem & cortex & it generally affects
motor cortex. Due to effect on brain stem there is calmness or drowsiness & due to effect on
cortex, decreased activity but all reflexes are present.
2) Inhibition of adenosine at different synapses & this action leads to antianxiety.
3) It blocks dopamine receptors: dopamine receptors are of 2 types- 1) Doe- excitatory receptor, 2)
Doi-inhibitory receptor
It blocks Doe receptor & due to blockage of this receptor there is muscular rigidity (catalepsy) &
also causes reduction in Spontaneous Motor Activity (SMA).
This block the receptor which present in CTZ, it leads to antiemetic effect (vomiting centre in
CTZ). This effect due to this drug, it only controls vomition due to motion (travelling) due to
central nervous system or brain, not due to local irritation of GIT. It is used during
transportation of animal.
4) It has antihistaminic effect: it nullifies the effect of histamine. Used as antipruritic.
5) Antiautonomic effect: 2 types of effect- antiadrenergic & anticholinergic effect
Antiadrenergic effect: it blocks the receptors & reduces the blood pressure.
Anticholinergic effect: it reduces all secretions so used as preanaesthetic.
6) Weak antispasmodic action: reduce spasm of muscle
7) It cause depletion of catecholamines in hypothalamus & due to this action it is able to control
over heat stress (heat stroke)
8) It cause release of prolactin, so it get galactagogues effect (increase milk secretion)
9) It causes release of epinephrine from adrenal medulla, leads to hyperglycaemia.
10) It has got muscle relaxation power due to paralyzing skeletal muscle.

Clinical uses:
1) Used as preanaesthetic, because they cause CNS depression, reduce dose of anaesthetic, reduce
secretion & antiemetic.
Usually given before 1 hour of anaesthesia.
2) Used as trazquilizer for restraining the animal or reduce excitement or even performing minor
surgical operations.
3) Very strong antiemetic to control vomition so used for motion (travelling) sickness.
4) In human used in vomition during pregnancy.
5) Used in dermatitis or pruritis.
6) Used in tetanus to control animal & relaxation of muscles.
7) Used as psychotropic, used in depression or epilepsy
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8) Used in spasmodic colic.

9) Used in pseudopregnancy, to control abnormalities.

Dose & route:

1) Chlorpromazine:
Dose: 0.5-1mg/kg, I/M or I/V
2-4mg/kg, orally
Not used in horse
2) Acepromazine:
Most commonly used in horse.
It is most potent phenothiazine derivative
Dose: 0.05-0.07mg/kg, I/M;
0.025-0.035mg/kg, I/V
In horse there is incidence of phymosis&paraphymosis.
In other animals almost same dose is used.
3) Trichlorpromazine: (siquil)
Commonly used in veterinary practice.
It must be use separately in single syringe.
Dose: 1-2mg/kg, I/V
2-4mg/kg, I/M
Siquil is not used in cat because it causes stimulation of simbic system (excitement)
For large animals: 0.2-0.4mg/kg, I/V or I/M
4) Prochlorprazine: (stometil commonly given in motion sickness)
Dose: 1-4mg/kg, orally
0.5-1mg/kg, I/M or I/V

Contraindications:
1) Never use epinephrine (lifesaving drug) if animal is under the influence of phenothiazine drug.
Reason: usually epinephrine given during shock, low blood pressure due to dales s reversal
phenomenon
generaly Receptors epinephrine B.P
But phenothiazine already occupy -receptors, Hence now
Epinephrine occupy -receptors B.P further

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2) Phenothiazine should not to be given if local anaesthesia is already given. If done then severe
hypotension by local anaesthesia.
3) Phenothiazine should not be used during organophosphate toxicity. During this toxicity lot of
excitement & convulsion, if phenothiazine is given then aggregation of organophosphate.
4) Contraindicated in horse, due to violent incoordinated movement.

II. Butyrophenone derivatives:

1) Droperidol, 2) haloperidol, 3) azaperone
Most of actions similar to phenothiazines.
a) Butyrophenones block the action of dopamine, epinephrine & nor-epinephrine.
b) Butyrophenones have the action like GABA, as it get the similar action of GABA it inhibit the
action of nervous system.
c) It blocks the action of glutamic acid at synapse.
d) It blocks the -receptors, so epinephrine is contraindicated.
e) Strong antiemetic drug, net effect is tranquilizer & reduce Spontaneous Motor Activity (SMA),
reduce catalepsy (muscular rigidity), strong antiemetic property & reduce stress.
f) Among all droperidol is most potent, it is 10 times more potent than haloperidol & 400 times
than azaperone.
Clinical uses:
1) It is used as immobilization of wild animals. (due to catalepsy)
2) Antiemetic effect, this effect is 1000 times more as compared to chlorpromazine.
3) Used as anti-stress agent
4) Duration of action is very short & around ½ to 4 hours.
5) Droperidol has wide margin of safety.
6) Dose: droperidol 0.01mg/kg, I/M or I/V
Haloperidol 0.1mg/kg, I/M or I/V
Azaperone 0.8mg/kg, I/M or I/V
7) Droperidol & haloperidol usually used as immobilization & antiemetic &azaperone as
tranquilizer, neuroleptanalgesia.
8) Fluanisone is latest introduced & similar to droperidol.

III. Benzodiazepines:
E.g. diazepam, chlordiazepam, midazolam

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o Action: interfere with action of catecholamines in brain

o GABA like action
o Specific receptors of benzodiazepines
o In addition to tranquilization, also have anticonvulsant & muscle relaxation property & also
anxiolytic property (reduction in excitement)
o It has no antiemetic effect.
Clinical use:
a) Commonly used as preanaesthetic
b) Used as anticonvulsant& muscle relaxation
c) In human side use as nervous depression & induce sleep.
d) Dose: diazepam 1mg/kg by any route I/M, I/V or orally
e) It also used as neuroleptanalgesic
f) Commonly combine ketamine & xylazine for complete anaesthesia.

Drawbacks:
a) Diazepam gives rise to tolerance (reduced effect on successive exposure)
b) It induces dependence (drug consumption become compulsory or habitual)
Antagonist to diazepam is flumazenil (used in suicidal case of human being)

IV. Thioxanthenes:
o E.g. chlorprothixene not used but has antihistaminic & antiemetic property.So used for
tranquilization & emesis
o Dose: 0.5-1mg/kg, I/V
o Used in dog & small animals (sheep & goat)

V. Rauwolfia derivatives:
o Reserpine it is natural alkaloid compound derived from plant Rauwolfia serpentine.
o It acts by causing depletion by nor-epinephrine
o It never used clinically, it may use for experimental purpose
o It acts as tranquilization & sedation.
o It has severe hypotensive effect.

SEDATIVES
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Definition: these are mild CNS depressant which induce drowsiness (lethergic) & it relieve the patient
from nervousness & excitement, whereas hypnotic (greek word = god of dreams) which induce sleep.
Hypnotic also called as soporofies or somnifacients.
These hypnotic act on R AS (Reticular Activating System) & depresses it.
Compounds for sedatives &hypntics:
i) Barbiturates: long acting are generally used e.g. phenobarbiturates
Dose: in dog 30-40mg/kg, orally
In cats 50-60mg total dose (12-15mg/kg)
ii) Choral hydrate: for large animals, dose 10mg/kg, orally
iii) Diazepam: (mainly sedative)
1-2mg/kg, I/M, I/V or orally
iv) Xylazine:
For small animals 1-2mg/kg, I/M
For large animals 0.1-0.2mg/kg, I/M

ANTICONVULSANTS
These are the agents which are administered to control convulsions, epilepsy, seizer, excessive CNS
stimulation & even during tetanic condition.
Convulsion or epilepsy commonly seen in dog, cat & human being.
Discuss separately because they only control convulsion without causing any depression to CNS.
There are 2 anticonvulsants , these only cause reduction in convulsion.
Mechanism of convulsions:
convulsion basically due to hyperactivity of motor cortex. In motor cortex some of neurons act as firing
point (stimulant) & these neurons even at lower threshold potential they require to fire stimulation.
Once these are stimulated, they are capable of stimulatingneighboring neurons & entire area gets
stimulated lead to convulsions.
Anticonvulsion drugs:
I. Phenytoin:
o It acts as stabilizing agent at synapse. It will allow to passes of impulses at higher threshold at
synapse. When it act on firing neuron, firing neuron not stimulate by lower threshold
stimulation.
It is due to expulsion of actively Na+ ions outside. Drug mainly acts on motor cortex without
affecting sensory cortex. So that is reason that there is no CNS excitement.
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o It inhibits GABA, will cause slight excitement (minor effect)

o Dose: 4mg/kg, orally, initially 4 times a day &repetition is decrease.
o As frequency increases, its dose has to be increase because it induces enzymes.
Epilepsy: treatment first start with phenobarbitone (4-6mg/kg, orally) then phenytoin & then
primidone (10-13mg/kg/day) & given for 1-2 month of period.
In addition to this there is combination of phenobarbitone & primidone available.
If convulsion is mild then diazepam orally 1-2 times per day is sufficient.

ANALGESICS
Analgesic: drug control the pain. It is categorized in 3 groups:
I. Neuroleptanalgesics
II. Narcotic analgesic
III. Non-narcotics or NSAIDs (Non-Steroid Antiinflammatory Drugs)

I. Neuroleptanalgesics: it is combination of neuroleptic drugs & analgesic drugs. It is recent

drug. Neuroleptics control anaesthesia & analgesics control pain.
Combinations:
i) Droperidol + fentanyl
ii) Fluanisone + fentanyl
iii) Acepromazine + etorphine

i) Droperidol + fentanyl
In this combination neuroleptics & analgesic in proportion of 50:1.
Droperidol: potent tranquilizer, potent antiemetic, but not having analgesic effect.
Fentanyl: very potent analgesic. Fentanyl is 100 times more potent then morphine & this fentanyl
causing analgesia acting on different opioid receptors & causes analgesia. After combining they
act independently not interfere in action.
Advantages:
1) It causes tranquilization
2) Strong antiemetic
3) Cough depressant
4) Good analgesic during operation & after operation.
5) Recovery s very smooth
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6) Respiration & heart rate not at all affected

7) Very good margin of safety
Disadvantages:
1) Any loud, animal get stand, because no narcosis & anaesthesia.
2) In certain species it is undesirable & unexpected CNS excitement (horse, cat, pig) so
mainly used in dog & lab animals.
Dose: combination contains 20mg droperidol& 4mg fentanyl per ml of injection.
1ml/10kg, I/M or 1ml/25kg, I/V
ii) Fluanisone + Fentanyl
Used in dog & lab animals
Dose: 0.5ml/kg, I/M
iii) Acepromazine + Etorphine
o Acepromazine is tranquilizer & strong antiemetic.
o Etorphine is thebaine derivative& 1000 times more potent than morphine. It is sedative &
analgesic. Etorphine is commonly used in immobilization of wild animals, it is very fast acting.
Dose 0.5µg/kg
o During immobilization always higher dose is given & then capturing animal brought back to
awaken, so antagonist diprenorphine, because small dose initially there is excitement & then
depression.
o This combination commonly used in horse.
Dose: acepromazine (0.1mg/kg) + etorphine (0.025mg/kg), I/V given after mixing

II. Narcotic analgesic

Pain sensation decrease due to depression of CNS & induce deep sleep. (pain unpleasant response
to mechanical, chemical or thermal stimuli)
o These are mainly opium alkaloids.
o Opium compound obtained from poppy seeds.
o Papaver somniferum plant from capsule of seed while given cut a milky white juice
comes out, which is dried & powdered, which contain many alkaloid categorized in 2
groups:
i) Phenanthrine derivatives: e.g. morphine, codine, thebaine (these are very potent analgesic)
ii) Benzyl isoqionolones: e.g. narcotine, papaverine & narceine (mainly have spasmolytic
activity)
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Out of all these morphine is important, so study in detail:

Morphine causes:
1) CNS stimulation 1st than CNS depression
2) Very good analgesic
3) Suffer severe constipation
4) Very good cough sedative
Types of pain:
1. Chronic state pain: this is due to some stimuli to nociceptor receptor, so by this
neurotransmitter bradykinin (substance-P) release causes pain. Also histamine, serotonin &
Ach released & cause pain.
2. Phantam limb pain: there are no receptors or neurotransmitters involved but still pain is
there. No drug till today to control this pain.
Contraindications of morphine:
1) Strychnine poisoning
2) Tetanus
3) Traumatic shock severe vasodilatation B.P
4) In head injury respiration depression
5) Pregnancy

Opioids all those drugs acting on opioid receptors

Opiates compound derived from morphine
Opioid receptors basically are G-protein coupled receptors. When drug act on these, they will
cause inhibition of adenyl cyclase, so the neurotransmitter movement stop & there is cure of pain.
Types of opioid receptors: 4 types
i) µ-receptor
2 subtypes µ1& µ2
µ1 responsible for analgesic effect
µ2 cause respiratory depression
ii) -receptor
For other effects of opioids
iii) -receptor
True opioid receptor, present in almost all the sites where opium is act.
All the opium definitely act on receptor
iv) -receptor
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These receptors are acted by only endogenous opioids e.g. -endorphine, enkephalins,
dynorphins.
Toxicity of morphine:
1) Initially CNS stimulation
2) Initially increases gastric motility
3) Causes habbit of consuming & tolerance
Antagonist of morphine:
Nalorphine
Naloxone
Diprenorphine
levolorphine
Mechanism of action of opium alkaloids/analgesics:
Act on opoid receptors, cause inhibition of adenyl cyclase release of substance-P (neurotransmitter)
is inhibited
Pharmacological effects:
o Initially CNS stimulation & then depression dog, human & monkey
o Only CNS stimulation rest of all species
1) Effect on CNS:
o Acts on cerebral cortex initially, euphoria, hallucinations, excitement, followed by sedation,
narcosis & analgesia.
o The analgesic effect is observed at very low dose, so at that dose other CNS functions are
not affected.
o At very low dose sensory cortex is affected & analgesia is there.
o All pains are controlled by morphine.
2) Action on spinal cord:
o Initially stimulation than depression
o Morphine is contraindicated during poisoning & tetanus
o In brain different centers are also get affected.
o Vagal, occulomotor & vomiting centre they are 1st stimulated & then depressed.

3) Effect on GIT:
Initially diarrhoea, salivation, vomition then followed by severe constipation & dryness of
mouth.
4) Effect on respiratory system:
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Only depression reduced & shallow respiration

Cough centre depressed so these agents used as excellent cough sedatives.
5) Effect on eyes:
Initially constriction of pupil & find pin-point pupil in humans, dogs & monkeys & later on
the size comes back to normal, but in rest of species there is dilatation of pupil.
Exception: in birds no effect of morphine on size of pupil because the muscles of pupil are
unresponsive to morphine.
6) Effect on vasculation:
Severe vasodilatation which cause fall in B.P.
In addition morphine cause increase in temperature (hyperthermia) in cattle, sheep, goat, horse
where in dogs, monkeys & human there is hypothermia.
Straub test: performed on rat & mice. There is stiffening of muscle of base of tail, so the tail
is raised when administration of morphine is done.
7) It induces habituation & it causes tolerance so subsequent higher dose is required.

Clinical uses of morphine:

Used in dogs at very low dose 0.1-0.2mg/kg, I/M
Used as preanaesthetic, analgesic, intestinal sedative & diarrhoea control by orally
Used as cough sedatives
Vasomotor, cough & respiratory centre orally depressed.

Morphine derivatives:
These are compounds derived from morphine or semisynthetic compound.
I. Codeine phosphate:- it is nothing but methyl morphine. Due to methylation there are some
changes, codeine is excellent expectorant & suppress the cough. On other hand analgesic property
completely reduced. Side effect of constipation is persists. Dose: 1.1-1.2mg/kg, orally.
II. Hydromorphine:- 5 times more potent in analgesic property than morphine. In this case
stimulation drastically reduced. Dose: 1.1-1.2mg/kg, S/C & used as analgesic drug.
III. Oxymorphine:- 10 times more potent in analgesic property. Also have sedative & narcotic
property. It is used neuroleptanalgesic drug & combined with triflupromazine.
IV. Diacetylmorphine:- it is heroin. It is very-very potent analgesic drug but highly addictive.
Morphine substitutes:
It is completely synthetic compound. In this case addiction property is not seen. They are generally
used as analgesic, narcotic, spasmolytic & sedative.
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I. Meperidine (Pethidine):- it has all above properties. It does not cause any stimulation, so no
vomition. It is clinically used in spasmodic colic & preanaesthesia. Used in labour pain in human.
Dose: 5-10mg/kg, I/M
II. Methadone:- this is potent analgesic, cough sedative & spasmolytic. Used in cough &
preanaesthetic. Dose: 1.1mg/kg, S/C & very small dose as preanaesthetic (0.1mg/kg)
III. Dextromethorphan:- purely cough sedative. Dose: 1.2mg/kg, orally
IV. Pentazocine:- 100% non-addictive, very-very good analgesic but sedation is very less. So it is
mostly used as post anaesthetic.
Dose: dog 2.5-3mg/kg, I/M
Horse total exceed 400mg (i.e. 1mg/kg, I/V)
V. Butorphenol:- it is analgesic, cough sedative & it is narcotic antagonist causes reversal of
narcosis. Dose: horse & dog 0.1-0.4mg/kg, I/V
VI. Thiorphenol:- it is enkephalins inhibitor which destruct enkephalinase & terminate activity of
enkephalin.

III. Non-narcotic Analgesic/ NSAIDs (Non-Steroidal Anti-inflammatory

Drugs)
These cause analgesia without affecting brain activity.
They have 3 main properties:
1) Analgesic, 2) antipyretic, 3) anti-inflammatory

Classification: classified in 10 groups

1. Salicylic acid: - aspirin, diflunisal, benorylate

2. Aniline derivatives: - paracetamol, phenacetin

3. Pyrazolone derivatives: - (largest t1/2 of 50-100 hour) phenylbutazone, oxyphenbutazone,

azapropazone

4. Indole acetic acid derivatives: - (most potent inhibitor of COX-2) indomethacin, sulindac

5. Anthranilic acid derivatives/Fenmetes: - meclofenamic acid & mefenamic acid

6. Aryl acetic acid derivative: - diclofenac

7. Propionic acid derivative: - ibuprofen (drug of choice for inflammatory joint), naproxane,

flurbiprofen, ketoprofen & fenbufen (prodrug)

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8. Oxicams: - piroxicam, tenoxicam, meloxicam

9. Selective COX-2 inhibitors: celecoxib, rofecoxib, valdecoxib, parecoxib

10. Sulfonanilides: - nimesulide

11. Miscellaneous: - flumixin, melaquinine

Common mechanisms of action:

1) Anti-inflammatory treatment mechanism:- whenever any injury to cell, membrane
phospholipase is liberated (Phospholipase A2). It acts on lipid & formation of acid called
arachidonic acid which acted upon by 2 enzymes 1) Cyclooxygenase (COX), 2)
lipooxygenase.
o Whenever acted by cyclo-oxygenase it leads to synthesis of prostaglandins & by
lipooxygenase formation of leukotrienes.
o These all NSAIDs inhibit COX, so inhibit production of prostaglandins.
o Some prostaglandins are beneficial & some are harmful.
o Different prostaglandins:-
PG1 causes inflammation, pyrexia & pain.
PGE1 & PGE2 responsible for vasodilatation
PGI2 causes severe fall in B.P
TXA2 Thromboxane causes platelet aggregation
PGD2 it is anti-aggregation factor for platelet.
o All these PGs sensitize nerves & induce pain.
2) Antipyretic mechanism:- any infection causes release of endotoxins. These endotoxins act
as pyrogen (raise temperature). These endogenous toxins cause release of PGE. This PGE
act on hypothalamus, it raises set point temperature.
o NSAIDs cause inhibition of PGE by inhibiting COX enzyme.
o This will also in addition to inhibition of PG, they also reduce heat production or loss
of heat from the body.
3) Analgesic mechanism:- NSAIDs block the action of substance-P (bradykinin) & cause
analgesia.

1. Salicylate:
This inhibits PG & SRSA (leucotrienes) & bradykinins.
This inhibit hyaluronic acid, cause heat loss because of vasodilatation, so sweating is set at
normal.
It inhibits platelets aggregation (TXA2) so it causes gastric bleeding if therapy is prolonged.
Aspirin causes less gastric bleeding than sodium salicylate.
It prevents thrombus formation in heart attack patients by inhibiting TXA2 & used in heart
patient.
Salicylates earliest drug introduced, sodium salicylate introduced in 1875 by Buss &
aspirin in 1899 by Bayer.

Dr. H. B. Patel & Satyajeet singh

~ 78 ~
VPT 311

Toxicity:
a) Gastric bleeding
b) In cats, it is contraindicated because it make glucuronic conjugation (it absent in cat)
Dose:
In dog 10mg/kg, orally
Aspirin
In large animals 30mg/kg, orally

In dog 10mg/kg, orally

Sodium salicylate
In large animas 50mg/kg, orally
Now-a-days buffered aspirin (disprin) does not cause gastric bleeding too much.

2. Aniline derivatives: (Para amino phenol derivates)

It is potent analgesic, antipyretic but not anti-inflammatory.
It is also called as paracetamol or acetaminophene.
Paracetamol is more toxic (hepatotoxic) & phenacetin is hepato & neurotoxic & these are
even more toxic than salicylates.
In metabolism paracetamol is converted into N-acetyl benzoquinone imine, which is
hepatotoxic.
Dose: 10mg/kg
Now-a-days combination ibuprofen + paracetamol is used.

3. Pyrazolone derivatives:
It is analgesic, anti-inflammatory but less antipyretic.
It induces microsomal enzymes & has high protein binding (phenylbutazone = 98%) &
half life in human is 72 hours.
It is c0mmonly used in doppiing in race horse.
Clinically used for laminitis & myositis.
Dose: in horse 10mg/kg, I/M
In dog 40-45mg/kg, I/M or orally
Metamizole more analgesic & less anti-inflammatory.

4. Indole derivatives:
Highly toxic (indomethacin) so not used clinically. E.g sulindac
It inhibits enzyme aldose reductase which is responsible for conversion of glucose to
sorbitol.
This prevents cataract.

5. Anthranillic acid derivatives:

Dr. H. B. Patel & Satyajeet singh
~ 79 ~
VPT 311

Commonly used as antirhuematic in horse.

Dose: 2.2mg/kg/day

6. Aryl acetic acid derivative:

Eg diclofenac
Selective COX inhibitor
Commonly used in veterinary but now banned.
In dog, it causes gastric bleeding.

7. Propionic acid derivatives:

e.g. ibuprofen, brufen, naproxen etc.
Anti-inflammatory & analgesic but poor antipyretic.
Dose: 10/mg/kg, orally or I/M
Neproxane it is commonly used in horses because it is used in laminitis & myositis.
When given orally 50% is absorbed only, so it is given I/V 10mg/kg
Protein binding is 99% & that is why the half life is around 96 hours.
In dog orally causes gastritis.
Now-a-days in dog & large animals ketoprofen is used 5mg/kg, orally or I/V.

8. Oxicams:
E.g. meloxicam (vet.) & piroxicam (human)
It is selective COX2 inhibitor.
[COX1 gives beneficial PG while COX2 give harmful PG]
So it inhibit the production of harmful PGs by inhibiting COX2
It has no any side effect when orally given (it does not cause acidity & gastric bleeding)
A very low dose is sufficient highly potent
Dose: 0.3-1mg/kg, orally or I/M
Half life is very long so single dose is sufficient for a week.

9. Selective COX-2 inhibitors:

E.g. celecoxib, rofecoxib, valdecoxib, parecoxib
Directly targets the COX-2 without affecting the COX-1. COX-1 is involved in the
synthesis of PGs & Thromboxane but COX-2 is only involved in the synthesis of PGs.
Therefore inhibition of COX-2 inhibits only PGs synthesis without affecting
thromboxanes & thus has no effect on platelet aggregation or blood clotting.
COX-2 is an enzyme responsible for inflammation & pain. Selectivity for COX-2 reduces
the risk of peptic ulceration.

10.Sulfonanilides:
E.g. nimesulide
Selective COX2 inhibitor but less anti-inflammatory action.
It also inhibit superoxide formation.

Dr. H. B. Patel & Satyajeet singh

~ 80 ~
VPT 311

It also inhibit the release of histamine, so can be used in shock or anaphylactic reaction.
Dose: 2mg/kg mostly available as oral preparation

11.Miscellaneous group:
E.g. flumixin, meglumine
Flumixin all 3 actions are very potent
Dose: @ 1mg/kg, I/V or I/M
Meglumine 2.2mg/kg, I/V in large animals.

One drug not fits in any category

I.e. xylazine
potent sedative & analgesic drug & muscle relaxant
It has got analgesic property similar to morphine not has any CNS stimulant activity.
Potent sedative drug
Very good muscle relaxant.
Mechanism of action:
o It acts on 2 adrenergic receptor present in brain only. So it is 2 adrenergic receptor agonist.
o It inhibits neuronal transmission hence it is good muscle relaxant.
o It causes stimulation of vomiting centre in brain & invariably causes vomition.
Side effects of xylazine in dogs & cats:
o It causes bradycardia & hypotension (low B.P & low heart rate)
It also causes aerophagia (taking air inside) in ruminants & causes bloat in rumen.
The margin of safety is very good in xylazine.
Ruminants are very sensitive to xylazine so they require 1/10th of the dose of dog & cats.
Pigs are insensitive to xylazine, so not a drug of choice in pigs.
I/M get effect in 10-15 minutes.
I/V get effect in 3-5 minutes.
Sedative effect last for 1-2 hours & complete recovery in 5-6 hours.
Dose:
Small animals 1-2mg/kg, I/M 0.5-1mg/kg, I/V
In ruminants 0.1-0.2mg/kg, I/M
Clinical uses:
1) Preanaesthetic
2) Minor surgical operations
3) Normal restraining of animal
4) Used in major operation like caesarean operation, in this xylazine is given & then operation is
performed by giving local anaesthesia.
5) Xylazine + ketamine combination is used in cats for major operation.
11-44mg/kg ketamine muscular rigidity
1-2mg/kg, I/M xylazine muscle relaxant & sedative.
6) In horse xylazine + ketamine + diazepam combination is used.
In xylazine toxicity, antidote yohimbine (0.1mg/kg, I/V)

Dr. H. B. Patel & Satyajeet singh

~ 81 ~
 VPT 311

CNS STIMULANTS
Those drugs stimulate nervous system.
Classified in 3 categories:
I. Predominately cortical stimulator
II. Predominately medullary stimulator Direct CNS stimulator
III. Predominately spinal stimulator
Nicotine, ammonia & lobeline Indirect or Reflexly CNS stimulator (clinically not used)

I. Cortical stimulator

A. Xanthine derivatives: these are alkaloid obtained from tea & coffee. Basically 3 alkaloids
a) Caffeine: 1,3,7-trimethylxanthine, obtained from coffee seed (Coffee arabica)
It affects dieresis, CNS & cardiovascular system
Mechanism: 4 mechanisms
1) It releases Ca+2 from the sarcoplasmic reticulum (skeletal & cardiac muscle) & also blocks the
adenosine receptors.
2) Phosphodiestrase inhibition & release of Ca+2 & probably exerted at concentrations much
higher than the therapeutic plasma concentration, while adenosine receptors blockade.
3) cAMP is metabolized by enzyme phosphodiestrase, it causes inhibition of phosphodiestrase
enzyme & more cAMP is available. So there is more steroid synthesis & release of hormones.
4) This caffeine causes im la i n f -adrenergic receptors so it causes cardiac stimulation.
Caffeine acts on adenosine receptors & block them & due to this blockage there is inhibition
of depression of cardiac pacemaker.
Clinical uses:
Given orally or I/M, when given I/M sodium-benzoate is added in caffeine which
increases solubility of it.
It is generally used in severe case of narcotic depression or sedation.
Dose: horse & cattle total dose 4mg
Sheep & goat total dose 1-1.5mg
Cat & dog total dose 100-500mg
In general there is wide margin of safety but in heavy dose lead to convulsion.
b) Theobromine: 3,7-dimethylxanthine, obtained from cocoa seeds (Theobroma cacao)
Mild effect on CNS, mainly affect cardiovascular system & dieresis.
c) Theophylline: 1,3-dimethylxanthine, obtained from tea leaves (Thea sinensis )
(Aminophylline semisynthetic)
Commonly available
o Having less CNS stimulant activity but more bronchodialator activity.
o Increases cardiac activity
o It got diuretic effect.
o It is more commonly used in respiratory depression like asthma etc.

Dr. H. B. Patel & Satyajeet singh

~ 82 ~
 VPT 311

o It is used in congestive heart failure.

o It is commonly used in condition in horses called as Broken wind
o Dose: dog total dose = 50mg
Horse/other 1-2mg/kg, orally or I/M or I/V
o In human it is used as spray.
o Asthalin spray aminophylline/salbutamol
Out of above 3, theobromine clinically not used.

B. Sympathomimetics:
o Commonly used amphetamine & ephedrine
o They are power pressure drugs increase B.P & cardiac output
o Amphetamine dextrorotatory (CNS stimulation) & leavorotatory (cardiovascular drug)
form.
o Dextrorotatory form causes temporary stimulation of nervous system which increases mental
& physical activity. So it is drug abuse for dopping (in horses)
o It has got effect anorexigenic effect which causes anorexia (loss of appetite), so it is used as
anti-obesity effect.
o Dose: 3-4mg/kg, S/C or I/M
o Ephedrine similar to amphetamine, given orally, 3-4mg/kg

II. Medullary stimulator

These are mainly respiratory stimulant & also called analeptics.
Clinical uses:
1) Used in post anaesthetic depression
2) Used in asphyxia
3) Used in neonate asphyxia
4) Used in drwning
5) Used in barbiturate poisoning
6) Used in heat & electric shock
7) Used in chronic hypoventilation with CO2 retention.
Compounds:
i) Doxapram:
It stimulates medullary respiratory centre & it acts on chemo-receptors present in carotid
arteries & aortic arch & stimulates the respiration & also increase the B.P.
Most superior respiratory stimulant, it has got very short duration of action.
It is used as an antidote of thiopentone toxicity.
Dose: dog 1-2mg/kg, I/V
Cattle & buffalo 0.5mg/kg, I/V
ii) Leptazol, metrazol:
Stimulation of medullary respiratory centre.
Stimulation of vasomotor centre so increase blood supply.
Inhibition of GABA leads to stimulation
Acts very rapidly but is has very low margin of safety.

Dr. H. B. Patel & Satyajeet singh

~ 83 ~
VPT 311

Dose: dogs & cats total dose 50-100mg, I/M

Horse & cattle total dose 0.5-1mg, I/M
Given in case of extensive barbiturate depression.
iii) Nikethamide: (Coramine)
Derivative of the nicotinic acid, action similar to doxapram
It initially causes stimulation & lately depression.
Commonly used in barbiturate & morphine depression.
Available orally mainly given in small animals
Dose: dog & cat 22mg/kg, orally or I/V or I/M or S/C
Available as drops
iv) Picrotoxin: (cocculin)
Natural compound obtained by seeds of plant Anamirta cocculus.
Get effect on medulla as well as spinal cord.
It is non-competitive antagonist of GABA.
Margin of safety is less.
As it stimulates spinal cord, it causes convulsion, so no use.
v) Bemigride: (antagonist of barbiturate)
Clinically used in barbiturate poisoning.
Dose: 20mg/kg, I/V
vi) CO2: (physiological analeptic)
When CO2 concentration increase in blood it stimulate respiratory centre.
CO2 can be given eternally & causes respiratory stimulation.
It causes severe acidosis when given externally.

III. Spinal stimulants

i) Strychnine
Alkaloid derived from seed of plant Strychnos nux-vomica.
Commonly available as nux vomica powder .
Basically acts on spinal cord.
In brain reinshow cell present & it does not allow impulse to pass continuously (motor
impulse) & this strychnine blocks these reinshow cells & give exgraded response &
motor impulse passes out.
GABA act on brain
Inhibitory neurotransmitter
Glycine act on spinal cord
So this strychnine causes inhibition of these GABA & Glycine, will cause exgrated
response & lead to condition hyperaesthesia
It causes severe convulsion & muscular spasm.
Clinically used very limited used as nervine tonic.
Powder form dose:
Horse & cattle 15-16mg
Sheep & goat 10-15mg
Pig 5-8mg always orally

Dr. H. B. Patel & Satyajeet singh

~ 84 ~
VPT 311

Dogs 0.5-1mg
Cats 0.1-0.5mg
The powder is dissolved & form solution & then given orally.

MUSCLE RELAXANTS
All these agents cause muscle paralysis, so used in convulsion & extreme contration.
They either cause flaccid or spastic paralysis.
These terminology more used for neuromuscular blockage.
These are divided into 2 groups:
I. Centrally acting:
Act on brain, but not cause anaesthesia. They expected to control muscle contraction.
E.g
i) Diazepam:
It is not specific for muscle relaxation.
ii) Mephenesin:
Specific centrally acting muscle relaxant & least effect on CNS.
Not used clinically, due to various adverse reactions (it causes thrombosis & haemolysis)
It acts on both skeletal & smooth muscle all centrally acting muscle relaxant.
iii) Guaifenesin:
Commonly used muscle relaxant.
Common irritant added in cough syrup.
It causes flaccid type of paralysis.
It acts as glycine agonist
It acts on monosynaptic & polysynaptic motor nerve.
It has got wide margin of safety.
Used as cough syrup.
Controlling convulsion, due to strychnine poisoning & tetanus convulsion.
But not used against GABA induced convulsions.
If given I/V haemolysis, so given orally mostly.
iv) Baclofen:
It has GABA like activity, so it can be used in reduce spasticity in neurological disorders.
v) Methocarbamol:
Mechanism not clear
Used in dog, cat & horse as muscle relaxant.
In dog & cat 40mg/kg, orally
Horse 5-20mg/kg, I/V
vi) Dantrolene:
Directly acting skeletal muscle relaxant.
It inhibits release of Ca+2 from sarcoplasmic reticulum.
It has also some effect on brain.

Dr. H. B. Patel & Satyajeet singh

~ 85 ~
VPT 311

It is only specific & effective treatment for malignant hyperthermia, a life-threatening disorder
triggered by general anaesthesia.
Dose: dog 2.5mg/kg, I/V
Horse & pig 1-3mg/kg, I/V

II. Peripherally Acting/Skeletal Muscle Relaxant/Neuromuscular Blockers

Act on neuromuscular end plate & called as neuromuscular blockade.
COMPETITIVE BLOCKER NON-COMPETITIVE BLOCKER
Non-depolarizing Depolarizing
Reversible blocker Irreversible blocker
Flaccid paralysis Spastic paralysis
I. Natural compounds E.g.
d-tubocurarine (obtained from plant Succinylcholine (suxamethonium)
Candrodendrum tomentosum or pot Decamethonium
curare) -toxin present in venom of poisonous snake
E.g.
II. Synthetic compounds like cobra
Gallamine
Pancuronium
Alcuronium

Both of these groups have antagonistic effect, if given together so combination has no effect at all.

Pharmacological effects of neuromuscular blockers:

Effect on Cardiovascular system:- severer vasodilatation fall in B.P
Most of these agents when given rapid I/V injection, release histamine which causes anaphylactic
reaction, severe bronchoconstriction leads to shock & death. So given in diluted form very slowly.

Clinical uses:
1) As preanaesthesia
2) In convulsion disorder
3) Capturing the wild animals
Dose:
1) d tubocurarine:
Cat, dog, pig 0.4-0.5mg/kg
Small ruminants 0.06mg/kg
2) Gallamine:
Dog & cat 0.1mg/kg
Rest animals 0.5mg/kg
3) Succinylcholine:
Dog & cat 0.5-1mg/kg
Cattle, buffalo & horse 0.04-0.05mg/kg

Dr. H. B. Patel & Satyajeet singh

~ 86 ~
VPT 311

MOOD ELEVATORS
Used in human in case of depression. Also called as thymoleptics/antidepressant.

Types of antidepressents:
1) Selective serotonin reuptake inhibitors (SSRIs)
E.g. citalopram, fluoxetine, fluvoxamine etc.

2) Selective serotonin reuptake enhancers (SSREs)

E.g. tianeptine

3) Serotonin-norepinephrine reuptake inhibitors (SNRIs)

E.g. duloxetine, milnacipram, venlafexine

4) Tricyclic antidepressant (TCAs)

E.g. imipramine, desimipramine, trimipramine, amitriptyline, clomipramine

5) Monoamine Oxidase inhibitors (MAO-inhibitors)/MAOIs

E.g. selegiline, iproniazid, isocarboxazid, moclobemide, mitheum chloride
Moclobemide reversible inhibitor of monoamine Oxidase A (RIMA)

Neurotransmitters in nervous system:

1) Neurotransmitters: chemicals released from nerve terminal & acts on specific receptor
2) Neuromodulators: these are chemicals which are released from cells other than neurons &
away from syneptic site but got effect on nervous system.
3) Neuroregulators: these are released from neurons but does not enter in circulation but affect
the functioning of other neurons.

Neuro-peptide

Neurotransmitter

Non-peptide
Neuro-peptide Non-peptide
Mol.Wt.> 300 Small molecule, Mol. Wt. < 200
Slow onset of action but for prolonged period Act very rapidly & short period of action
Released by Gut Two subgroups:
CCK (Cholecystokinin) 1) Amine:
Dr. H. B. Patel & Satyajeet singh
~ 87 ~
VPT 311

Substance-P (bradykinin) Acetylcholine

Endogenous opioids Dopamine
ACTH Norepinephrine
Angiotensin 5-HT
Histamine
2) Amino acid:
L-glutamate
L-aspartate
GABA
Glycine

Amine:
1) Acetylcholine:- it acts on nicotinic & muscarinic cholinergic receptors, stimulating in action
2) Dopamine:- act on D1 & D2 receptors, depression in action. Whenever excess of dopamine
causes schizophrenia & deficiency causes parkinson s disease.
3) Theses act on & receptors:
a) Norepinephrine:- stimulator/inhibitor
b) 5-HT/serotonin:- act on serotonin receptor. These are of 7 types 5HT1 to 5HT7. Basically
inhibitory in function & induces sleep.
c) Histamine:- act on H1, H2 & H3 receptors, action is inhibitory

Amino acid:
1) L-glutamate:- stimulation mammary function
2) L-aspartate:- stimulatory
3) GABA:- inhibitory
4) Glycine:- inhibitory

Antagonist:-
drug that interact with receptor or other component of effector mechanism & inhibits action of agonist.
1) Pharmacological antagonist:- receptor same
a) Competitive:- e.g. atropine, propranolol
b) Non-competitive:- e.g. organophosphate pesticide
2) Physiological antagonist:- opposing effect by other receptor
3) Chemical antagonist:- 2nd drug for changing structure of 1st drug
4) Physical antagonist:-e.g. adsorbent, charcoal, kaolin

Dose ratio:-effect of antagonism measured in term of dose ratio.

Dose ratio = ED50 after antagonism

ED50 before antagonism

Double reciprocal plot of Lineweaver & Burk method to analyse drug antagonism

Dr. H. B. Patel & Satyajeet singh

~ 88 ~
VPT 311

Therapeutic index more more selectivity of drug

Second messengers:-
The cytoplasmic components which carry forward the stimulus from the receptor are known as 2 nd
messenger. E.g. cAMP, cGMP, Ca+2, G-protein, IP3, DAG
1st messenger is being the receptor itself.
1) cAMP:- as 2nd messenger by Sutherland. In energy metabolism, cell division & differentiation,
ion transport, smooth muscle contraction
2) cGMP:- cardiac cells, bronchial smooth muscles.
3) IP3:- release Ca+2 from intracellular store
4) DAG:- activate protein kinase C & control phosphorylation of amino acids.
IP3 & DAG:- by michell. Both are degradation products of membrane phospholipid.
5) Ca+2:- bind to protein calmodulin. Release arachidonic acid by activating phospholipase &
initiate synthesis of PGs & leukotrienes.
6) G-proteins:- it is only 2nd messenger present on cell membrane, other all are intracellular. It is
consist of , & .

Basket cells hippocampus, cerebellar cortex

Granule cells olfactory bulb
Purkinje cells cerebellar cortex
D-cells spinal cord
Pyramidal cells/giant cells cerebrum

Important points:
-globulin fraction is separated from serum by dialysis.
Riboflavin stains the urine
A drug that reverses plasma-protein binding is termed as protein hydrolysate
Methotrexate never used with aspirin.
Antidote of heparin overdose is protamine sulfate.
AlCl3 is mainly used as antiperspirant.
Salicylic acid is primarily used as keratolytic agent.
All tetracycline antibiotics are destroyed by alkali hydroxides.
Moxan (moxalactam) is most closely related to cephalosporins
Drug of choice for leprosy sulfone therapy
Drug used in treating 2nd & 3rd degree burn is mafenide (trade name = sulfamylon)

Parts of prescription:
1) Date:-
2) Identity of owner & detail of patient:-
3) Superscription:-
Rx means you take & symbol of roman god Jupiter

Dr. H. B. Patel & Satyajeet singh

~ 89 ~
VPT 311

4) Inscription:-
It is heart of prescription in which drug dose, route & ingradients are written
Curative/basis
Adjuvant enhance action of curative drug
Corrective prevent untoward reaction of curative/adjuvant
Vehicle suitable medium
5) Subscription:-
Directions for pharmacist to compound & diagnose the medicine.
6) Transcription:-
Directions given to owner to administer drug
7) Prescriber signature:-

Instruments:
1) Plethismograph:- used for screening of anti-inflammatory activity of drug.
2) Hg-manometer:- for recording blood pressure of animal.
3) Metabolic cages:- for effect of diuretic & antidiuretic drug.
4) Convulsiometer:- study of effect of anticonvulsing effect of drug.
5) C k le climbing a a a :- for screening effect of drug on CNS
6) Analgesiometer:- for studying analgesic property of drug.
7) Magnus apparatus/heart perfusion assembly:- study the effect of various drugs on heart.
8) Actophotometer:- for measuring Spontaneous Motor Activity (SMA)

Dr. H. B. Patel & Satyajeet singh

~ 90 ~
Class Notes- VPT 321

E.g. zafirlukast, montelukast

7) Anti-inflammatory agents:
E.g Beclomethasone,
Budesonide
Flunisolide
Fluticasone used as Inhalor
Mometasone
Triamcinolone
Prednisolone used in horse for relief from COPD

5. Analeptics:
Drugs which stimulate the respiration & they are used to relieve the respiratory depression
especially due to overdose of anaesthesia or due to toxicity of other CNS depressant drugs.

E.g

a) Doxapram
Dose: Horse: 0.5-1.0 mg/kg, I/V
Dog & cat: 1.0-5.0 mg/kg, I/V
Foal: 0.02-0.04 mg/kg, I/V
b) Nikhetamide
Dose: 2-4 mg/kg, P/O or I/M or I/V
c) Methyl xanthine:
Stimulate the medullary respiratory centre.
E.g caffeine

AUTOCOIDS
Auto = self, coids = remedy

Also called “local hormone” (because they synthesized locally & act locally & degraded
quickly)

While hormone synthesized by specific gland, poured into blood stream & carried to target
cell.

Autocoids have 3 classes:

1) Amines

By Dr. H. B. Patel & Satyajeet Singh ~ 84 ~

Class Notes- VPT 321

E.g histamine, 5-HT

2) Lipids
E.g. PAF, Eicosanoids

3) Peptides
E.g. Angiotensin, rennin, bradykinin

Histamine
Source:

Animals, plants, bacteria, venom.

Found in all tissue, higher in lungs, skin, GIT, mast cells, histaminergic neurons in brain.

Synthesis:

l –histidine

Histidine decarboxylase

Histamine

N-methyl histidine

N-methyl histamine imidazoleacetic acid (IAA)

N-methyl imidazoleacetic acid urine

Physiological functions of histamine:

1) contraction of intestinal smooth muscle

2) sensation of pain & itching in CNS
3) tissue growth & repair
4) body temperature regulation
5) stimulation of gastric secretion (H2)
6) cardiac stimulation (H2)
7) vasodilation (H1)
8) increased vascular permeability (H1)
9) contraction of most smooth muscle, except blood vessels (H1)

Pathological functions of histamine:

By Dr. H. B. Patel & Satyajeet Singh ~ 85 ~

 Class Notes- VPT 321

1) peptic ulcer
2) itching/pain
3) vasodilation/decreased B.P
4) type I hypersensitivity reaction

o Histamine produces effects by acting on H1, H2 or H3 (and possibly H4) receptors on

target cells.
o All receptors are excitatory except vascular smooth muscles.

I. H1 receptors:

Location
o Smooth muscles of intestine
o Smooth muscles of bronchi
o Smooth muscles of blood vessels
o Uterus
o Brain
Functions:
o Contraction of intestinal smooth muscle
o Constriction of bronchi
o Relaxation of vascular smooth muscles
o Vomition induction
o CNS stimulation
o Afferent nerve stimulation
H1 agonist:
Histaprodifen
H1 blockers:
Mepyramine, phenaramine

II. H2 receptors:

Location:
o Gastric parietal cells
o Heart
o Brain
o Mast cells
Functions:
o stimulation of gastric secretion
o increase heart rate
o CNS excitation

H2 agosnists:
Amthamine

By Dr. H. B. Patel & Satyajeet Singh ~ 86 ~

 Class Notes- VPT 321

H2 blockers:
Ranitidine, cimetidine, roxatidine

III. H3 receptors:

Location:
Brain

Function:
Excitation in brain

H3 agonist:
α-Methylhistamine, imetit, immepip

H3 blockers:
Thioperamide

Pharmacological effects of histamine:

1) Vascular smooth muscles:
Cause intense vasodilation producing hypotensive crisis.

2) Heart:
Increase force of Contraction (Positive Inotropic effect)
Increase heart rate (Positive Chronotropic effect)
Increase coronary blood flow

3) Triple response:
Intradermal injection of histamine causes flush, flare & weal formation known as
triple response.
Flush reddening at the point of injection (local vasodilation)
Flare surrounding redness (in sensory nerves releasing a peptide mediator)
Weal escape of fluid from capillary (direct action on blood vessels)
Sting of bee, scorpion contain histamine.

4) Extravascular smooth muscles:

o Bronchiole muscle
Constriction in man
Relaxation in cat, sheep, rat

o GIT
Increase motility & tone
Increase secretion of gastric acid

5) S/C injection:
Causes pain & itching

By Dr. H. B. Patel & Satyajeet Singh ~ 87 ~

Class Notes- VPT 321

ANTIHISTAMINES :

Mechanism of action:
1) Release inhibitors: reduce the degranulation of mast cells that results from
antigen-IgE interaction, so no membrane lysis of mast cells & no histamine
release.
E.g. Corticosteroids, cromolyn, nedocromil

2) Physiologic antagonist: it causes vasoconstriction so no effect of histamine

release action.
E.g. epinephrine
Injection of epinephrine can be lifesaving in systemic anaphylaxis in which
massive release of histamine.

3) Histamine receptor antagonists

Classification of H1 blockers:
1) Ethanolamine derivatives
E.g. diphenhydramine, carbinoxamine

2) Ethylenediamine
E.g. pyrilamine, antazoline

3) Alkyl amine (selective H1 blocker)

E.g. pheniramine, chlorpheniramine, bromopheniramine

4) Piperazine
E.g. hydroxyzine, cyclizine, meclizine

5) Phenothiozine
E.g. promethazine, trimeprazine

6) Miscellaneous
E.g. cyproheptadine

Other classification:
1) Highly sedative
E.g. promethazine, diphenhydramine

2) Moderately sedative
E.g. cyproheptadine, pheniramine

3) Mild sedatives
E.g. chlorpheniramine (Avil), cyclizine
By Dr. H. B. Patel & Satyajeet Singh ~ 88 ~
Class Notes- VPT 321

4) Non-sedative
E.g. cetrizine, astemizole, fexofenadine

Pharmacological effects antihistamine:

1) Antihistaminic effect
2) Antimuscarinic effect
3) Antiemetic effect (E.g. cyclizine, promethazine)
4) CNS sedation (but not by cetrizine)
5) Local anaesthetics (E.g. promethazine, diphenhydramine)

Clinical uses of antihistamines:

1) Allergic disorders
2) Anaphylactic syndrome
3) Motion sickness
4) Eczema
5) Sedation
6) Preanaesthetic

Serotonin/5-HT/5-Hdroxytryptamine
Serotonin was the name given to an unknown vasoconstrictor substance found in the serum
after blood had clotted. It was identified chemically as 5-hydroxytryptamine in 1948 and
originate from platelets. It was subsequently found in the gastrointestinal tract and central
nervous system (CNS), and function both as a neurotransmitter and as a local hormone in the
peripheral vascular system.

Distribution, biosynthesis & degradation:

5-Hydroxytryptamine occurs in the highest concentrations in three organs.

1) In the wall of the intestine. Over 90% of the total amount in the body is
present in the enterochromaffin cells in the gut.
2) In blood. 5-HT is present in high concentrations in platelets, which accumulate
it from the plasma by an active transport system and release it when they
aggregate at sites of tissue damage.
3) In the CNS. 5-HT is a neurotransmitter in the CNS.

5-HT arises from a biosynthetic pathway similar to that of noradrenaline, except that
the precursor amino acid is tryptophan instead of tyrosine. Tryptophan is converted
to 5-hydroxytryptophan (in chromaffin cells and neurons, but not in platelets) by
the action of tryptophan hydroxylase. The 5-hydroxytryptophan is then
decarboxylated to 5-HT by amino acid decarboxylase. Platelets possess a high-

By Dr. H. B. Patel & Satyajeet Singh ~ 89 ~

Class Notes- VPT 321

affinity 5-HT uptake mechanism, and platelets become loaded with 5-HT as they
pass through the intestinal circulation.
The mechanisms of synthesis, storage, release and reuptake of 5-HT are very similar
to those of noradrenaline. Many drugs affect both processes randomly, but selective
serotonin reuptake inhibitors (SSRI) have been developed and are important
therapeutically as antidepressants.
5-HT is often stored in neurons and chromaffin cells as a cotransmitter together
with various peptide hormones, such as somatostatin, substance P or vasoactive
intestinal polypeptide.

Degradation occurs mainly by monoamine oxidase, forming 5-hydroxyindoleacetic

acid (5-HIAA), which is excreted in urine

Pharmacological effects of 5-HT:

1) GIT
By 5-HT1 increases secretion & peristalsis
By 5-HT3 slow the motility of intestine
2) Smooth muscles of uterus & bronchiole: causes contraction
3) Platelets: platelet aggregation by 5-HT2 receptor
4) CNS: 5-HT excites some neurons and inhibits others
5) Nerve endings: 5-HT stimulates nociceptive (pain-mediating) sensory nerve
endings by 5-HT3 receptor. If injected into the skin, 5-HT causes pain.

Classification of 5-HT receptor:

Currently there are 15 known receptor subtypes. These are divided into 7 classes (5-HT1-
7), with further subtypes of 5-HT1 (A-F) and 5-HT2 (A-C). All are G-protein-coupled
receptors, except 5-HT3, which is a ligand-gated cation channel.

Main 5-HT receptor subtypes

Receptor Location Main effects Agonists Antagonists

Neuronal inhibition
Spiperone
Behavioural effects: sleep, Buspirone
1A CNS Methiothepin
feeding, thermoregulation, 5-CT
Ergotamine (PA)
anxiety
CNS
Presynaptic inhibition
Vascular
1B Behavioural effects Ergotamine (PA) Methiothepin
smooth
Pulmonary vasoconstriction 5-CT
muscle
CNS Cerebral vasoconstriction
Sumatriptan Methiothepin
1D Blood Behavioural effects:
5-CT Ergotamine (PA)
vessels locomotion
CNS Neuronal excitation Ketanserin
2A LSD
PNS Behavioural effects Cyproheptadine

By Dr. H. B. Patel & Satyajeet Singh ~ 90 ~

Class Notes- VPT 321

Smooth Smooth muscle contraction Methysergide

muscle (gut, bronchi, etc.)
Platelets Platelet aggregation
2B Stomach Contraction α-Me-5-HT -
CNS
α-Me-5-HT
2C Choroid Cerebrospinal fluid secretion Methysergide
LSD
plexus
Neuronal excitation
(autonomic, nociceptive Ondansetron
PNS
3 neurons) Chlorophenyl- Tropisetron
CNS
Emesis biguanide Granisetron
Behavioural effects: anxiety
5-Methoxy-
PNS (GI Various experimental
Neuronal excitation tryptamine
4 tract) compounds (e.g. GR113808,
increased GI motility Metoclopramide
CNS SB207266)
Tegaserod
5 CNS Not known Not known Not known
6 CNS Not known Not known Not known
CNS
GI tract 5-CT Various 5-HT2 antagonists
7 Not known
Blood LSD No selective antagonists
vessels

2-Me-5-HT = 2-methyl-5-hydroxytrypamine
5-CT = 5-carboxamidotryptamine
LSD = lysergic acid diethylamide
PA = partial agonist
α-Me-5-HT = α-methyl 5-hydroxytrypamine

Actions and functions of 5-hydroxytryptamine:

Important actions are:

o increased gastrointestinal motility (direct excitation of smooth muscle and

indirect action via enteric neurons)

o contraction of other smooth muscle (bronchi, uterus)

o mixture of vascular constriction (direct and via sympathetic innervation) and

dilatation (endothelium-dependent)

o platelet aggregation

o stimulation of peripheral nociceptive (pain sensitive) nerve endings

o Excitation/inhibition of central nervous system neurons.

Physiological and pathophysiological roles include:

o In periphery: peristalsis, vomiting, platelet aggregation and haemostasis,

inflammatory mediator, sensitisation of nociceptors and microvascular control

o In CNS: many postulated functions, including control of appetite, sleep,

mood, hallucinations, stereotyped behaviour, pain perception and vomiting.

By Dr. H. B. Patel & Satyajeet Singh ~ 91 ~

Class Notes- VPT 321

Clinical conditions associated with disturbed 5-hydroxytryptamine function include

migraine, carcinoid syndrome, mood disorders and anxiety.

Eicosanoids
In mammals, the main eicosanoid precursor is arachidonic acid.
The initial and rate-limiting step in eicosanoid synthesis is the liberation of arachidonic
acid, from phospholipids by the enzyme phospholipase A2 (PLA2).

The free arachidonic acid is metabolised by several pathways, including the following:

o Cyclo-oxygenase (COX). Two main isoform forms, COX-1 and COX-2,

transform arachidonic acid to prostaglandins and thromboxanes.

o Lipoxygenases. Several subtypes synthesise leukotrienes, lipoxins.

Platelet Activating Factor/PAF

PAF is released from activated inflammatory cells by phospholipase A2 and acts on
specific receptors in target cells.

Pharmacological actions include vasodilatation, increased vascular permeability,

chemotaxis and activation of leucocytes (especially eosinophils), activation and
aggregation of platelets, and smooth muscle contraction.

PAF is implicated in bronchial hyperresponsiveness and in the delayed phase of

asthma

Bradykinin

BK is a peptide 'clipped' from α-globulin, kininogen, by kallikrein.

It is converted by kininase I to an octapeptide, BK1-8, and inactivated by kininase II
(angiotensin-converting enzyme) in the lung.

Pharmacological actions:
o vasodilatation
o increased vascular permeability
o stimulation of pain nerve endings
o stimulation of epithelial ion transport and fluid secretion in airways and
gastrointestinal tract
o Contraction of intestinal and uterine smooth muscle.
There are two main subtypes of BK receptors: B2, which is constitutively present, and
B1, which is induced in inflammation.

By Dr. H. B. Patel & Satyajeet Singh ~ 92 ~

 CHAPTER-1
HISTORY, BRANCHES AND SCOPE OF PHARMACOLOGY
Pharmacology : (Greek word “pharmacon” = drug) Study of drug and its effect on living organism, which
include drug source, action, absorption, distribution, metabolism and excretion, clinical application, side
effect, toxic effect, dose and dose rate.
Drug : (French word "drogue"= dry herb) Any compound which is used for diagnosis, prevention, treatment
and mitigation of disease in human or animals.
History :
● Nakul (3000-2500 B.C). : Practiced Veterinary Medicine
● Hippocrates (460-375 B.C) : Father of Medicine (Modern medicine finds its origin with the "DoCtrine of
Hippocrates". Formed prnciple above all do not harm. Given concenpts of four elements of nature and body.
● Paracelsus (1493-1541 BC) : Started use of mercury in medicinefor treatment of syphillis. “All the
substances are poison ther is none which is not poison. Right dose differenetiates drug from poison.”
● Theophrastus (380-287 B.C) : Classification of medicinal plants.
● Dioscorides (77 B.C) : Wrote "Materia medica"
● Pedanius Dioscorides : Compiled first materia medica.
● Galen (131-2001 A.D) : Advocated polypharmacy, it means use of multiple drugs at single time and
preparation of galen termed as galenical preparation.
● John Hunter (1728-1793) : English physician deals with clinical pharmacology.
● William Withering (1741-1799) : Use of digitalis (foxglove) extract for treatment of dropsy and conges-
tive heart failure.
● Emperor Shennung (2753-2700 BC) : Compiled “Pan Taso”, (Chines Herbal Materia medica)
● Friedrich Serturner (1841) : Isolated morphine from opium
● Francois Magendie (1783-1855) : Introduced experimental pharmacology
● Claude Burnerd (1813-1878) : (French physiologist who pioneered animal experimentation and vivi-
section. Recognized as father of modern physiology and experimental medicine.
● Rudolf Buchheim (1820-1879 BC) : Established first pharmacology laboratory at the university of
dorpat, Estonia.
● Oswald Schmiedeberg (1838-1921) : Father of Modern Pharmacology. He was professor of phar
macology at University of Strasburg, France. He established pharmacology as an independent disciplene.
● Paul Ehrlich : Father of Chemotherapy.
● John J. Abel : Father of Pharmacology (USA). Isolated adrenaline and acetylcholine.
● L. Meyer Jones : Edited first edition of Veterinary Pharmacology and Therapeutics (1949).
Recognized as Father of Modern Veterinary Pharmacology.
● Kahun Papyrus (2000 BC) and Eberspapyrus (1550 BC) described collection of many herbal
preparations used by ancient egyptians.

Branches of Pharmacology and scope

● Pharmacology is a branch of science that deals with sources of drug,its physico chemical properties,
its absorption, distribution, metabolims and excretion of drug, clinical application of drug, adverse drug
reaction and toxicity of drugs. Different branches of pharmacology are discussed as under :

● Pharmacokinetics: It is study of absorption, distribution, metabolism and excretion of drug.

● Pharmacodynamics: It is study of mechanism of action of drugs i.e., its biochemical and physiological
effecst on body.
● Pharmacotherapy: It is the treatment of disease with the help of drug.
● Therapeutics: It is practical branch of medical science which deals with application of knowledge of all

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 sciences in the treatment of any disease.
● Pharmacotherapeutics: Study of drug effects in disease state. In other words it is the response of an
organism to drug in disease state.
● Pharmacy: It is collection, preparation, standardization and dispensing of drug in different dosage forms.
● Pharmacognosy: It is study of source and identification of drugs.
● Pharmacometrics: It is quantitative and qualitative measurement of drug effect in relation to dose
administered. i.e. intensity of effect. (dose-response relationship)
● Experimental pharmacology: Study of effects and mechanism of action of drug in the laboratory animals.
● Comparative pharmacology: It is study of Relative action of drug on different species of animals.
● Applied pharmacology: It is application of knowledge of pharmacological science in drug discovery
and development or to treat a disease.
● Clinical pharmacology: It is evaluation of drug in clinical condition.
● Chemotherapy: It is Branch of pharmacology which deals drugs that selectively inhibits or kills
specific agents that causing diseases.
● Toxicology: It is study of toxicity or adverse effect of drugs.
● Neuropharmacology: It is study of action and effects of drugs on nervous system.
● Immunopharmacology: It is study of drug induced immunosuppression and immunomodulation.
● Molecular pharmacology: It is study of chemical interaction between drug molecules and chemical
groups in cells at molecular level. It explains the mechanism of drug action and the effects observed.
● Pharmacoepidemiology: Study of the variations in drug response between individuals in a population
or groups of population.
● Pharmacogenetics: It is generally regarded as the study or clinical testing of genetic variation that gives
rise to differing response to drugs. It deals with the genetic basis of individual variation in response of drug.
● Pharmacogenomics : It is the study of prediction of drug response and its variation among the popu-
lation based on genetic make up.
● Pharmacoeconomics: It is the study of economics of drug used and derived effects or benefits. It
includes explaination regarding the cost-benefit analysis, cost-minimization analysis, cost-effective-
ness analysis and cost-utility analysis of the drug.
● Pharmacovigilance : It refers to the collection, investigation, maintenance and evaluation of spontane-
ous reports of suspected adverse events associated with use of marked medicinal products/drugs.
Basic Terms in Pharmacology
● Prodrug: It is a form of drug which after metabolic activation in vivo produces the therapeutic effect.
● Dose: It is total quantum of drug given at a time.
● Dosage: It is the amount of drug administered to a patient in order to produce the desired therapeutic
effect and expressed as quantity per unit body weight (mg/kg). Only exception in antineoplastic drugs
where quantity is expressed in mg/mt2 of body surface.
● Posology: It is science which deals with drug-dosage determination.
● Metrology: It is branch of science that studies weight and measures used in pharmacy.
● Placebo: It is reffered to an agent/substance/preparation consisting of a pharmacologically inert substance
(dummy drug) to simulate the real drug therapy in exerting psychological impact of medication in humans. A
placebo is usually given to the human patient with imaginary illness to satisfy the patient desire.
● Dosage regimen/dose schedule: It is described as the dose, frequency, duration and rate of the
administration of drugs. e.g. 10 mg/kg, P.O., bid for 5 days
● Loading dose: It relatively large dose of drug which is required to produce onset of the therapeutic effect.
● Maintenance dose : It is dosage given during course of therapy following loading dose to maintain
desired therapeutic effect/level produced by loading dose.
● Divided dose: It is defined as definite fraction of drug's full dose given frequently at shorter interval so that
full dose can be administered within a specified period of time (usually 24 hours but not morning to evening).
● Lethal dose: Dose of drug that produces death/mortality/lethality/fatality in animals.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER-2
SOURCES AND NATURE OF DRUGS
Sources of Drugs
1. Plants/vegetables 2. Animals 3. Minerals
4. Microbes 5. Synthetic source 6. Other natural sources
1. Plants : Majority of drugs are obtained from plants. Whole plant does not used as drug but some active
principle act as drug. Active principles have pharmacological effecst. eg. Ricin is active principle of castor.
a Alkaloids :
● Suffix is "ine"
● Basic heterocyclic nitrogenous compound of plant origin that are physiologically active.
● Insoluble in water, soluble in alcohol and form salt with mineral acid. Salt is used clinically
● Alkaloid containing O2 are solid in nature eg. Atropine
● Alkaloid do not containing O2 are liquid in nature. eg. Nicotine
● Many alkaloids are potent poisons.
● Alkloids and their salts are precipited by KMNO4 and tannic acids.
Examples of alkaloids: Morphine, cocaine, reserpine, atropine, quinine, strychnine, nicotine etc.
b. Glycosides:
● Non reducing organic compund with ester bond which upon hydrolysis gives a sugar (glycon)
and a non sugar part (aglycon).
● Non volatile, usually bitter in taste, soulble in water and polyorganic solvent.
● When glycon part is glucose than glycosides are called "glucoside"
● Agylcon (Non sugar) part is responsible for pharmacological activities.
● Glycon (sugar) part is responsible for water solubility, tissue permeability and duration of action.
Examples of glycosides : Digoxin, digitoxin, gitalin, ovanain, linamerine, dhurine

c. Oil : There are two types of oils.

i. Fixed oils:
They are glycerides (esters) of oleic, palmitic or stearic acids.
They exist in solid or liquid form.
Thay are non volatile in nature.
They form salt with alkali.
They are insoluble in water, sparingly soluble in alcohol but soluble in ether.
Edible oil : Mustard oil, Coconut oil, Peanut oil, Ground nut oil etc.
Medicinal value : croton oil, castor oil etc.
ii. Volatile oil / essential oil / aromatic oil / etheral oil
On room temperature, they get evapourated.
No nutritive value but have medicinal value
Not soluble in water, but soluble in alcohol, ether, esters and other organic solvent.
Alcoholic solution of volatile oil is known as essance which is used in perfumes.
e.g. turpentine oil, eucalyptus oil, peppermint oil, clove oil, asfoetida oil
iii. Mineral oil: Distillates of petroleum products. eg. kerosine, petroleum, vaseline, paraffin oil.

d. Gums : Secretory products of plants, chemically mucopolysaccharides, colloid in nature, used as

emulsifying agent e.g. gum acacia (emulsifier) and agar (purgative/laxative)

e. Tannins : It precipitate metals salts, alkaloids and proteins. Non nitrogenous complex phenolic
compound used as astringents e.g. catechu, Tannic acid.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 f. Resins : Formed by polymerization or oxidation of oil, examples of natural resins/terpenes inculdes
lac (insect) or rosin (plant)
g. Oleoresin: Combination of oil and resins, e.g. male fern extract, canada balsum
h. Saponins : Soap like activity, used for reduction of surface tension
2. Animal source:
i. Hormones: hormonal therapy
ii. Vitamins: vitamin A and D from shark liver, Cod fish liver oil
iii. Antisera: hyperimmune serum (antibody present)
iv. Blood and blood products
v. Bone powder: Sources of calcium and phospherous.
vi. Enzymes
3. Mineral source : Obtain from mining operations from rocks, soils etc. eg. MgSO4 , Aluminium trisilicate,
Ferrous sulphate (used for anaemia), Potassium chloride (used for liquefaction of cough)
4. Microbes : Antibiotic, antifungal, antihelmintics, antiviral, anticancer etc.
5. Synthetic source : Antimicrobials synthesized in laboratory through chemical processes
6. Other natural sources : Seaweed or marine algae is the source of iodine, many vitamins, certain
antibiotics and nutritional (protein) suppliments

Natural Sources of the drugs:

Ergot alkaloids (like ergometrine) and Claviceps purpurea
Lysergic acid derivative
Yohimbine Pausinystalia yohimbae (bark)
Reserpine Rauwolfia serpentina
Pilocarpine Pilocarpus jaborandi, P. microphyllus
Muscarine Amantia muscaria (Poisonous mushroom)
Nicotine Nicotiana tobaccum
Physostigmine Physostigma venenosum
Atropine Atropa belladonna
Dathura spp. like Datura stramonium
Picrotoxin Anamrita cocculus
d-Tubocurarine Strychnos toxifera
Chondodendron tomentum
Cocaine Erythroxylum coca
Digitoxin Digitalis purpurea, Digitalis lanata
Digoxin Digitalis lanata
Ouabain (Strophantin-G) Strophantus gratus
Strophantin-K Strophantus kombe
Penicillin-G (Benzylpeniciilin) Penicillium notatum
Penicillium chrysogenum
Sreptmycin Streptomyces griseus
Gentamicin Micromonospora purpurea
Oxytetracycline Streptomyces rimosus
Rifampicin Streptomyces mediterrance
Amphotericin-B Streptomyces nodosus
Griseofulvin Penicillium griseofulvin
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER - 3
PHARMACOLOGICAL TERMS & DEFINITIONS
1. Gastrointestinal tract:
● Mouth antiseptics : Inhibits growth of micro-organism in oral cavity eg. potassium chlorate, 4%
KMnO4, alcohol based mouth wash
● Dentifrices : Agents which clean teeth eg. tooth paste, powder
● Sialagogues/sialics : Drugs which increase volume of saliva mainly used to treat xerostomia eg,
pilocarpine, chewing gum
● Antisialagogues/asialics : Drugs which decrease volume of saliva manly used to treat ptylasism
eg. opium/morphin
● Emollients and demulcent : Drug which provide soothing, protecting and cooling effect to part on
which they are applied. Emollients are applied externally and demulcent are meant for internal
use, given orally for soothing GIT
● Stomachics : Drug which increase gastric secretion.
● Bitters : They are stomachics and bitter in taste, they stimulate appetite.
● Aromatic : Agents containing volatile oil and often are very pungent.
● Gastric antacid : Drug which decrease gastric pH by neutrilizing gastric HCL.
● Antistomachics: Agents which decrease gastric secretion.
● Gastric sedative : Drug which soothens gastric mucous membrane, relieve gastric pain and
control vomition.
● Emetics : Drugs which produce vomition.
● Antiemetics : Drugs which control or prevent vomition.
● Carminative : drug which prevent formation of gas and also help in expulsion of gases from
stomach and intestine.
● Purgatives/cathartics/evacuents/aperients/laxatives : Drug which increase evacuation of
bowel.
● Astringents: Agents that protect the inflammed intestinal mucosa by precipitating the
superficial proteins and help in reducing intestinal irritation and check bleeding.
● Antizymotics : Drug that arrest or control fermentation.
● Lavage : The agents used in aprocess of washing out the stomach/intestinere known as lavaging agent.
● Choleritics : Agents that increase bile formation and secretion.
● Cholagogues : Agents that help in contraction of gall bladder and increase bile flow into intestines.
● Lipotropics/Hepatotonics: Agents that increase hepatic function.
● Probiotics: Thes are the products containing microorganisms / compounds that supports the
useful and harm less microbes in body against the harmful ones. They are used to restore or to
establish desirable gastrointestinal balance to promote the health.
● Prokinetics: These are the agents that increase the motility of a segment of gastrointestinal tract
and thereby augument transient of material through that area.

2. Urogenital system :
● Diuretics : Drug which increase volume of urine formation.
● Urinary sedatives : Drugs which relieve irritability of urinary tract.
● Anaphrodisiacs : Drugs which decrease sexual desire.
● Aphrodisiacs : Drugs which increase sexual desire and libido.
● Ecbolics/oxytocics : Drugs which cause contraction of uterine muscles.
● Emmenagogues : Drugs that favours the occurance of heat.
● Galactagogues : Drugs that increase secretion of milk.
● Lactagouges: Drugs that stimulates letting down of milk.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 ● Tocolytics (uterine sedatives) : Drugs causes relaxation of uterine muscles.
● Contraceptives: Drugs which are used to prevent the conception after mating in females usually.
Now a days male contraceptives like spermicidal gel is also available.
3. Cardiovascular system:
● Haemostatics/Styptics/: Agents that arrest/stop bleeding.
● Haematinics: Agents that increase the formation of haemoglobin in RBC.
● Coagulants: Agents that promote blood clotting.
● Anticoagulants: Agents that prevent blood coagulation.
● Cardiac depressants/Antiarrhythmics: Agents that prevent cardiac arrhythmia.
● Vasoconstrictors: Agents that increase BP through constriction of blood vessels
● Vasodilators: Agents that decrease BP through dilatation of blood vessels.
● Antihypertensives: Agents that decrease the elevated BP.
● Antiangina drugs: Agents that promote coronary blood circulation and prevent cardiac arrest.
● Cardiac stimulants: Agents that stimulate the contraction of a failing heart.
● Cardiotonics: Agents that reduce size of enlarged heart by increasing the force of contraction.
4. Respiratory system :
● Expectorents: Drugs that increase liquefaction and facilitate expulsion of bronchial secretion.
● Analeptics/respiratory stimulants: Drugs that increase depth and rate of respiration.
● Bronchodilators : Drugs that causes dilatation of bronchioles for better resparation
● Antitussive : Drugs that supress cough reflex.
● Decongestant : Drugs which relieves nasal congestion
5. Nervous system:
● Sedatives: Are the drugs which reduce the excitement and calm the subject without inducing
sleep.e.g. phenobarbitone.
● Hypnotics: Are drugs that induces and/maintains sleeps, similar to normal arousable sleep.
● Narcotics: Are the drugs which induces deep sleep or narcosis in which the patient cannot be
easily aroused. e.g.Morphine.
● General anaesthetics: are the drugs which produces loss of all sensation and consciousness.
e.g.ether.
● Tranquillizers /Neuroleptics / Ataractics: Are the drugs which reduce mental tension and pro-
duce calmness in hyperactive subject without inducing sleep or depressing mental function.
● Analgesics: Are the drugs that selectively relieves pain by acting on the CNS or on peripheral pain
mechanisms, without significantly altering consciousness. eg. pethidine, aspirin etc.
● Antiepileptic/ Anticonvulsants: Are the drugs which are used in treatment or control of epilepsy
convulsion. eg. phenytoin.
● CNS stimulants: Are drugs whose primary action is to stimulate CNS or to improve specific brain
functions. They may be a convulsants (eg. strychnine). analeptics (eg.doxapram) Psychomimetics
(eg.amphetamines).
6. Peripheral nervous system:
Skeletal muscle relaxants : Are drugs that act peripherally at the neuromuscular junction/ muscle
fibre itself or centrally in the cerebrospinal axis to reduce muscle tone and / or cause paralysis,
eg. d-tubocurarine, dantrolene, mephenesin etc.
Local anesthetics: Local anesthetics are drugs which upon topical application or local injection cause
reversible loss of sensory perception, especially of pain, in a restricted area of the body. They block
generation and conduction of nerve impulse at all parts of the neuron where they come in contact,
without any structural damage.eg. Procaine, lidocaine etc.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
7. Eye:
● Mydriatics: Drugs that dilate pupil
● Miotics: Drugs that contract pupil.

8. Metabolism:
● Antipyretics/febrifuges: Drugs which reduce elevated body temperature.
● Alteratives: Drugs which modify tissue changes and improve nutrition of various organs.

9. Skin:
● Demulcents: Are inert substances which sooth inflammed/ denuded mucosa or skin by preventing
contact with air/ irritants in the surroundings. They are, in general, high molecular weight substances
and are applied as thick colloidal / viscid solutions in water.eg glycerin, gum acacia, propylene glycol
etc.
● Emollients: Are bland oily substances which soothen and soften skin. They form an occlusive film
over the skin, preventing evaporation, thus restoring the elasticity of cracked and dry skin. eg.
Olive oil, liquid paraffin.
● Adsorbants and Protectives : Are finely powdered, inert and solids capable of binding to
their surface (adsorbing) noxious and irritant substances. They are also called protective be-
cause they afford physical protection to the mucosa or skin. eg. zinc oxide, calamine, starch etc.
● Astringents : Are substances that precipitate proteins, but do not penetrate cells, thus affecting
the superficial layer only. They toughen the surface making it mechanically stronger and decrease
exudation. e.g. tannic acid, zinc oxide.
● Irritants: Are agents those stimulate sensory nerve endings and induce inflammation at the site of
application.
● Rubefacients : Irritants which cause local hyperemia with little sensory component are called
rubefacients.
● Vesicants : Stronger irritants which also lead to increased capillary permeability and collection of
fluid under the epidermis forming vesicles are termed vesicants.
● Counterirritants : Certain irritants produce a remote effect which tends to relieve pain and in-
flammation in deeper organs are called counterirritants. eg. turpentine oil, methylsalicylate.
● Keratolytics : Are drugs which dissolve the intracellular substance in the horny, layer of skin. The
epidermal cell swell, soften and then desquamate. They are used on hyperkeratotic lesions chronic
dermatitis, ring worms etc. e.g. salicylic acid, benzoic acid.
● Diphoretics : Drugs that increase sweating.
● Anhydrotics : Agents that decrease sweating.
● Depilatories : Agents that remove superficial hair (unwanted).
● Caustics : Agents that cause death of the tissue.
● Refrigerants : Agents that cause coolness of the areas of contact.
● Antipruritics : Agents that reduce irritation and itching.
● Detergents : Agents that are used as cleansing agents.
● Deodorants : Agents that eliminate or mask unpleasant odours.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER - 4
PHARMACOKINETICS
Routes of Drug Administration
There are different routes of admnistration of drug for aniaml body. The pharmacological effecst and therapeutic
outcome depend on routes of admnistration. Following factors affecst choice of route of administration.
1. Physicochemical properties: Hihgly lipophilic drugs are better aborbed from GIT. While polar / ionized
compounds are not absorbed through GIT.
2. Formulation: Water insoluble drug, suspension, emulsion should not be given through IV routes.
3. Nature of drugs: Acid labile drugs and peptides are not suitable for oral absorption bacause of inacti-
vation by gastric HCL and pepsin enzyme.
4. Onset of action: For quick response of treatment in emergency, IV route is most appropiate. For
delayed absorption, implants or depot preparation are given through SC route which provides prolong
duration of action.
5. Types of response required: Many drug produce multiple responses depending upon routes of ad-
ministration and dose.
The example is magnesium sulphate.
Laxative - Oral - 50 gm
Purgative - Oral - 100 gm
Muscle relaxation - IV or SC - 20 % solution
Euthaenasi - IV - Saturated solution
6. Site of desired action: To treat local lesion, topical routes is prefered. For obtaining systemic effects,
parenteral route is employed.
7. Rate of biotransformation : Drug having shorter half life is to be given via intravenous infusion. eg.
oxytocin
8. Condition of patients: Unconscious patients /head trauma / mouth injury do not allow oral admnistration.
Oral route is also not practical for furious animals. Anthelmintics should be given orally because, they
requires direct contact with parasites.
Routes of admnistration is classified in to three main categories.
1. Oral/enteric/per-orum / per-os
2. Parenteral: away from the enteric route (other than GI tract) e.g. Injection, inhalation
3. Topical/local/external
Oral route (P/O) :
● Absorption takes place in 30-60 minutes but in ruminants, it takes 3-4 hours.
● Mainly drug absorbed from small stomach and intestine.
● Empty stomach favours absorption.
● Presence of food may modify rate and extent of absorption.
● Too irritant drugs can not be give through oral routes.
● It is employed to produces systemic as well as local effecst. eg. Antacid produces local effecst by acid
neutrilization. Paracetamol produces systemic effects.
Advantages :
● Convenient and safe (self medication is possible)
● No sterility of drug is required
● Mass application of medication through feed and water is possible (in poultry).
● No specific equipment is required.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 ● Economical and cheaper.
Disadvantages:
● Slow onset of action causes delayed response.
● Risk of aspiration in animals is likely to cause aspiration pneumonia.
● It is not useful in vomition and diarrhea
● It is not poosible to use oral admnistration of drug unconscious / violent / un cooperative animals.
● Acid labile and pepsin substrate can not be given.
● Some time, it may cause gastric upset.
● Gastric barrier : Some drugs have poor oral bio availability. eg. Gentamycin, Neomycin,
● In ruminants, large amount of ingesta causes dilution of drug concentration.
Parenteral route :
Injectable route:
Advantages:
● Rapid onset of action
● It avoids hepatic bypass.
● It is practical route of drug admnistration for un-cooperative/furious/unconscious animals.
Disadvantages:
● Requies accurate dose, specifically in Intravenus administration.
● It is costly and less safe.
● Pain and injury at the site of injection,risky route of administration.
● Preparation should be sterile and pyrogen free.
● It requires skilled person for administration.
Intravenous route (I/V): Drug solution is directly injected into vains of body. In bolus injection, drug is given
at a time instantly. In infusion, drug is slowly injected over a period of time along with fluid.
Advantage:
● Fastest absorption (within seconds): same molecule circulates three times in one minute.
● No loss of drug i.e. 100% bioavailability
● Large quantity can be injected e.g. saline
● Used for irritant drugs
● Precise control over dose.
Sites of intravenous injection in different animals:
Cattle : jugular and ear vein Dog : recurrent tarsal, radial Cat : radial, femoral vein
Horse : only jugular vein Rat and mice: tail vein Rabbit : ear vein
Guinea pig : directly into heart Swine : jugular and recurrent tarsal vein
Sheep and goat : jugular, ear vein and sephanous vein in hind leg

Disadvantages:
● Only soluble substance can be administered (only clear solution).
● Not suitable for oily drugs (oil base injection cannot be given)
● Aseptic precaution, pyrogen free and sterile formulation, and skilled person is required.
● If there is leakage in perivascular space, it causes sever irritation and phlebitis.
● Chances of air embolism is always there.
● It provides shorter duration of action baceuse of faster metabolism.
● It is most risky route of drug administration as all the vital organs are directly exposed to higher
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 concentration of drugs.
Intramuscular route (I/M): The drug is injected deep within skeletal muscels. Skelatal muscles being a
highly vascular and less richly supplied with nerves are employed for IM injections. In large animals, gluteal
muscles or neck muscles are used for IM injection.
Advantage:
● Absorption of drug is farely rapid. 5-30 minutes is required for absorption
● Liquid / suspension / oily formulation can be given.
● Mild to moderately irritant drug can be given.
● The duration of action is longer as compared to IV and shorter as compared to SC.
Disadvantage:
● Large volume cannot be administered
● Maximum pain in I/M injection due to irritation.
● Incidence of formation of local abscess/scar/fibrosis.
● It is not suitable for emergency treatment.
● IM is most common way of drug administration in veterinary practice.

Subcutaneous route (S/C): Drug is injecetd sub cutaenously i.e. below skin. The loose skin folds is used
for SC injection.
Advantages :
● It provides prolong effects of drug.
● It is suitable for implantats and depots formulation.
● It provides sustained release / ix quantum release. It is alos employed for depot preparation
specially for hormone administration.
● Large volume can be administered.
● It is commonly used in In infants because of smaller veins.
● Vaccinations are given mainly SC routes. The absorption is very slow. This triggers the immune
system for longer period.
Disadvantages:
● Slow onset of action
● This route is not suitable for Irritant drugs. Irritant drugs lead to sloughing of skin
● Some time permanant marks/scars develop at the site of admnistration.
● In shock condition, reduction in peripheral perfusion reduces the absorption of drugs.

Intraperitoneal (I/P) : The drug is deposited in peritoneal cavity. Peritoneal membrane provides surface
for absorption. The intraperitoneal injection is most suitable for pediatric patients and labotaory animals.
Advantage :
● Large absorption area (volume), so we can inject large quantity
● Absorption is as good as I/V
Disadvantages:
● Leads to peritonitis

Intrathecal: Inside subarachnoid space of spinal canal e.g. local anaesthetics

Intracardiac: Drug is directly injecetd in heart. It employed only in emergency. For eg., adrenaline is injectd
in acute cardia failure in to heart.
Intraarticular: Drug is deposited in joint. This is used in arthritis. Steroids and NSAIDs are given via this
route for obtaining local effects.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
Intradermal: The drug is inject within layers of skin. It is used for allergy testing. eg. Diagnostic purpose
(tuberculine test, penicillin hypersensitivity testing)
Intraarterial: Drug is injectd into arteries. This distributes drugs in selective / restricted area. eg. Mainly
followed for anticancer drug, dye and contars media for diagnostic imaging in MRI/ CT Scan
Transmucosal: Across the mucosa i.e., Drugs go to mucosal layer
a. Sublingual route : Drug is kept below tongue. It provides rapid absorption without hepatic first pass
effects. It is used by heart patients for nitroglycerine drugs to have quick vaso dilation effect on coronary
artery.
b. Intramammary : Drug is injecetd inside teat canal for treatment of mastitis.
c. Transrectal : Introduce drug inside the rectum, used when animal is not cooperative or in vomiting
conditions.

Transcutaneous: Across the skin

1. Drug placed above the skin and crosses the skin and goes into the body
a. Inunction: Rubbing over skin, so drug go inside.
b. Iontophoresis: Application of galvanic current increases penetration of drug through skin layers.
c. Jet injection: Drug is injected with lot of force through tinny jets. so drug is able to cross the skin
directly (in this case needle do not touch the skin).
d. Transdermal patches: Trnsdermal patch directly deliver the drug to skin for longer duration. The
application of trasndermal patch is employed for analgesic drugs like fentyl in neoplastic pain.
2. Inhalation route : Drug is inhaled through respiratory tract and absorption takes place through lung.
Due to large pulmonary area, drug is quickly absorbed in blood circulation. Thus, absorption is quite
fast. eg. Gaseous anesthetics, aerosol and gaseous preparation.

3. Topical routes: In this route, absorption of drug donot take place. Drug remains at the site of injection.
Theorically drug should not entered the systemic circulation. This route is employed for local effecst.

a. Intraocular : Directly into eye. eg., eye drop

b. Intraaural: Inside ear eg, Ear drops
c. Intravaginal : eg.Pessary
d. Intrarectal : For local effect. eg. enema in constipation
e. Intrauterine : In case of pyometra
f. Intramammary : For local effect, teat canal
g. Topical application/skin application : For wound and ulcer
h. Buccal/oral cavity : eg. Mouth gels

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
Pharmacokinetics [Pharmacon = drug and Kinetics = movements]

Definition:
● It is study of time course of absorption, distribution, metabolism and excretion (ADME) processes of drug.
● It is study of temporal changes in concentration of drugs in relation to time.
● Pharmacokinetics helps to understands “What happens to drug in body? Or what body does on drugs?
Out of ADME, Absorption and distribution determine concentration of drug at the site of action in body.
Biotransformation and excretion are responsible for elimination of drug and termination of action of drug.
Study of pharmacokinetics is essential step to determine optimum dosage regimens of drugs.

Pharmacokinetics includes four main processes:

● Absorption from the site of administration
● Distribution within the body
● Metabolism/ Biotransformation
● Excretion

A. Translocation of drug molecule across biological membrane (Biotransport of drug): For any
drug to produce its effect, it is essential to achieve an adequate concentration in the fluid bathing near
the target sites of action. The drug molecules move around in the body along with blood streams to
long distances at faster speed. This movement is function of cardiovascular system. It is not affected
by chemical nature of drug. Another movement of drug (diffusional movement) involves movement of
drug over molecule by molecule over a short distance.

Tissue-Bound Drug

Free Drug in Distribution Fluids

Elimination
Site of Action Drug-Melabolizing
Receptor Distribution
Enzymes

Drug in Dosage Form

Biotransformation

Dissolution

Free Drug
Drug in Solution Absorption Unchanged Drug
Excretion
at +
Absorption Site Metabolities
Protein-Bound Drug Urine
(Plasma)

Figure-1 : Relationship between pharmacokinetic processes with the duration of action of drugs
(Source: Adams, 2001)
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
Passage of drug across the Cell membrane
The biological membrane is made up of lipid bilayers which regulates the passage of drug across cell
membrane. The thickness of lipid bilayer is 100 A. The polar ends of lipid bilayers are oriented at the two
O

surfaces and the non-polar chains are embedded in the matrix. The proteins freely float through the membrane
and some of the intrinsic ones surround aqueous pores of the channels. The plasma membrane of cell is
semipermeable membrane allowing only specific substances / nutrients to cross. For example, water and
glucose are freely permeable while sucrose can not cross the membrane.

1) Simple diffusion
(A) Passive transfer
2) Filtration

1) Facilitated diffusion

(B) Specialized transport 2) Active transport

3) Endicytosis

Figure-2 : Processes of movements of drugs across Cell membrane

(A) Passive transfer

1) Simple diffusion:
● Lipid soluble drug crosses the cell membrane through diffusion.
● Diffusion is a passive process/ no energy is required / non saturable process.
● Rate of diffusion is influenced by concentration gradients across the cell membrane, lipid solubility
as well as water solubility of drug.
● Highly lipid soluble drug cannot contact aqueous pores so cannot diffuse though cell membrane.
● Highly water soluble drug cannot penetrate cell membrane.
● So, optimum lipid and water solubility is required.
● Drug having molecular weight of 100 – 400 daltons can cross cell membrane easily.

pH and Ionization of Drugs

● Most drugs are either weak acids or weak bases and exist in solution as both non-ionized and
ionized forms.
● Non-ionized form is usually lipid soluble and can readily cross the biologic membranes.
● Ionized forms are virtually excluded from trans-membrane diffusion because of poor lipid solubility.
● The degree of ionization of a drug/organic electrolyte depends on its pKa (dissociation constant)
and pH of the environment.
● pKa value is the negative logarithm of the acidic ionization/dissociation. It is a constant value for
an acid or a base.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
The concept of pKa is derived from the Henderson-Hasselbach equation.

Molecular Concentration of Non-ionized acid

For an Acid : pKa = pH + log
Molecular Concentration of Ionized acid

OR

100
% Ionized drug =
1 + Antilog (pKa – pH)

OR

Molecular Concentration of Ionized drug

For a Base: pKa = pH + log
Molecular Concentration of non-ionized drug

OR

100
% Ionized drug =
1 + Antilog (pH – pKa)

From above equation,

● pH = pKa, conc. of ionized drugs = conc. of non-ionized drug = 50%. Thus, pKa is equal to pH at which
half of the drug is in ionized state
pH > pK, Unionized drug > Ionized drug This equation is right for basic drug,
●
● }
pK < pH, Ionized drug > Unionized drug vice-versa is true for acidic drug

Clincal significance of pH and pKa values:

● Alkaline pH favours dissociation of weak acid and hence absorption is reduced.
● Acidic pH favours dissociation of weak base and hence absorption is reduced.
● In other words, acidic drugs are better absorbed in acidic environment. eg. Aspirin is a acidic drug which
remains unionized/undissociated in stomach at acidic pH, so absorption is good compared to intestine.
● Alkaline drugs are better absorbed in alkaline environment.
● For acidic drugs, the lower the pKa, stronger is the acid, whereas for basic drugs higher the pKa,
stronger is the base.
● Weak acidic drugs are well absorbed from the GIT of dogs and cats.
● Similarly, acidic urine of carnivores helps in promoting passive absorption of acidic drugs (pKa values
ranging from 3.0 to 7.2) from the distal renal tubules. Conversely, urinary alkalization favors ionization
of organic acids and promotes/enhances their excretion.
● Acidic urine favors excretion of alkaline drugs.
● Alkaline urine favors excretion of acidic drugs
● Acidic drugs are more ionized when pH is higher than its Pka values.
● Basic drugs are more ionized when pH of aqueous phase is less than its pKa values.
● Most of the therapeutic drugs/agents have pKa value between 3.0 and 11.0
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 pKa Values of some Weak acids & Bases (at 25o C)
Weak Acids pKa Weak Bases pKa
Salicylic acid 3.00 Reserpine 6.60
Aspirin 3.50 Tylosin 7.10
Phenylbutazone 4.40 Lincomycin 7.60
Sulfadiazine 6.48 Quinine 8.40
Phenobarbital 7.20 Praciane 8.80
Barbital 7.91 Ephedrine 9.36
Boric acid 9.24 Atropine 9.65

Effect of pH on the Ionization of Salicylic Acid (pKa 3.0)

pH Percent Non-Ionized
1 99.00
2 90.00
3 50.00
4 9.09
5 1.00
6 0.10

2) Filtration:
● It is Process of drug movement through pores and channels.
● Molecules having mol. wt. less then 100 Dalton can pass these pores
● Polar / non-polar drugs are suitable for filtration.
● Hydrostatic pressure and osmotic pressure are forces behind filtration.
● It is energy dependent process.
● It is the least significance process for drug transport as size of pore in most of the tissues is of
lesser than 4 A unit.
O

● It is observed in capillary movement of drug because they are having larger pores.
● Capillaries in brains resist filteration.
● Examples includes renal excretion, removal of drug from CSF and movement of drug across the
hepatic sinusoidal.
Diffusion
Diffusion through
through aqueous
lipid channel Carrier

EXTRACELLULAR

MEMBRANE

INTRACELLULAR

Figure-3 : Routes by which solutes can traverse cell membranes (Source: Rang et al., 2003)
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
B) Specialized transport
1) Active transport:
● Movement of substances against a concentration or electrochemical gradient.
● It requires carries and energy dependent. It is saturable process.
● It is also inhibited by process of competitive antagonism.
● Hydrophobic and large polar substances are transported using this process. eg. Renal and
biliary excretion of drug
Types :
i. Primary: Only one substance is transported at a time.
ii. Secondary: Two substances are transported, one is driving solute and other is actual
substances.
iii. Co-transport: Both are transported in same direction eg. Sodium co-transport of glucose
and amino acid in intestinal epithelium.
iv. Anti-port: Both substances are transported in opposite direction eg. Sodium counter transport
of hydrogen ions.
2) Facilitated transport:
● It requires carriers but, not energy.
● Substrate does not move against a concentration gradient (Downhill).
● It is Saturable/structure specific/ competitive process eg. transport of glucose in RBC,
absorption of Vit B1/B2/B12 along with intrinsic factors.
3) Pinocytosis:
● Pinocytosis (cell drinking) is the process by which cells engulf small droplets and may be of
some importance in uptake of large molecules.
● Active process / saturable / competitive to structural similarity. eg. Cellular nutrients like fats/
starch/proteins/fat soluble vitamins / drug like insulin / oral polio vaccine are transported
using this process.

Differences amongst different transport systems

Characteristics Simple diffulsion Facilitated Active transport
Incidence Commonest Less common Least common
Process Slow Quick Very quick
Movement Along conc. gradient Along conc. gradient Against conc. gradient
Carrier Not needed Needed Needed
Energy Not required Not required Required

Drug absorption : Process of movement of drug from its site of absorption to general circulation / blood
stream is termed as absorption. Optimum rate and extent of absorption will in turn determine the
concentration at site of action.
If drug is absorbed completely but very slowly, therapeutic concentration is never achieved. Reversely, if
drug is absorbed rapidly, the onset of action is very fast with shorter duration of action because of rapid
excretion.
Acidic drug at acidic pH remains in unionized form so absorption occurs. Thus, acidic pH favours absorption
of acidic drug.The examples of acidic drugs are aspirin, phenybutazone, sulphadiazine, acetazolamide.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
Alkaline drug remains unionized at alkaline pH. Alkaline pH favours absorption of basic drug, eg. Morphine,
quinine, atropine etc. In general, more drug is absorbed through intestinal mucosa then gastric mucosa
because of larger surface area.

Factors affecting process of drug absorption and bioavailability

A) Physico-chemical properties of drug
B) Nature of the dosage form
C) Physiological factors
D) Pharmacogenetic factors
E) Disease states

(A) Physico-chemical properties of drug:

(i) Physical state: Liquids are absorbed better than solids. Crystalloids absorbed better than colloids.
(ii) Lipid or water solubility: Drugs in aqueous solution mix more readily than those in oily solution.
However at the cell surface, the lipid soluble drugs penetrate into the cell more rapidly than the
water soluble drugs. Thus, a drug with balanced water and lipid solubility will be absorbed better.
(iii) Ionization: Most of the drugs are organic compounds. Unlike inorganic compounds, the organic
drugs are not completely ionized in the fluid. These drugs exist in two forms. Unionized component
is predominantly lipid soluble and is absorbed rapidly and an ionized is often water soluble
component which is absorbed poorly. Most of the drugs are weak acids or weak bases. It may be
assumed for all practical purposes, that the mucosal lining of the G.I.T is impermeable to the
ionized form of a weak organic acid or a weak organic base.

Acidic drugs: Rapidly absorbed from the stomach e.g. salicylates and barbiturates.

Basic drugs: Not absorbed until they reach to the alkaline environment i.e. small intestine when administered
orally e.g. pethidine and ephedrine.
(B) Nature of the dosage form :
(i) Particle size and state: Small particle size is important for drug absorption. Drugs given in a
dispersed or emulsified state are absorbed better e.g. Vitamin A and D.
(ii) Disintegration time and dissolution time: Disintegration time : It is time taken by tablet to brake
and to disintegrate into smaller pieces in a bio-phase of absorption. Longer the disintegration
time, slower is the absorption and delayed onset of action.
Dissolution time: It is time taken by drug to enter into solution phase, or time taken to release the
drug from solid dosage form. Lipid solubility / Molecular size / pKa of drug / aqueous solubility will
influence the dissolution time. It is also influenced by dosage forms i.e. Aqueous solution / Oily
solution / Suspension / Tablets / SR tablets.
(iii) Formulation: Usually substances like lactose, sucrose, starch and calcium phosphate are used
as inert diluents in formulating powders or tablets. Fillers may not be totally inert and may affect
the absorption as well as stability of the medicament. So, a faulty formulation can render a useful
drug totally useless therapeutically.
c) Physiological factors:
i) Gastrointestinal transit time: Rapid absorption occurs when the drug is given on empty stomach.
However certain irritant drugs like salicylates and iron preparations are deliberately administred
after food to minimize the gastrointestinal irritation. But for some drugs, the presence of food in
the GI tract increases the absorption of certain drugs e.g. griseofulvin, propranolol and riboflavin.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 ii) Presence of other agents: Vitamin C enhances the absorption of iron from the GIT. Calcium
present in milk or antacids forms insoluble complexes with the tetracycline antibiotics and reduces
their absorption. Milk or milk products or antacids containing heavy metals impair absorption of
tetracyclines and certain fluoroquinolones (due to chelation).
iii) Area of the absorbing surface and local circulation: Drugs can be absorbed better from the
small intestine than from the stomach because of the larger surface area of the former. Increased
vascular supply can increase the absorption. Because of extensive area and rich blood supply of
its mucosal surface, small intestines are the principal site of drug absorption for all orally
administered drugs.
iv) Enterohepatic cycling: Some drugs undergo recycling between intestines and liver before they
reach the site of action. This increases the bioavailability e.g. phenolphthalein.
v) Metabolism of drug/first pass effect: Rapid degradation of a drug by the liver during the first pass
(propranolol) or by the gut wall (isoprenaline) decreases the bioavailability. Thus, a drug though
absorbed well when given orally may not be effective because of its extensive first pass metabolism.
(D) Pharmacogenetic factors: Individual variations occur due to the genetically mediated reason in drug absorption
and response. eg. Expression of drug transporters across the biological barriers varies in individuals.
(E) Disease states: Absorption and first pass metabolism may be affected in conditions like malabsorption,
thyrotoxicosis, achlorhydria and liver cirrhosis. Hypovolemic perfusions reduces blood supply. Bacterial
infections alter permeability of membrane. Diarrhea / constipation alter transient time.
Drug Absorption after Oral Administration: Solid and liquid dosage forms like tablet, powder, syrup, elixir
etc., are given via oral route. Three basic steps for absorption of any drug incude:
1. Release from the dosage form (dissolution).
2. Transport across the GIT mucosal barrier.
3. Passage through the liver.
Each of above three process affects the rate and extent of drug absorption i.e. bioavailability. The dissolution
is a rate limiting process. The dissolution of drug can be manipulated by use of water soluble salts of drugs.
Following its release, the drug in solution must be stable in the environment within the stomach (reticulo-
rumen) and small intestines. It must be sufficiently lipid soluble to diffuse through the mucosal layer/barrier
to enter the hepatic portal venous blood.
Rate of gastric emptying / motility of intestine / change in blood supply to intestine / diarrhea / constipation
/ poor solubility and stability of drugs are other important factors to be considered.
Rate of gastric emptying is an important determinant of the drug absorption following oral administration.
Prokinetics increase the gastric emptying time and reduces drug absorption while spasmolytics reduce
gastric emptying time and increase drug absorption.
Examples of drug absorption:
● Absorption of polar antibiotics is slow and incomplete e.g. aminoglycosides and quaternary ammonium
compounds like atropine sulfate, propantheline etc.
● Aminoglycosides: Poor absorption due to low lipid solubility.
● Penicillin V: better absorption as compare to Penicillin G due to acid resistance.
● Oxytetracycline HCl: Water soluble salts-good absorption-but with food containing cations gets cheleted.
● Cephalexin is an acid stable drug, so, it is fit for oral administration.
Pulmonary Absorption : Gaseous and volatile anesthetic agents given by inhalation are rapidly absorbed
into the systemic circulation by diffusing through/across pulmonary alveolar epithelium.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
Absorption after IV Injection : Injection of a drug solution administered directly into the blood stream gives
a predictable concentration of the drug in plasma and in most instances, produces an immediate
pharmacological response.
Absorption after IM/SC Injection
● An IM and SC route gives rapid absorption.
● Peak concentration (Cmax) is achieved within 30-60 hrs.
Factors Influencing absorption from IM/SC site
● Vascularity of site / concentration of drug / degree of ionization / lipid solubility of drug.
● Different sites give different rate of absorption eg. Injection in neck region and thigh region will give
different rates of absorption.
● Concurrent administration of drug may decrease or increase the absorption from injection site. eg.,
Epinephrine with lignocaine for local infilteration results in slower absorption of lignocaine and hence,
there is less toxicity and longer duration of action.
● No routes except IV gives 100 % bioavailability.
● Sustained release preparation gives longer effects eg, Procaine penicillin G (oil in aluminium
monosteareate), amoxicillin tryhydrate, oxytetracyclines base in 2 pyrilidone vehical system etc.
● Prolong duration time may also be due to reduced rate of release of drug from dosage (Longer
dissolution time)
● But disadvantage is unpredictable or uneven intensity of response.
● Extremely slow absorption can be achieved through insoluble drug incorporated in compressed palate.
eg. S/C implants of diethyl stilbosterol, testosterone, deoxycorticosteroids

Per cutaneous absorption

Systemic absorption after topical application depends upon several factors like :
● Drug must dissolve and release from dosage or vehicle.
● Lipid solubility is essential
● Oil in water emulsion increases absorption.
● Anionic surface active agent like sodium lauryl sulphate in aqueous cream increases absorption. As it
increases water solubility and permeability of skin.
● Di-methyl sulphoxide increases penetration.
● Skin abrasion increases absorption.
● For skin infection which is deeply located in the layers of epidermis, systemic therapy is essential for
optimum time.

Absorption from sustained-release preparations: The prolonged action provided by Sustained-release

preparations is due to their limited availability for absorption, which may be attributed to slow dissolution of
the drug.

Bio-availability (F): The fraction of an administered drug that reaches the systemic circulation intact is
termed as bioavailability. eg. if 100 mg of a drug is administered orally and 70 mg of the same is absorbed
intact (unchanged), the bio-availability of the same is expressed as 70%.

Determination of bio-availability
AUCoral
F= X 100 Where, AUC = Area under curve in plot of plasma conc. vs. time graph
AUC IV
85
For example: If AUCIV =112 µg.h.ml-1 and AUCoral = 85 µg.h.ml-1 then F= X 100 = 75.89 %
112
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
Factors influencing bio-availability :
● First-pass hepatic metabolism
● Solubility of the drug
● Chemical instability of the drug
● Nature of drug formulations
❖ Particle size of the drug
❖ Salt form of the drug
❖ Crystal polymorphism
❖ Presence of excipients/vehicles

Bioequivalence
Two related drugs are bioequivalent if they show comparable bioavialability and similar time (Tmax) to achieve
peak plasma concentrations (Cmax).

Therapeutic Equivalence
Two similar drugs are therapeutically equivalent if they have comparable efficacy and safety.

DRUG DISTRIBUTION
It is movement of drug from systemic circulation to different parts or organs of body including site of action.
Drug after absorption enters systemic circulation, from where, it enters extravascular space and reaches
to different tissues and organs. Drug is not uniformly distributed in all the organs/tissues of body. Some
organs may receive or retain higher concentrations of drugs than other parts.

Factors affecting drug distributions

i. Rate of blood flow to organ: Blood flow to the brain, liver and kidneys is greater than skeletal muscles,
whereas adipose tissue has a still lower rate of blood flow. Skin and keratinized tissues have least flow.
ii. Tissue/Capillary permeability
iii. Physico-chemical properties of drug.
iv. Transport/ carrier system
v. Rate of administration : Rapid absorption - more fast distribution
vi. Plasma protein binding

Protein binding: Most of the drugs possess physicochemical properties for protein binding. Acidic drugs
generally bind to plasma albumin and basic drugs to α1-acid glycoprotein. Bound form and free form of drug
exists in dynamic equilibrium. The binding to albumin has quantitative effects.

Binding of drugs with plasma proteins affect :

1) Drug distribution: High molecular weights of plasma proteins prevent bound drugs from diffusing out
of capillaries into the tissues. Thus, high plasma protein binding drugs has lower distribution.
2) Drug effects: Only free drug fraction alone is pharmacologically active since it penetrates the target
organ/receptor/tissue.
3) Drug elimination: Free drug alone is filtered at the glomerulus and also excreted into saliva and milk.

Clinical significance of plasma protein binding:

● Highly plasma protein bound drugs are largely restricted to the vascular compartment and tend to
have a lower volume of distribution (Vd).

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
● The bound fraction is not available for action. However, it is in equilibrium with the free drug in plasma
and dissociates when the concentration of the free drug is reduced due to elimination. Plasma protein
binding thus acts as a temporary reservoir/storage for the drug.
● High degree of protein binding generally makes drug long acting because bound drug fraction is not
available for metabolism and excretion.
● Two highly protein drugs should not be given together. They tend to displace each other while competing
for the same binding site and making available of freer drug molecules which can produce drastic
pharmacological response or toxic/harmful effects.
● Highly protein bound drugs should not be given to hypoproteinemic subjects. Due to lack of binding
sites, more free dug molecules can produce drastic pharmacological response or toxic/harmful effects.

Grading of Protein Binding of Drugs:

1) Extensively protein bound drugs (>80% protein binding) eg. warfarin: 99%, Phenybutazone: 98%,
Propanol: 97%; frusemide, digitoxin, propanol, quinidine, phenytoin, diazepam and valproate have protein
binding more than 80%.
2) Moderately protein bound drugs (50-80% protein binding)
3) Lowly protein bound drugs (<50% protein binding) eg. theophyline 1%, Codeine 10%, Morphine 12%

Accumulation of drug in specific tissue :

Eye (ratina); Chloroquine Hair: Arsenicals
Kidneys: Heavy metals Liver: Chloroquine, Paracetamol
Lung: Chlorpromezine, Antihistamine Skin: Chloroquine and Phenothiazine
Thyroid: Iodine Teeth and bone : Oxytetracycline, Fluoride, Lead

Blood Brain Barrier (BBB)

The BBB is composed of :
(i) Continuous layer of endothelial cells having tight junctions
(ii) Overlapping endothelial layer is continuous basement membrane.
(iii) Perivascular foot process formed by astrocytes that encircles 85% capillary diameter.

Above three characteristics form barriers for movement of molecules from blood stream to brain. Moderately
lipid soluble substances diffuse through BBB, but polar or ionized drugs cannot penetrate it. Region of
brains like Hippocampus, CTZ lacks BBB, so at these locations lipid insoluble or polar substance can enter
the brains.
● Inflammation in form of meningitis, can disrupt the integrity of BBB, allowing normally impermeable
substances to enter brain e.g. penicillin in the treatment of bacterial meningitis.
● Several peptides, including bradykinin and ekephalins, increase BBB permeability by increasing
pinocytosis and this process/approach is used as means of improving access of chemotherapy during
treatment of brain cancer.
● Some water soluble drugs like L-Dopa and methyl dopa, endogenous sugars and aminoacids are
transferred across BBB through active process.

Other biological barriers :

● Choroid plexus forms blood CSF barriers.
● Trophoblast cells separating maternal and foetal blood vessels provide blood placenteal barriers.
● Other barriers included blood testis barriers, blood prostrate barriers, eye globe barriers.

Factors affecting drug distribution between various body fluid compartments :

1) Permeability across tissue barriers 2) Binding with compartments
3) PH partition 4) Fat (Lipid): water partition coefficient
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
Volume of Distribution: Apparent volume of distribution is the hypothetical volume of the body fluid that is
needed to dissolve the total amount of the drug to attain the same concentration as that in the blood.
Q
Vd = where Q = total amount of drug in the body; Cp = conc. in plasma
Cp
Following IV route,
Dose (mg/kg)
Vd area (L / kg)= where β = Rate constant (slow) of elimination phase
β x AUC
Following Extra vascular route (IM/SC/PO),
Dose (mg/kg)
Vd area (L / kg)= xF
β x AUC

Elimination Half Life (t1/2): Elimination half-life (t1/2) is the time required by the body to eliminate 50% of the
administered drug. About 96.9% of drug is eliminated in 5 half-lives and 98.4% drug is eliminated in 6 half-lives.
Drug elimination: Drugs elimination involves bio-transformation (drug metabolism) and drug excretion.
DRUG METABOLISM: Drugs are chemical substances, which interact with living organisms and produce
some pharmacological effects and then, they should be eliminated from the body unchanged or by changing
to some easily excretable molecules. The process by which the body brings about changes in drug molecule
is referred as drug metabolism or biotransformation.
Enzymes responsible for metabolism of drugs:
a) Microsomal enzymes: Present in the smooth endoplasmic reticulum of the liver, kidney and GIT eg.
glucuronyl transferase, dehydrogenase, hydroxylase and cytochrome P450. They are inducible by
drugs, diet and other factors.
b) Non-microsomal enzymes: Present in the cytoplasm, mitochondria of different organs. eg. esterases,
amidase, hydrolase. They are non inducible.
Microsomes: Spherical vesicles of endoplasmic reticulum. They can be separated by ultracentrifugation.
Metabolism of drug takes places in two phases:
1. Phase-I reactions : It is also known as non synthetic or non conjucative phase and involved Oxidation,
reduction and hydrolysis reactions.
2. Phase-II reactions (conjugations/synthetic reactions): Glucuronidation, sulfate conjugation,
acetylation, glycine conjugation and methylation reactions.
Phase-I and Phase-II reactions take place mainly in the liver, though some drugs are metabolized in sites
other than liver. This is known as extra hepatic biotransformation. It is of least importance.
Examples of extrohepatic biotransformation :
Plasma: Hydrolysis of suxamethonium by choline esterase
Lungs: Various prostanoids, Nortryptiline, Baclomethasone, Aldrenine, Acetophenon, Phenol, isoprenaline.
GIT : Tyramine,Ssalbutamol, Terbutaline, Isoproterenol, Morphine
Skin : Dapsone, Betamethasone, Capcichine, Propanolol, Monoxidil
Phase-I Reactions: Phase-I reactions usually either unmask or introduce into the drug molecule polar
groups such as-OH,-COOH and NH2. In phase-II reactions, these functional groups enable the compound
to undergo conjugation with endogenous substances such as glucuronic acid (i.e. glucuronidation), acetate
(acetylation), sulfate (sulfuric acid ester formation) and various amino acids. These drug conjugates are
water soluble and invariably inactive pharmacologically. Although Phase-I reactions usually yield products
with decreased activity, some may give rise to products with similar or even greater activity.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
1) Oxidation
● Microsomal oxidation is the most prominent phase-I reaction in the metabolism of lipid soluble drugs
and steroid hormones.
● It increasing hydrophilicity of drugs by introducing polar groups like -OH.
● Microsomal enzymes have a specific requirement for reduced nictinamide adenine dinuleotide phosphate
(NADPH) and molecular O2 and are classified as mixed function oxidases (MFOs).
A wide range of oxidative reactions, are known to occur in microsomes and examples include:
Reduction : The reduction reaction takes place by the enzyme reductase which catalyze the reduction of
azo (-N=N-) and nitro (-NO2) compounds.

Reduction Reactions Parent Drug Metabolite

Nitroreduction Chloramphenicol Arylamine
Azoreduction Protonsil Sulfanilamide (Antimicrobial)
Alcohol dehydrogenases Chloarl hydrate Trichlorethanol

Hydrolysis
Hydrolytic reactions do not involve hepatic microsomal enzymes and occur in plasma and many tissues.
Both ester and amide bonds are susceptible to hydrolysis.

Reactions Parent Drug Metabolite

Hydrolysis Acetylcholine α Choline + acetic acid
Procaine P-Aminobenzoic acid + Diethylaminoethanol

Phase-II Reactions (Conjugation/Synthetic Reactions)

(Also referred to as Detoxification process)
This is synthetic process by which a drug or its metabolite is combined with an endogenous substance
resulting in various conjugates such as glucoronide, ethereal sulfate acetate, glutathione, methylated
compound and amino acid conjugates. All phase-II enzymes are of non-microsomal type except enzyme
which catalyzes glucoronidation. The major conjugation reactions are:
1) Glucuronide synthesis/Glucuronidation
2) Sulfate conjugation
3) Acetylation
4) Glutathione conjugations
5) Methylation
6) Amino acids conjugations
Oxidative Reactions Parent Drug Metabolite
Hydroxylation Phenybutazolne Oxyphenybutazone
Phenobarbital p-Hydroxyphenobarbital
Aliphatic hydroxylation (side chain oxidation) Pentobarbital Pentobarbital alcohol
Ddealkylation Phenacetine Acetaminophen
N-oxidation Trimethylamine Trimethylamine oxide
Sulfoxidation Chlorpromazine Chlorpromazine sulfoxide
Deamination Amphetamine Phenylacetone
Desulfuration Parathion Paraoxon
1) Glucuronide synthesis/Glucuronidation
● It is most important metabolic pathway for drugs and certain endogenous compounds like steroid
hormones, thyroxine, bilirubin etc.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
● The activated donor form of glucuronic acid is the nucleotide-uridine diposphate glucuronic acid (UDPGA).
● Synthesis of glucuronide involves transfer of the conjugating agent from the nucleotide to an acceptor
molecule which is mediated by glucuronyl transferase- a microsomal enzyme.
● Some drugs are excreted largely as glucuronides (morphine, slaicylates, acetaminophen/paracetamol,
chloramphenicol etc.).
● Glucuronides are more water soluble than the parent drugs and are highly ionized at physiologic pH
which facilitates their excretion.
● Glucuronides that are excreted into bile may undergo hydrolysis by β-glucuronidase (elaborated by gut
microflora) in the intestine and the liberated free drug may then be absorbed and an entero-hepatic
cycle may be established (characterized by appearance of secondary peaks).
● Certain breeds of fish do not synthesize glucuronides due to deficiency of UDPGA.
● Defective synthesis of glucuronides in cats is due to low level of the transferring enzyme “glucuronyl
transferase” rather than deficiency of UDPGA.
2) Sulfate conjugation
● Sulfate conjugation is an important metabolic pathway for phenols and aliphatic alcohols.
● The enzymes for sulfate conjugations are cytoplasmic sulfotransferases and the co-factor (Endogenous
donor) is 3’ phospho adenosine 5’ phospho sulfate (PAPS).
● Some drugs that form ethereal sulfate include phenol, acetaminophen, morphine, isoproterenol, ascorbic
acid etc.
● Capacity for sulfate conjugation in pigs is limited and subject to saturation due to low level of
sulfotransferase.
3) Acetylation
● Conjugation with acetate is restricted to amines.
● Acetylation is carried out by a cytoplasmic enzyme acetyltransferase.
● The acetyl donor is Acetyl coenzyme- A.
● Acetylation of all types of amino groups takes place in human beings and several species of animals.
Dog and fox do not acetylate aromatic amino group.
● Dogs appear to have a specific deficiency in arylamine acetyltrasferase due to the presence of a
natural specific inhibitor of this ezyme.
● Acetylation is the principal metabolic pathway for sulfonamides in man, rabbits and rats but is
accompanied by aromatic hydroxylation in ruminants.
● Acetylation decreases water as well as lipid solubility.
4) Glutathione Conjugation
● Glutathione is g-glutamyl-cysteinyl glycine tripeptide that occurs in most tissues especially in the liver.
● Glutathione-s-transferase catalyzes the reaction between glutathione and aliphatic halides. The
conjugate product is further hydrolyzed with the removal of glutamyl and glycine residues followed by
N-acetylation by acetyltrasferase.
● The end product of glutathione conjugation is mercapturic acid which is highly water soluble and easily
excretable in urine.
5) Methylation
● Adrenaline is methylated to metanephrine by catechol-o-methyl transferase. Here the source of methyl
group is S-adenosyl methionine (SAM).
6) Amino acids (Glycine and Glutamate) Conjugation
● Carried out by mitochondrial enzyme N-acetyl transferase and is restricted to carboxylic acids, especially
aromatic ones.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
Metabolic Biotransformation Mediated by GI Microbes
Ruminal microflora can also catalyse hydrolysis and reduction reactions e.g. cardiac glycosides are
hydrolyzed in the rumen and chloramphenicol is inactivated by reduction of the nitro group.
Bio-activation/Lethal Synthesis
Conversion of an inactive/non-toxic parent compound to an active/toxic metabolite is termed as bioactivation/
lethal synthesis. Some examples of lethal synthesis are:

Non-toxic parent compound Toxic lethal metabolite

Fluoroacetate Fluorocitrate
Parathion Paraoxon
Malathion Malaoxon
List of some Inactive drugs that produce active metabolites
Inactive parent compound Active metabolite
or prodrug
Cortisone Hydrocortisone
Prednisone Prednisolone
Cyclophosphamide Phosphoramide mustard
Chloral hydrate Trichlorethanol
Azathioprine Mercatopurine
Enalapril Enalaprilat
Zidovudine Zidovudine triphosphate
List of some active drugs that produce toxic metabolites
Active parent compound Active metabolite
Heroin Morphine
Codeine Morphine
Propranolol 4-OH Propranolol
Imipramine Desmethyl imipramine
Diazepam Nordiazepam & Oxazepam
List of some active drugs that produce active metabolites
Active parent compound Toxic metabolite
Paracetamol N-Acetyl-p-benzoquinone imine
Halothane Trifluoroacetic acid
Sulfonamide Acetylated metabolites
Methoxyflurane Fluoride
Microsomal Enzyme Induction
● The phenomenon of increase in the microsomal enzymes expression or activity is known as enzyme
induction and those agents, which cause enzyme induction, are called enzyme inducers.
● A number of drugs like phenobarbital (barbiturates), rifampicin, ethanol, carbamezepam, griseofulvin,
etc. and carcinogenic agents like 3-methylcholanthrene are known to induce microsomal enzymes.
● Enzyme induction can increase drug toxicity if its metabolite is toxic eg. paracetamol whose Phase-I
metabolites are mainly responsible for their toxicity will increase.
● Enzyme inducers can enhance the metabolic rate of self as well as other co-administered drugs with
significant clinical implications like reduction in efficacy and duration of action of drugs.
● Mechanism of enzyme induction is incompletely understood. However, the inducers appear to promote
the transcription of cytochrome P450 gene (CYP450).
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
Microsomal Enzyme Inhibition
● The phenomenon of decrease in the microsomal enzymes activity is known as enzyme inhibition and
those agents, which cause enzyme inhibition, are called enzyme inhibitors.
● Certain drugs/chemicals are also known to cause enzyme inhibition.
● Competitive enzyme inhibitor: Quinidine-potent inhibitor of cytochrome P2D6.
● Non-competitive inhibitors include drugs such as ketoconazole which forms a tight complex with haeme
iron (Fe3+ form) of cytochrome P3A4 causing reversible non-competitive inhibition.
● Other examples of inhibitors are cimetidine, chloramphenicol, erythromycin etc.
First Pass-Effect/Pre-Systemic Metabolism: The liver or sometimes the gut wall metabolizes some
drugs so efficiently that the amount of intact drug reaching the systemic circulation is less than the actual
amount absorbed. It is loss of drug before it reaches systemic circulation. This phenomenon is known as
pre-systemic metabolism or first-pass effect and is important for many clinically used drugs. Pre-systemic
metabolism or first-pass effect is encountered only with oral/enteral routes of administration.
Pre-systemic metabolism or first-pass effect is generally a nuisance in clinical practice because a much
larger dose of the drug is required when it is to be given by oral route.

Drugs Undergoing Substantial Pre-systemic Metabolism

Aspirin Lignocaine Chlormethiazole
Metoprolol Chlorpromazine Morphine
Dextropropoxyphene Nortryptaline Glycerine trinitrite
Pethidine Imipramine Propranolol
Isosorbide dinitrate Salbutamol Levodopa
Verapamil

Drug excretion: Excretion of drugs means the transportation (removal) of either unaltered or altered metabolized
form of drug out of the body. The major processes of excretion include renal excretion, hepatobiliary excretion
and pulmonary excretion. The minor routes of excretion are saliva, sweat, tears, milk, vaginal fluid, nails and
hair. The rate of excretion influences the duration of action of drug. The drug that is excreted slowly, the
concentration of drug in the body is maintained and the effects of the drug will continue for longer period. Polar
drugs and compounds with low lipid solubility are mainly excreted through kidneys and bile.

Renal excretion
● Compounds with limited lipid solubility and predominantly in ionized state at physiologic pH are excreted
through kidneys in urine. A major part of excretion of chemicals is metabolically unchanged or changed.
● Drugs excreted unchanged- most of the penicillins, cephalosporins, aminoglycosides, most tetracyclines
(except doxycycline), diuretics (except ethacrynic acid), cardiac glycosides, d-tubocurarine, gallamine etc.
The excretion of drug by the kidney involves.
i) Glomerular filtration
ii) Active tubular secretion
iii) Passive tubular reabsorption.
The function of glomerular filtration and active tubular secretion is to remove drug out of the body, while
tubular reabsorption tends to retain the drug back in the body.
i) Glomerular filtration: It is a process, which depends on (a) the concentration of drug in the plasma
(b) molecular size, shape and charge of drug (c) glomerular filtration rate. Drugs which are not bound
with the plasma proteins can only pass through glomerulus. All the drugs which have low molecular
weight can pass through glomerulus e.g. digoxin, ethambutol, etc. In congestive cardiac failure, the
glomerular filtration rate is reduced due to decrease in renal blood flow.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
ii) Active tubular secretion: The cells of the proximal convoluted tubule actively transport drugs from
the plasma into the lumen of the tubule e.g. acetazolamide, benzyl penicillin, dopamine, pethidine,
thiazides, histamine.

iii) Tubular reabsorption: The reabsorption of drug from the lumen of the distal convoluted tubules into
plasma occurs either by simple diffusion or by active transport and is affected by the pH of urine being
formed. When the urine is acidic, the degree of ionization of basic drug increase and their reabsorption
decreases. Conversely, when the urine is more alkaline, the degree of ionization of acidic drug increases
and the reabsorption decreases.

Hepato-biliary (Bile) Excretion

● Compound with molecular weight > 300 Da, presence of polar groups and conjugation with glucuronic
acid facilitates biliary excretion.
● Endogenous steroids, chloramphenicol, morphine, digoxin, bilirubin etc. form glucuronide and excreted
through the bile.
● Depending on lipid solubility, some drugs are reabsorbed from the small intestine (eg. tetracyclines)
and produce entero-hepatic recycling/ re-circulation leading to delay in elimination and increase in
drug half-life.

Gastrointestinal excretion: When a drug is administered orally, a portion of the total drug remains
unabsorbed and excreted unchanged in the faeces. The drugs which do not undergo enterohepatic cycle
after excretion into the bile are also subsequently passed with faeces eg. aluminium hydroxide changes the
faeces into white colour, ferrous sulfate into black and rifampicin into orange red colour.

Pulmonary Excretion: Drugs that are readily vaporized, such as many inhalant anaesthetics and alcohols
are excreted through lungs. The rate of drug excretion through lung depends on the volume of air exchange,
depth of respiration, rate of pulmonary blood flow and the drug concentration gradient.

Sweat: A number of drugs are excreted into the sweat either by simple diffusion or active secretion e.g.
rifampicin, metalloids like arsenic and other heavy metals.

Mammary excretion: Many drugs, mostly weak basic in nature, are accumulated into the milk. Therefore,
such drugs should be used cautiousally in lactating animals age they may enter into young one through
dam milk and produce harmful effects eg. ampicillin, aspirin, chlordiazepoxide, coffee, diazepam, furosemide,
morphine, streptomycin.
Relationship between total body clearance (ClB), volume of distribution (Vd) and half-life (t )
½

Rate of elimination
Clearance (ClB) = = β x Vd
Plasma conc.

0.693 0.693 x Vd
Half life (t ) = =
½ β ClB

ClB x t = 0.693 x Vd
½

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER - 5
PHARMACODYNAMICS
● Pharmacodynamics is the study of biochemical and physiological effects of drugs and their mechanism
of action. In laymen term it means “what drug does to the body?”
● A drug can’t initiate new cellular function but can modify existing cellular functions.
● A drug produces its effect by interacting with certain macromolecular components of cells/tissues
called receptors. Thus, Receptors may be defined as functional macromolecular component of the
cell/tissue with which the drug interacts and produce its effect.
TARGETS FOR DRUG ACTION
1) Receptors eg. Receptors for hormones, neurotransmitters (NTs)
2) Ion-channels eg. sodium, potassium, chloride chanels
3) Enzymes eg. Na+ - K+ - ATPase target for cardiac glycosides, dihydrofolate reductase, AChE,
cytochrome oxidase etc.
4) Carrier molecules eg. Plasma proteins involved in transport processes
5) Structural proteins eg. tubulin.
6) Cellular constituents like Membrane sterols e.g. nystatin, amphotericin-B bind to ergosterol.
7) Nucleic acid- Cancer chemotherapy
I. Receptors :
● The receptors are also interacted by the natural endogenous substances like NTs (e.g. ACh, NE etc.),
hormones (eg. estrogen, androgens etc.), autacoids (eg. histamine, serotonin etc.) which regulates
the function of the organisms.
● Drugs interact with receptors and produce their effect by either stimulating or suppressing the ongoing
cellular processes.
● The natural drug receptors are mostly enzymes located in the cell membranes. The interaction between
a drug and these receptors produces either a direct effect on the cell or an indirect effect through
activating or promoting synthesis or release of another intracellular regulatory molecule called the
second messengers.
● The direct effects of the receptors include alteration in the activity of trans-membrane enzymes, ion-
channels, guanine nucleotide binding proteins (G-proteins) etc.
● The second messenger concept includes stimulation or inhibition of adenyl cyclase (for synthesis of
cAMP) or guanyl cyclase (for synthesis of cGMP), phospholipase etc.
II. Enzymes : Some drugs instead of acting on receptors, directly act on enzymes.
1) Direct inhibition of enzymes eg. NSAIDs inhibit cyclooxygenase (COX) enzymes. Neostigmine
inhibit acetylcholinestrase enzyme.
2) False substrate: Drug act as false substrate eg. methyldopa. Dopamine is converted in nor-epinephrine
(act as neurotransmitter) with an enzyme dopamine α-oxidase. In some diseases more concentration
of dopamine is required, so drug methyl DOPA is given. This methyl DOPA acts as false substrate.
When enzyme acts on it, it converted into methyl norepinephrine or meta-norepinephrine.
III. Carriers : These are molecules responsible for transport of big substance across (amino acid, glucose,
bigger ions) cell membrane. Many drugs bind to carrier and inhibit its function eg. Furosemide act as
diuretic, given in case of anurea, it acts on “Na+ carrier” and inhibit it. Hemicholium inhibit transport of
choline, hence stop the formation of acetylcholine.
IV. Ion channels: Drugs directly interact with ion channel and modulates transport of ions through channels.
Eg. local anesthesia directly block local Na+ ion channels in neurons. Ameloride, a diuretic, it blocks
channel of Na+ ions reabsorption. Verapamil and diltiazem are calcium channel blockers.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
Drug binding to Receptors: Binding of drugs to receptors takes place through the following
physicochemical ineteractions:
1) Ionic forces
2) Hydrogen bonding
3) Hydrophobic interactions
4) Vander-Waal forces
5) Covalent bonding- duration of drug action is prolonged generally.
● Vanderwall bond, ionic bond, hydrogen bonds are weaker bond and are easily breakable and reversible,
so drug action is temporary. Covalent bond are stronger and if formed generally are irreversible.
Difference between specific receptors and non-specific receptors: For specific receptors, minor
change in molecular structure of the drug causes major change in the pharmacological response, whereas,
non-specific receptors have very low specificity for chemical structural requirements.

Drug action and Drug effect: Drug action is be defined as method, manners or ways by which drug influences
the cell functions. Drug effects/pharmacological effects/response is results of drug action on cellular processes.
Penicillin on microbes or aspirin on headache or pain eg. Penicillin interferes with incorporation of essential
amino acids/compounds into cell wall (“ACTION”) and cause cell lysis/death (“EFFECT”). Aspirin inhibits
prosta glandins (PGs) synthesis (“ACTION”) and relieves headache or pain (“EFFECT”).
Drug-Receptor Interaction: The drug-receptor interaction is the first step which initiates the subsequent
physiological and/or biochemical changes which are observed as effects/response of the drug.

Stimulus
Drug + Receptor à Drug-Receptor Complex Effects
Classification of receptors: Receptors are classified into 4 categories
1) G-protein coupled receptor:
● They are transmembrane protein present on cell membrane and linked with with Guanine nucleotide,
so called G-protein coupled receptors.
● They have haptamer structure and are serpentile in shape.
● Discovered by Gilmer and Gudberg.
● These are membrane bound receptors which mediates there action throgh guanine nucleotides.
● They are many types like Gs (s for stimulatory), Gi (i for Inhibitory), Go, Gq and G13.
2) Kinase coupled receptor:
● Membrane bound/present on cell membrane.
● It has 2 domains, 1 outside and 1 inside the cell.
● Outer domain called - ligand binding domain.
● Inner domain called - Catalytic domain. eg. insulin receptor, tyrosine kinase linked receptor, guanine
cyclase linked receptor.
3) Ion channel coupled receptor:
● Present on cell membrane and associated with ion channel.
● When drug bind with this, it regulate closing and binding of channel.
● These are fastest acting receptors.
eg. Nicotinic receptors, GABA receptors, Glutamate receptors
4) Steroid receptor:
● Situated inside the cell, so also called as cytosolic receptors.
● They are soluble in nature, number are variable.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 ● When drug act on it, bring out translocation, transcription for protein synthesis, so it is slowest
receptor in action. It takes 22-24 hours.
eg. mineralocorticoids, glucocorticoids

Theories of drug action : The drug-receptor interactions as the basis of drug-induced effects gave rise to
different theories of drug action.
1. Drug receptor theory : The receptor concept of drug action was first proposed by Paul Ehrlich, and
subsequently by J.N. Langley (1878). According to this theory each drug act on its matching receptor,
which is structure specific, to produce a pharmacological response. All drugs have different receptors.
One type of drug will not react with the receptors of another type i.e. specific receptors for specific
drugs just like “Lock and Key” system where a only particular key can open a particular lock e.g.
noradrenaline will interact only with adrenergic receptors.
2. Occupancy theory: Proposed by A.J. Clark (1936). Pharmacological or drug response is directly
proportional to portion of receptors occupied by drug. Maximum response is obtained when all the
receptors are occupied. This theory could not explain the phenomenon that partial agonist occupies
full population of receptors but fails to elicit maximum response.
3. Stepheson theory: Stepheson (1956) coined term efficacy. The efficacy is defined as ability of drug
to produce response. According to him, highly efficacious drug produces maximum response even
though they combine with small fraction of receptors. On contrary, poor efficacious drugs can not
produce maximum response even though they combine full fraction of receptors.
4. Rate theory: W.D.M. Paton proposed in late 1950s. Drug response is directly proportional to drug receptor
complexation. The drug response is determined by rate at which drug combines with receptors and leaves
the receptors, i.e., greater rate of association and dissociation between drug and receptors, greater is the
response. Antagonist combines with receptors at faster rate but dissociate at very slow rate.
5. Drug induced protein chanhe theory : Drug induces some temporary changes in the structure of
receptors making it active.
6. Two State Receptor theory: Receptor theory states that “an agonist combines with a site on a
receptor and the receptor becomes activated and triggered a response from the cell. When the drug
leaves, the receptor returns to the non-activated state, i.e. regenerated which is essential for further
cycles”. Receptor theory is also known as macromolecular perturbation theory / model theory.

Principles of Drug Actions

Drug affinity: The ability of a drug to interact or combine with its receptor is called drug affinity.
Intrinsic activity: The ability of a drug to produce the pharmacological response (Both drug affinity and
intrinsic activity depends on chemical structure of drug).
Drug efficacy: The maximum effect a drug can produce which depends on both drug affinity and intrinsic
activity.
Agonist: An agonist is a drug that interacts with its receptors and produces an positive effect i.e. it has both
affinity and efficacy e.g. isoproterenol, histamine, morphine etc.
Full agonist: Agonist which is able to produce maximum response.
Antagonist : An antagonist is a drug, which interacts with the receptors and prevents an agonist from
binding to the receptors to produce its effect e.g. atropine, propranolol, chlorpheniramine, naloxone etc.
Inverse agonist: Drug binds withreceptor like agonist but produces opposite effect. eg. B-carboliones on
benzodiazepine receptors.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
Partial agonist : An antagonist having some effects similar to agonist is called a partial agonist or mixed
agonist-antagonist. They have high affinity but low intrinsic activity. e.g. nalorphine
An agonist fully participates in the drug-action-effect sequence, whereas an antagonist has only action.
Agonist has affinity and efficacy while antagonist has only affinity and no efficacy.
Value of Intrinsic activity (IA) : For Full agonist = 1; Antagonist = 0; Partial agonist = > 0 but < 1, Inverse
agonist = 0 to -1.

Non-Receptor Mediated Drug Action : Non specific actions of drugs inculdes physical actions and chemical
actions. Physical actions are due to the physical properties of drug eg. osmotic diuretics, saline purgatives
(MgSO4), adsorbents. Chemical actions include simple chemical nutrilization of pH eg. Antacids (Aluminium
hydroxide), alkalizers like sodium bicarbonate.
DOSE-RESPONSE RELATIONSHIP OF DRUGS
The response to a drug varies according to its dosage i.e. the magnitude of the drug effect is a function of
the dose administered. The relationship between the responses produced by different doses is expressed
by graphical representation called dose-response curve.
There are two types of dose-response curves- graded dose-response curve and quantal (“All” or “None”)
dose-response curves.

(A) Graded-Dose or Gradual-Dose Response Curve : The graded dose-response curve gives the
relation between dose of the drug and intensity of the response in a single biological unit. The curve
depicts that when the dose exceeds a critical level (threshold dose) the response also increases
progressively until it reaches a steady level called ‘ceiling effect”. The threshold dose may be defined
as the minimum dose that is required to produce an observable response. The dose that produces the
ceiling effect, is called the ceiling dose, and may be defined as the amount of drug that is required to
produce a maximal response. Any further increase in the dose above the ceiling dose will not increase
the level of response. The shape or such graded response curve is hyperbola on simple graph paper,
but sigmoid in shape when dose is taken as log value on logarithm scale.

Threshold Dose Celling Dose

Response

Response

Log Dose Dose

(B) Quantal Dose-Response Curve

The quantal (“All” or “None”) dose-response curve represents the percent response of animals to
doses of a drug in a group of population. Each animal receiving a dosage is categorized as “responding”
or “not responding”. The population responding to each doses, are recorded as % dead, % alive, %
responded or % not responded. The relation is based on “all” or “none” phenomenon, which cannot be
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 quantitatively measured such as occurrence of sleep, convulsions, emesis etc. These quantal
responses, when plotted against log doses, does not show a linear regression. However, the percent
response is converted/transformed to probits, the relationship becomes linear. The graph is sigmoid
in shape in both normal & logarithmic graph paper. This type of curve is used for estimating/determining
median effective dose (ED50) and median lethal dose (LD50) values.

Applications of dose response curve:

(1) To know margin of safety of any drug
(2) To compare potency of drug
(3) To compare efficacy of two drug

Median Effective Dose (ED50) : Median effective dose may be defined as the amount of drug that would
be expected to produce a desired therapeutic effect among 50% of the population to which it has been
exposed. It is used for drug response.

Median Lethal Dose (LD50): Median lethal dose may be defined as the amount of drug/compound that
would be expected to produce a lethal effect (mortality) among 50% of the population to which it has been
exposed. It is used for toxic compounds.

ED50 and LD50 indicate therapeutic and toxic potency of drug, respectively. Based on value of ED50, drug
are classified into less effective, more effective and most effective. Similar for LD50,less toxic, more toxic
and most toxic.

MEASURES OF SAFETY
Therapeutic Index (TI) : It is the ratio between LD50/ED50. The wider the TI, safer is the drug. Ideal TI is
8-10 but some drugs like anticancer and anaesthetics have low TI.
Therapeutic Ratio (TR): It gives more precise margin of safety; as in quantal dose response curve,
portion between 16 to 84 per cent is more linear in nature. TR= LD25/ED75. Ideal value of TR is 4.
Standard safety margin: SSM is the ratio between LD1/ED99 or LD0.1 / ED99.9. The drug safety could be
better expressed by using a ration derived from two extremes of respective quantal response curves i.e.
ratio of least toxic dose and most effective dose.
Certain safety factor: It represents dose effective in 99 out of 100 or 999 out of 1000.
CSF = [(LD1/ED99)-1]/100

TERMS USED IN RELATION TO DRUG ACTIONS

Potency : It is defined as dose required to get predetermined effect. Potency & safety have no any
relationship. Potency and dose are inversely related. Higher the potency, less dose is required. Potency is
a relative term, it is not used isolated, and there must be comparison to other drug (reference/standard).
For example, Morphine @ 0.2 mg/kg and hydromorphine @ 2.0 mg/kg produce same response, then
hydromorphine is 1/10th Potent than morphine.
Latent period / Latency: It is time interval between termination of administration of drug and time at which desired
therapeutic response is observed. It’s value is the shortest for IV route of administration and longest after oral route.
Duration of action: It is a time interval during which drug continuously maintains desired therapeutic
response. The value depends on route of administration. The shortest for IV and longer for IM and SC
routes.
Onset of action: It is a interval between administration of drug and appearance of its first sign of drug
action.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
Reserve receptors: Reserve receptors are excess of drug receptors that are required for the maximal
response of the drug. Reserve receptors are also known as spare receptors.
Silent or inert receptors: Silent or inert receptors are receptive substances with which the drugs bind,
but do not produce any effect e.g. plasma pproteins.
Orphan receptors : Receptors whose ligand are not yet known or discovered.
Tachyphyalxis: Tachuphylaxis is a phenomenon in which the effect of a drug diminishes when it is given
continuously or repeatedly. This phenomenon often develops in the course of a few minutes e.g. effect of
repeated administration of tyramine on blood pressure. Tachyphylaxis is also termed as desensitization.
Tolerance: Gradual decrease in responsiveness to a drug. Requires day to week to develop e.g. tolerance
to alcohol.
Refractoriness: Loss of therapeutic efficacy.
Tachyphylaxis, tolerance and refractoriness may be due to following mechanisms:
a. Change in receptors
b. Loss or down-regulation of receptors.
c. Exhaustion of mediators.
d. Increased metabolic degradations due to induction of microsomal enzymes.
e. Physiological adaptations.

Drug resistance: Referred to loss of effectiveness of antimicrobial agents.

Summation/ Additive effects: If the pharmacological effect of two drugs administered together is
quantitatively equivalent to the sum of the individual expected effects, when administered alone, this
phenominon is called “additive effect or summation”. Such drugs generally share the same mechanism/
mode of action e.g. ephedrine + aminophylline as bronchodilator, streptomycin + dihydro-streptomycin as
antibacterial.

Synergism: If the pharmacological effect of two drugs administered together is quantitatively greater than
that is explainable on the basis of simple summation of their individual effects is called “synergism”. Though
the dresired effects are same, the drugs do not share common mode of action e.g. penicillin + streptomycin
as antibacterial, codeine + aspirin as analgesic, pyrimethamine + sulfadiazine as choloroquine-resistant
antimalarial, trimethoprin + sulfamethoxazole as antibacterial.

Potentiation: When the effect of a drug is considerably increased due to concurrent administration of
another drug or chemical is known as potentiation e.g. potentiation of acetylcholine by physostigmine.

Target tissue (Organ) : It is the site where the drug is intended to produce its effect e.g. anesthetics on the
CNS.

Therapeutic effect: It is the beneficial/useful desired effect produced by either direct or indirect action of
the drug.

Placebo: Derived from a Latin word meaning “I may please you”. A placebo is an agent or preparation
consisting of an inert pharmacological agent (usually starch or lactose) to stimulate the psychological
impact of medication in man. Placebo plays an important role in clinical drug trials in human beings.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 FACTORS AFFECTING / MODIFYING DRUG ACTION AND DRUG DOSAGE

Dosage or dosage regimen: Refers to the dose schedule of the drug to be employed for accomplishment
of an intended purpose and includes duration of therapy and frequency of drug administration.
Dose: refers to the total amount of a drug to be used through a specified route to elicit the intended effects
in a given subject.
Dose rate: It is an expression of a dose in terms of amount of the drug per unit body weight e.g. mg/Kg or
mg/m2 (unit per surface area in case of cancer chemotherapy).

Factors affecting drug effect & drug dosage are:

1) Physiological factors: Species, age, sex, circadian cycle
2) Genetic factors: Intra-species variations
3) Pathological factors: Hepatic dysfunction, renal dysfunction, GIT disorders
4) Environmental factors: Ambient temperatures, dietary factors
5) Therapeutic factors: Route of drug administration, pharmaceutical factors,

1) Physiological factors
● Species
The same drug may produce variying degree of response qualitatively and quantitatively in different
speceis. eg, Morphine-CNS excitation in cats while in other speceis it causes sedation.
Atropine from Atropa belladona leaves is non toxic in rabbits as it has enzyme atropinase which hydrolses
the atropine.
❖ Cats are highly susceptible to aspirin toxicity due to deficiency of glucuronyl transferase enzyme.
❖ Carnivores and primates respond to central or local emetics (apomorphine or Zinc sulfate/copper
sulfate). Ruminants and equines do not respond to emetics due to absence of efficient vomiting
mechanisms/reflex.
● Age: Very young and very old (geriatric) man and animals require low dosage compared to adults.
Neonates owing to immature metabolic and excretory function, they are more prone to toxic effecsts
of drugs. Older patients because of reduces hepatic and renal activity due to ageing needs lower dose
of drug than adults.
● Sex: Variation is less frequent but do occurs. It is due to difference between physioloigcal function and
endrocrine profile. E.g., Red squil is more toxic in femal as compared to male rats.
● Body weights: Dose of drug is calculated on the basis of body weight. Variation in body weights
especilly in pregnancy, dehydration, edema, obesity and other condition must be considered while
determing the dosage of drugs.

2) Genetic factors
● Idiosyncrasy is defined as unusual response of drugs to normal dose. It may be due to some genetic
factors.
● The collie breed of dog is more susceptible to ivermectin toxicity. This is due to lowere expression of
eflux drug transporter protein (P-GP) genes.

3) Pathological factors
● Liver diseases- Slower metabolic biotransformation/slower biliary excretion.
● Kidneys disorders- Slower excretion of drugs/drug retention.
● GIT disturbances-Diarrhoea (absorption of drugs), vomiting (non-retention of oral drugs) and constipation
(- absorption of drugs).
● Presence of abscess or purulent conditions- Effect of LAs is reduced.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
4) Environmental factors
● Ambient conditions can interfere pharmacokinetic profile of many drugs.
Temperature , humiduty and other environmental factors directly or indirectly influences the drug
response and dose.
❖ High altitude with low atmospheric pressure reduces oxidation of drugs due to low availability of O2.
❖ - Ambient temperature- induces procaine toxicity in pups due to rapid absorption owing to vasodilation.
❖ Ethanol toxicity is more pronounced in winter as it causes excessive vasodilation (skin). Presence of
chilled air exagreat the heat loss.
● Dietary factors
❖ Quality and quantity of food present in stomach interferes /reduces drug absorption (eg. astemizole,
captopril, many antibiotics).
❖ Presence of divalent cations (Al, Mg, Ca) reduces absorption of oxytetracyclines and fluoroquinolones.
❖ High fat/oil intake increases bioavailability of griseofulvin.
❖ Use of tea infusion/decoction can interfere with absorption of alkaloids notably ephedrine, codeine etc.
❖ Vitamin-C and copper ions increases iron absorption by reducing ferrous for to ferric state for quicker
absorption and assimilation.
❖ MAO-inhibitors and Tyramine rich food (cheese, alcoholic beverages, yeast extract, broad beans etc.)
leads to hypertensive crisis.

5) Therapeutic factors: Route of drug administration and frequency of drug administration depends on
tolerance. Repeated exposure and frequent treatment may cause down regulation and tolerance.
Reversly due to some genetical changes, receptors may exhibits supersensitivity and produces
exagreated response.

Pharmaceutical factors: Liquid dosage are more rapidly absorbed as compare to solid. In solid dosage
formulation, size of particles, dissolution time, disintegretion time is crucial factors in determining
absorption of drugs. Vehicle system or drug delivery system play important role in prodicung
pharmacological effecst.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER-6
DRUG SCREENING AND BIOASSAY OF DRUG
Drug screening denotes all methods by which pharmacological effecsts of newer drugs are being evalu-
ated. The primary target of screening is to identifye potenctially the new chemicals having known /unknown
or suspected pharmacological effects.
The basically there are three types of screening.
(1) Simple screening: It involves study of one or two pharmacological effects of chemials under investi-
gation. For eg., Screening for hypoglycemic effecs.
(2) Programmed screening: It involves screening of chemicals through series of well planned test or
procedures. For e.g., screening of chemical for antihypertensive effecst conducts all the tests includ-
ing urinary output, cardiovascular functions, heart rate, blood pressure, blood perfusions etc.,
(3) Blind screening: When ever, no information is available on substances under investigation or nothing
is known abour test substances, blind screening is employed. It involves extensive pharmacoligical
tests. If results are prominent, then substances are subjectd to simple or programmed screening.
Type of drug assay :
1. Bioassay or biological assay
2. Chemical assay: Estimation by chemical method and it is the most commonly used method.
Different techniques used are spectrophotometry, fluorimetry and sophisticated chromatographic
methods. Many drugs can be assessed by chemical methods. They have high sensitivity and
specificity but may be costly.
3. Immunoassay: It is a physicochemical assay which depends on the reaction between an antigen
(e.g. a hormone) and its specific antibody in the test tube. The antibodies are obtained from sera
of previously sensitized animals like rabbits. It is highly sensitive and can measure hormones and
other biologically active substances. Radio receptor assay and Enzyme Linked Immunosorbent
Assay (ELISA) are other types of Immunoassays.
Bioassay: It is short hand term used for biological assay. It refers to estimation of the potency of drug
(biologically active substance) by using biological method. It may be quantitative or qualitative.
Qualitative bioassay : It is used when it is not possible to quatify the response produced by drug, eg.,
abnormal deformity, induction of sleep and mood alteration.
Quantative bioassay : it is used when it is possible to quantify the response produced by drug , eg.,
Principle : To compare the test substance with the standard preparation of the same to find out how
much test substance is required to produce the same biological effect as produced by the standard.
Thus the stander and the test drugs should as far as possible are identical. Dose Response curve
forms the basis of bioassay.
Methods for bioassay :
1. Interpolation method
2. Direct matching or bracketing assay : This is the simplest method. In this method the responses
of different doses of known standard solution of the drug and a fixed dose of unknown test solution
(T) are recorded. Finally the dose of standard solution producing the response which exactly
matches T will be found. As this method involves repeating T inside a bracket of standard doses, it is
also called bracketing assay.
3. 2+1 or Three point assay: In this method, repetition of three doses, two of the standard (S1, S2)
and one of the unknown (T) is done randomly to obtain a series of responses. Then the concen-
tration of unknown is calculated graphically.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
4. 2+2 or Four point assay: Four point assay involves two doses of standard and two doses of test
solution.
Bioassay can be carried out either on intact animals or isolated tissues. For bioassay of a particu-
lar drug appropriate animal or isolated preparation should be selected.
Following are some examples of isolated tissues or animals selected for bioassay of different drugs
Drug Animal/Preparation of choice
Adrenaline Cat/dog-Rise in B.P.
Noradrenaline Spinal cat - rise in B.P.
Histamine Isolated guinea pig ileum contraction
Acetylcholine Isolated frog rectus abdominis contraction
Digitalis Guinea pig- death due to cardiac arrest
Insulin Mice-hypoglycemic convulsions

Advantages:
1) Sensitivity: sometimes when concentration of active substance is below the limit detect
by chemical or other methods, bioassay can be used.
2) When structure of active substance is unknown.
3) When the response of drug and concentration is poorly correlated.
4) When nature of drug to be tested is very complex and it’s concentraion is not measurable in biological
matrix.

Disadvantages:
1) Biological variation- errors arising due to it.
2) Time consuming, tedious.
3) Experimental animal needs to be sacrificed.

Indication & Uses of bioassay: Indicated for substances derived from plant or animal sources. Synthetic
drugs usually don’t required bioassay.

Bioassay can be used for:

1) Standardization of drugs of natural origin (biostandardization).
2) Estimation of biologically active substances like acetylcholine, adrenaline, noradrenaline, serotonin
etc. in body fluids and extracts.
3) Screening of new compounds for biological activity-including synthetic compounds.
4) When drug is a complex mixture of substances of varying structure and activity e.g. digitalis,
posterior pituitary extract.
5) Diagnosis and Research:Concentration of gonadotropins in blood of mice estimated by injecting these
fluids in animal (chemical methods if available are preferred).
6.) Estimation of ED 50, LD 50 and thus to establish therapeutic and toxic profile.

Requirement of Bioassys:
It must be accurate, precise, specific, sensitive, stable and simple to perform.
1) The animals to be used in bioassay must be easily available.
2) It should cause minimum pain to animals.
3) The bioassay must use least numbers of live animals.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER - 7
ADVERSE DRUG REACTIONS
Drugs are chemical that affects the living system. All drugs are harmful at (refer Pharmacological antagonism
high doses. Some drugs cause side effects and/or adverse effects.
● Side effects: Side effects of a drug is due to normal pharmacological action of the drug e.g. constipation
due to morphine when used as analgesic or CNS depression by conventional anti-histamines.
● Adverse or untoward effects: Adverse or untoward effects of a drug occurs following prolonged
therapeutic use e.g. prolonged use of antibiotics in chronic infections leads to development of super-
infections, ototoxicity (due to aminoglycosides0 or nephrotoxicity (due to sulfonamides).
● Iatrogenesis: derived from a Greek word “iatros”= physician. Iatrogenesis means physician-produced
disease.The term refers to the production of abnormal or pathological conditions due to the drug
administered e.g. oral administration of aspirin or indomethacin for prolong period may precipitate
peptic ulcers.
● Idiosyncrasy: It is defined as a genetically-determined abnormal response to a drug or a chemical
e.g. hemolytic anemia following administration of primaquine (antimalarial drug) due to deficiency of
glucose-6-phosphate dehydrogenase.
● Hypersensitivity/allergic reactions: It is an acute adverse reactions that results from prior sensitization
to a particular drug or chemically-related substances. Most frequently seen in man e.g. penicillin allergy.
● Anaphylaxis: An anaphylactic reaction occurs when an animal is exposed to a protein to which it had
been previously sensitized. The initial exposure does not cause any reactions, but the second or
subsequent exposure to the same protein triggered severe reactions characterized by acute
bronchoconstriction and cardiovascular shock e.g penicillin anaphylaxis.
DRUG TOXICITY: Toxicity is defined as the inherent capacity of a substance to cause harmful effect.
Type of toxicity: 1. Acute toxicity, 2. Sub-acute toxicity, 3. Chronic Toxicity
Acute Toxicity
● Occurs when an animal gets exposed to a single high dose of the compound.
● Toxic signs – tremors, vomition, convulsions, dyspnoea, coma and death may be observed.
● Experimental acute toxicity studies helps in calculating LD50 values of the compound.
Sub-acute and chronic toxicity :
● Repeated exposure of low doses for 3-6 months, Routine pathology, Histopathology of vital organs
● Teratogenecity: Derived from the word “tera”= monster. It is the inherent capacity of a drug/substance to
produce teratogenesis/fetal abnormalities when the drug is exposed to pregnant animals during the first
trimester of pregnancy e.g. thalidomide tragedy. Thalidomide, an antemetic produced “phocomelia” or
“sealed limbs” in thousands of children born to mothers who had taken the drug to prevent morning sickness
during early pregnancy.
● Carcinogenecity: It is the inherent capacity of a drug/substance to produce carcinogenic (tumor-
inducing) effect e.g. DDT, 2,4-D, 3-methylcholanthrene etc. Mutagenecity: It is the inherent capacity of
a drug/substance to produce gene mutagenesis e.g. many carcinogens.
● Ototoxicity: It is the inherent capacity of a drug/substance to produce hearing impairment including
deafness e.g. aminoglycoside antibiotics.
● Nephrotoxicity: It is the inherent capacity of a drug/substance to produce renal damage e.g.
sufonamides, aminoglycosides etc.
● Hepatotoxicity: It is the inherent capacity of a drug/substance to produce hepatic damage e.g. CCl4,
chloroform, paracetamol etc.
● Neourotoxicity: It is the inherent capacity of a drug/substance to produce toxic/harmful effects on the
brain e.g. many CNS acting drugs.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER - 8
DRUG INTNERACTION
One drug may alter the dose or effect/s of another drug when two are used concurrently, these are called
drug interactions, that leads to
● Increase in response to one or both drugs
● Decrease in response to one or both drugs
● Abnormal alteration in response to one or both drugs
Drug interactions are of two types:
I) Pharmacokinetic interactions: One drug alters the pharmacokinetics of second drug thereby affecting
the concentration (and effect) of one / both drug in system.
● Antacids decrease absorption of aspirin, warfarin, ciprofloxacin etc.
● Phenylbutazone displaces warfarin from albumin binding sites.
● Phenobarbitone, rifampin etc. induces hepatic microsomal enzymes causing increased metabolism
of pentobarbitone, digitoxin, warfarin, morphine etc.
● Chloramphenicol inhibits hepatic microsomal enzymes causing decreased metabolism of
pentobarbitone, tolbutamide, phenytoin etc.
II) Pharmacodynamic interactions: There is no alteration of pharmacokinetics of either drug but there
is alteration of biological response to one / both drugs.
● Atropine antagonize effect of acetylcholine (pharmacological antagonism)
● Adrenaline (bronchodilator) and Histamine (brochoconstrictor)
● Aminoglycosides and cephalosporins potentiate nephrotoxicity.
Addition: Two drugs are said to be additive if combined effect produced by them when used together is not
more then sum of their individual effects (2+3=5). eg Aspirin + paracetamol as analgesic, Ephedrine +
Theophyline as brochodilator
Potentiation: One drug have less or no effect but in combination with another drug it shows significant
effects. e.g. isopropanol alone is not showing hepatotoxic effect but along with ethanol it shows h i g h
hepatotoxic effect. ( 0 + 3=5)
Synergism: combined effect is more than additive drug effect.(2+3=8) e.g. Sulphonamide + trimethoprim,
adrenaline + desipramine, Captropril+diuretics
Antagonism: When two drugs used simultaneously or one after another produce effect that is less than
sum of their individual effects. (7+3= 6) eg. tannins + alkaloids – chemical antagonism
Glucagon + insulin-physiological antagonism
Morphine + naloxene, Diazepam + bicuculine-pharmacological antagonism.
Examples of few drug-drug interaction :
● Procaine with adrenaline: adrenaline cause vasoconstriction and decrease absorption of procaine.
● Amoxicillin with clavulanic acid : clavulanic acid inhibit â-lactamase enzyme which hydrolyse
amoxicillin.
● Chloramphenicol with pentobarbital: Effect of pentobarbital increased as chloramphenicol inhibits
metabolism of pentobarbital by inhibiting hepatic microsomal enzymes.
A general rule that would reduce or avoid adverse effect due to drug-drug interaction is as follows:
“Never mix a cationic drug with an anion drug unless there is some definite reason to use them”. Cationic
drugs include atropine, aminoglycosides, local anesthetics, lincosamides, polymyxins, marolids,
chlorpromazine and promethazine. Anionic drugs include sulfonamides, penicillins, cephalosporins, heparin,
EDTA and barbiturates.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER - 9
DRUG DESIGNING, DEVELOPMENT AND BIOPROSPECTING
Drug designing: The design of grug involves many approach. Most dominant approcah includes modifica-
tion of existing structure of drug using SARs. The combinatorial chemistry and medicinal chemistry are
core branches of science which are involved in drug designing. The design of drug depends mainly on
identification of target and probability of interaction with target. Addition or deletion of certian chemical
groups or functional moiety give rise to series of compound with diversified pharmacological prospectus.
They are frist screened for pharmacological activities. Now a days modern approachs like HTS, in silico
testing ect are used. These techniques gives faster and cheaper results.
Drug development: Development of new drug is a complex process consuming huge time and financial
resources depending upon regulatory frame work of country in which drug is to be approved for market.
The basic process of drug development is discussed here.
Pre-clincal studies: After screening, promising candidates are subjectd to pre-clnical evaluation or
studies. It includes acute, sub acute and chronic toxcity study. Caricinogenicity, mutagenicity and repro-
ductive toxicity are also included in this phase. Pharmacokinetics data in different species of laboratory
animals are also generated.
Clincal evaluation: It includes four phase of drug testing.
Phase-I: It included pharmacokinetics of drug in small group of healthy volunteers. Pharmacokinetics and
pharmacodynamic parameters are worked out.
Phase II: It covers pharmacokinetics and pharmacodynamics, dose ranging, efficasy and safety study in
small group of patients (50-300 patients).
Phase III: Large scale controlled clincal trial for safety and efficasy in large group of patients (500 to 1000 plus)
Phase IV: It is also known as post marketing surveliance. It is collection of reports regarding adverse drug
reaction, relative comparison with existing drugs and pharmacoeconomics.

BIO-PROSPECTING
It is defined as search for plant and animal species from which medicinal drugs and other commercially
valuable compounds can be obtained. Bioprospecting is the process of discovery and commercialization
of new products based on biological resources. Bioprospecting can be defined as the systematic search
for and development of new sources of chemical compounds, genes, micro-organisms, macro-organisms,
and other valuable products from nature. It entails the search for economically valuable genetic and
biochemical resources from nature.

Advantage:
● Stimulates authentic research in natural sources of drugs.
● It provides economical compensationn and scientific credits to owner country.
● It increases foucsed research efforts in the herbal medicine.

Disadvantage:
● Pharmaceutical companies or researchers shows dicinclination towards economic compensation
and scientific credtis to host country to which these resoures belong.
● Natural resources and biodiversity are exposued to higher human interferance and invasions.
● The legal frame work regarding use of bio resources and sharing of discovery has not attained mature.
This leads to conflict at local and international level causing hinderance in development of new drugs.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER - 10
BIO PHARMACEUTICS AND GENE THERAPY
The term ‘biopharmaceutical’ was first used in the 1980s and came to describe a class of therapeutic
protein produced by modern biotechnological techniques, specifically via genetic engineering or by hybridoma
technology (in the case of monoclonal antibodies). This usage equated the term ‘biopharmaceutical’ with
‘therapeutic protein synthesized in engineered (non-naturally occurring) biological systems’. More recently,
however, nucleic acids used for purposes of gene therapy and antisense technology have come to the front
and they too are generally referred to as ‘biopharmaceuticals’. Moreover, several recently approved proteins
are used for in vivo diagnostic as opposed to therapeutic purposes.

Biopharmaceutics: It is modern branch of pharmcology which deals with production and therapeutic
application of biopharmaceuticals.

Biopharmaceutical: ‘Biopharmaceutical’ includes ‘therapeutic protein synthesized in engineered (non-

naturally occurring) biological systems’. More recently, nucleic acids used for purposes of gene therapy
and antisense technology are also included in ‘biopharmaceuticals’.

Terms like ‘biologic’, ‘biopharmaceutical’ and ‘biotechnology medicine’ can be differentiated by following
definitions:-

Biopharmaceutical: A protein or nucleic acid based pharmaceutical substance used for therapeutic or in
vivo diagnostic purposes, which is produced by means other than direct extraction from a native (non-
engineered) biological source.

Biotechnology medicine/ product of pharmaceutical biotechnology: Any pharmaceutical product used

for therapeutic or in vivo diagnostic purposes, which is produced in full or in part by biotechnological means.

Biologic (Biological products): A virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component
or derivative,allergenic product or analogous product, or arsphenamine or its derivatives or any other trivalent
organic arsenic compound applicable to the prevention, cure or treatment of disease or conditions of human
beings.

Several example includes function human proteins (ADH, oxytocin, GnRH, TSH, ACTH, Insulin,
Somatostratin); enzymes (Proteins, antibiotics, antibodies, hormones, cytokines).

GENE THERAPY: Gene therapy in simple terms is the introduction of a gene into a cell, in vivo, in order to
ameliorate a disease process. Human clinical trials have focused on the correction of monogenic deficiency
diseases, cancer and AIDS. It is prevention and treatment of diseases through manipulation of gene functions.
It involves replacement of defective genes or supplementation of non functional genes or supression of
abnormal genes. Recominant DNA technology forms the basis of synthesis of therapeutic genes.

Entire process is of two steps. First step involves insertion of therapeutic gene to vectors. Second step
included introduction of vectors containing gene in to patient through in vivo-ex vivo means. In-vivo means
includes injection of suspension of the vector having therapeutics genes intravenously in to targets or local
tissues. Ex vivo means includeds insertion of therapeutic gene in to steam cells followed by intravenous
injection. Gene therapy has proved very promising teratment for the diseases like haemophilia, thalesemia,
immunity disorder. These diseases are not treated by conventional treatment. IL-12 based gene therapy
has been tried for antitumor effect on spontaneously occurring tumors in large animals and proved safe and
well tolerated by the animals.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER 11
DIGESTIVE PHARMACOLOGY
CONTENTS :
1. Sialagogues/salivary stimulants 2. Antisialagogues/asialics/sialic inhibitors
3. Appetite stimulants/appetizers 4. Anorexigenic
5. Stomachics 6. Antistomachics/gastric sedatives
7. Astringents 8. Antidiarrhoeal drugs
9. Demulcents 10. Carminatives/antiflatulants
11. Antizymotics 12. Antiulcers
13. Rumenotonics 14. Prokinetics
15. Antacids 16. Purgatives
17. Emetics 18. Antiemetics
1. Sialogogues: Sialogogues or sialics are the salivary stimulants which increases volume and fluidity
of saliva.
Use:
1) Iatrogenic (drug induced) hypoptylism (less secretion of saliva)
2) As an ingradient in tonics preparation.
3) Xerostomia (dryness of mouth due to lack of normal secretion)
Classification :
a) Reflex sialogogues/bitters
b) Cholinergic sialogogues
c) Direct acting sialogogues
a) Reflex sialogogues/bitters: eg. gentian: Its main active principle is gentiopicrin (bitter glycoside),
obtain from root and rhizome of Genatina lutea; Cinchona (quinine); Chirrata : It is available from
Swatia chirrata, active principle is chirrata; and Turpentine oil; Outer covering of orange: active
principle is limonene and terpene
Precautions to be taken while using bitters :
i. Bitter salts should not used chronically because they may produce gastritis, gastric catarrh.
ii. Bitter should not be used in gastritis.
iii. Bitter should be given half an hour before the milk or food to achieve their full effect.
iv. Bitter should not give for more than 1 weak.
v. If given in large dose, initially it will stimulate secretion and then response to irritation or stimulation
decrease.
b) Cholinergic sialogogues: eg. Nicotine, Cholinesters, Cholinomimetic alkaloids like carabachol,
AchE inhibitors etc.
c) Direct acing sialogoges: eg. alcohol, Iodine etc.
2. Antisialogogues/asialics/sialic inhibitors: Decrease saliva secretion
Use: For preanaesthetic medication to reduce excessive salivation that may occur during anaesthesia
eg. atropine, hyoscymine, glycopyrolate (synthetic antimuscarinic drug)
3. Appetite stimulant:
● Drug which increase appetite (desire to eat)
● Appetite is psychological function.
● Appetite stimulants also called as appetizers.
● Used to overcome anorexia
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
Examples include :
i. Diazepam (particularly benzodiazepam): they act on CNS produce sedation, stimulate hunger centre
and modifies appetite.
ii. Glucocorticoides: antistress, gluconeogenesis
iii. Cyproheptadine: they are 5-HT antagonist and prevent their stimulatory action on hypothalamic satiety
centre.
iv. Betazole: histamine antagonist
v. Anabolic steroids: increases appetite, weight gain, haematopoesis. eg. stanazolol 0.25 mg/kg P/O
daily
Adverse effects: Hepatotoxicity, msculinization, early closure of epiphyseak plate.
4. Anorexigenic: Drugs which produce anorexia or suppress appetite by acting on CNS.
Classification:
a) Centrally acing anorexigenics:
● Amphetamine: Act on α-receptor. It is misused to reduce body weight.
● Mephentamine
b) Drug which act by blocking 5-HT receptor:
● They are called as SSRI (Selective Serotonin Reuptake Inhibitor) eg. Fenfluramine, fluoxetine
5. Stomachics: Drugs which promote functional activity of stomach by increasing secretion and gastric
motility.
Uses: (a) Hypochlorhydria; (b) Achlorhydria; (c) Anorexia and (d) Ruminal atony: Commonly encountered
in field because constimation causes decreasesd ruminal motility.
Examples include :
i. Muscarinic agents: Ach (Acetylcholine), Carbachol, Bethanechol, Pilocarpine, Neostigmine and
Physostigmine
ii. Histamine (H2) agonist: Histamine, Betazole
iii. Dopamine antagonist:
eg. Metoclopramide (Perinorm®)
● It increases tone in the lower cardiac sphincter.
● It increase frequency and force of gastric contraction(gastrokinetic effect)
● It relaxes pyloric sphincter.
● It increases peristalsis in duodenum and jejunum.
● It has local antiemetic action.

Uses of dopamine antagonists:

● To promote gastric emptying in pre-operative condition
● Oesophageal spasm
● Oesophageal obstruction
iv. Alkaline salts: (sodium bicarbonate, carbonate salt)
MOA: They liberate CO2 which increases secretion and vasodilation in gastric mucosa.
v. Bitters: (gentian, ginger, turpentine oil)
MOA: They cause stimulation by irritation
vi. Cisapride, mosapride, neostigmine: Increases Ach secretion in myentric plexus by acting on
5HT4 receptor and increases gastric motility and intestinal motility.
6. Antistomachics/gastric sedatives:
Drugs which supress functional activity of stomach by decreasing secretion and gastric motility.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 Uses: (a) Hyperacidity; (b) Diarrhoea and (c) Ulcer
Classification :
i. Antimuscarinic agents (e.g. atropine)
ii. Adrenergic drugs (e.g. adrenaline)
iii. Antispsmodic (e.g. morphine, codeine, pethidine),
Morphine and nicotine decreases motility and act as antidiarrhoeal agent
iv. H2 blockers (e.g Ranitidine, Cimetidine)
v. Cholecystokinin
vi. Gastric inhibitory peptides
7. Astringents: Drug which help in forming a protective layer and exert protective action on intestinal
mucosa against the irritants by precipitating surface proteins in the mucosa. eg. Tannic acid (in strong
tea), catechu powder (in crata and chalk), aluminium hydroxide gel etc.
Uses: (a) Gastritis; (b) Enteritis; (c) Mouth ulcer and (d) Diarrhoea
8. Antidiarrhoeal drug: They act against diarrhoea, mainly used for treatment of acute diarrhoea.
Classification:
a) GI mucosal adsorbent or protectant
b) GI motility inhibitors/spasmolytic/antispasmodic
c) Anti-infective agents/antimicrobial agents
d) NSAIDs
a) GI/mucosal adsorbent or protectant: They reduce the irritation of intestinal mucosa caused by
bacterial toxins and other non specific toxins by adsorption of these toxins on their surface. Most
adsorbents itself are biologically inert.

Examples include
i. Activated charcoal:
● Adsorbs toxins, so used for medical purpose as a part of universal antidote in toxic cases.

● Made from wood source by burning them at high temperature under high pressure in vaccum.
● 1-2 gm/kg BW

ii. Kaolin (China clay/aluminium magnesium silicate)

iii. Pectin (Indigestible carbohydrate derived from apples)
iv. Bismuth salts: (carbonate, subsalicylate etc)
● Useful in acute diarrhoea of animals
● Can be used against E. coli toxins
● Also posses antimicrobial activity against H. pylori.
● Bismuth subsalicylate has anti-COX enzyme property, so it also has anti-inflammatory effect.

b) GI motility inhibitors/spasmolytic/antispasmodic:
● Reduces motility of GIT and supresses muscular spasms, associated with diarrhoea
● Spasm is increased/prolonged contraction of muscles.

Classification :
i. Opium derivatives: Morphine (used in ancient time to releive pain but abused today), pethidine etc.
ii. Atropine
iii. Loperamide : It is an opoid drug. It is agonist of µ−receptor in myentric plexus of large intestine.
Contraindicated in cat and children below 2 years of age as it produces toxicity Dose: 0.08 mg/kg BW
iv. Diphenoxylate : It is centrally acting opoid drug, and often combined with atropine to treat acute
diarrhoea.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 v. Dicyclomine: It is also known as dicycloverine. It is an antispasmodic and antimuscarinic agent.
It relieves smooth muscle spasms of GIT and act as a smooth muscle relaxant. It blocks action
of Ach on muscerinic receptor present on a smooth muscles. It is mainly used in spastic colic of
equine and other animals like cattle, buffalo, sheep, goat, cat and dog.
c) Anti-infective agents/antimicrobial agents: Diarrhoea is associated with microorganisms
Amoebiasis/giardiasis: Metronidazole, tinidazole, ornidazole and furazolidone
Traveller’s diarrhoea: It occur due to contaminated food and water consumption during journey.
Drugs used to treat it are ciprofloxacin, ofloxacin, amoxicillin, metronidazole, sulpha antibiotics, neomycin
and nitrofuran
d) NSAIDs: Meloxicam, aspirin etc.
9. Demulcent: Drugs which reduce irritation and provide soothing, protecting and cooling effect to the
part on which they are applied (Lubrication, coating, protection). They are given orally for soothing GI
tract.
Uses:
I. To prevent animal from effect of toxicant like calcium carbide (fruit ripening agent) if eaten by animal.
II. To mask unpleasant tastes, stabilize emulsions and act as suspending agent (eg. gums) eg.
Starch, honey, gum, glycerine, propylene glycol, liquid paraffin, proteins (egg albumin and gelatin),
liquorice (from Glycerrhiza glabra plant)
10. Carminative/antiflatulants: They causes expulsion of gases from the stomach or rumen and relieves
distension of stomach rumen and associated pain.
Actions : They have a mild irritant action on mucous membrane and tend to relax the GI musculature
particularly the cardiac sphincter of stomach which play role in the releasing gas from the stomach.
Uses: In Tympany/bloat. eg. Turpentine oil, mineral oil (liquid paraffin), asafoetida, peppermint oil (Mentha
piperita), ginger (Ginger officinale), clove (Eugenia caryophylus), cardamon (Eattaria cardamon),
coriander (Coriander sativum: its seeds are popular mouth freshner), Caraway (Cumin carvi), anise
seed (Pimpenella anisum, Active principle is anethone), nutmeg (Miristica fragrance), fennel seed
(Foeniculum vulgare: variyali).
Anti-foaming agents : Many antiflatulants are anti-foaming agents which act as surfactant and are
used to treat froathy bloat The defoaming action of surfactants relieves flatulence by dispersing and
preventing formation of mucous surrounded gas pockets.eg. arachis oil, turpentine oil, organic silicsns
(dimethicone, simethicone).
Note:
1) Dose of turpentine oil : Large animals:15-60 ml; Sheep, Goat: 5-15 ml
2) Pudina contains mentha or menthol and used to make peppermint oil.
3) Panacea of GI disturbance : Ginger
11. Antizymotics: Drugs which prevent or decrease bacterial or enzyme fermentation which is used to
prevent further gas production in tympany and bloat in ruminants. eg. Chloroform, chloral hydrate,
turpentine oil (It is also an anti-foaming agents), ethyl alcohol, formaline, phenol, polymerised methyl
silicon, polyethylene Glycol (PEG) surfactant.
Treatment of tympany/Bloat : Drugs are given intra-rumianlly through rumen puncture.
Cattle: Turpentine oil (30 ml) + groundnut oil/linseed oil/vegetable oil (25-300 ml)
Sheep, goat: Turpentine oil (4-8 ml) + groundnut oil/linseed oil/vegetable oil (30-60 ml); Formaline
(4-6 ml) + water (300 ml)
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
12. Anti-ulcers: To treat the ulcers produced by gastric hyperacidity
Classification :
i. Antacids: Neutralize gastric acid (Systemic and non-systemic)
ii. Antimuscarinic drugs: Decrease GIT secretion and produce anti-ulcer effect eg. Pirenzepine
iii. H2 receptor blocker : Decrease gastric HCl secretion by blocking histamine (H2) receptor eg.
Ranitidine, Cimetidine, famotidine
iv. Proton pump inhibitors: Proton pump inhibitors are inactive at neutral pH and becomes active
at pH < 5. They inhibits H+ - K+ ATPase enzymes and block entry of H+ from ECF into ICF, so HCl
is not synthesized. eg. Omeprazole, Lansoprazole, Esomeprazole etc.
v. Prostaglandin analogue: eg. Misoprostol (a methyl analogue of PGE1 : methyl-PGE1-ester) it
produced cytoprotective effect and used as antiulcer agent.
vi. Ulcer-protectives : eg. Sucralfate, colloidal bismuth subcitrate (CBS)
● It is a complex formed from combination of sucrose octasulfate and polyaluminium hydroxide.
● In acidic environment, this octasulfate polymerise to form viscous and sticky substance which
form the coating over ulcerated mucosa and thus prevent the back diffusion of H+ and protect
ulcer from acid.
● It also inhibit the bile and pepsin activity
● Also increase prostaglandin synthesis
● These agents also produce cytoprotective effect in the ulcer.
vii. Anti-Helicobacter pylori drugs: H.pylori is gram negative bacilli which decreases mucosal
protective mechanism and cause ulcers. Anti bacterial agents which are effective against H.
pylori are amoxicillin and or clarithromoycin in combination with metronidazole or tinidazole.
13. Rumenotonics: Drugs which increases ruminal motility. A mixture of compounds are used as
rumenotonics. eg. Antimony potassium tartrate, cobalt sulphate/cobalt chloride, ferrous sulphate, copper
sulphate, manganese sulphate, zinc sulphate, choline chloride/thiamine monohydrate, nicotinic acid,
dried yeast sodium acid phosphate etc.
14. Prokinetics: Drugs which promote downward movement of ingesta through the GIT by inducing
coordinated GIT motility. They improve gastro-duodenal motility and facilitated gastric emptying.
Uses: (a) Gastritis; (b) Impaction; (c) Reflex oesophagitis (Oesophageal reflux); and (d) ruminal atony
Classification:
a) Dopamine antagonist:
b) 5-HT4 Agonists: (By increase release of Ach)
c) Cholinomimetic agents: (by inhibition of AchE enzyme)
a) Dopamine antagonist: eg. Metoclopramide, Domperidone (D2 antagonist). Metoclopramide and
Domperidone are dopamine D2 receptor antagonists. Within the gastrointestinal tract, activation
of dopamine receptors inhibits cholinergic smooth muscle stimulation; blockade of this effect is
the primary prokinetic mechanism of action of these agents. These agents increase oesophageal
peristalsis, increase tone of cardiac sphincter (contraction), decrease tone of pyloric sphincter
(relaxation) and enhance gastric emptying but have no effect upon small intestine or colon motility.
Metoclopramide and Domperidone also block dopamine D2 receptors in the chemoreceptor trigger
zone (CTZ) of the medulla, resulting in potent antinausea and antiemetic action.
Dose : Dog and cat: 0.2-0.5 mg/kg, P/O or S/C, TID
b) 5-HT Agonists: (By increase release of Ach) : These are chemically related to Metoclopramide
but these promote gastric emptying and enhance small and large intestine motility but have no
effect upon oesophageal motility. eg. Cisapride, Mosapride (5-HT2 and 5-HT4 Agonists)

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 c) Cholinomimetic agents (AchE enzyme inhibtors) : Neostigmine can enhance gastric, small
intestine, and colon emptying. Other example is pyridostigmine.
15. Antacids: Agents that neutralize gastric acid and increase the pH value of gastric contents. They are
not much popular in vet. medicine as requires frequent administrations.
Uses: (a) Acidity/acidosis (b) Abomasal/peptic ulcer (c) Abomasistis/gastritis (d) Reflex oesophagitis
(GERD= Gastro-Esophageal Reflux Disease)
Mechanism of Action : They neutralize gastric HCl to form salt and water. Their action is for short
period (2-3 hours). They are not absorbed locally. They also induce PGE synthesis locally which gives
cytoprotective effect.
Classification: Antacids are of two types :
A. Systemic antacids: Which are absorbed in the blood. eg. Sodium acetate, sodium bicarbonate, sodium
citrate
B. Non-systemic antacids: Which are remain primarily in the GI tract. They are mostly used in combination
with each other along with protectant, adsorbent and astringents.Unreacted alkali is readily absorbed,
causing metabolic alkalosis when given in high doses or to patients with renal insufficiency. They are
not absorbed at therapeutic dose and does not produce toxicity, but at higher dose given for longer
period, they may cause renal toxicity.
They can be classified further as:
a) Buffered antacids : Control pH rise below neutrality. eg. Aluminium hydroxide, aluminium
phosphate, magnesium trisilicate
b) Non-buffered antacids: Control pH rise beyond neutrality i.e. beyond pH 7.0 eg. magnesium
oxide, magnesium hydroxide (milk of magnesia), magnesium carbonate, calcium carbonate,
calcium phosphate, tribasics
Adverse effects:
1) Antacids change the pH value of gastric and intestinal contents so pepsin becomes inactive so pepsin
digestion is altered.
2) They neutralizes acid in stomach and intestine, so negative feedback mechanism activate, which
increases in gastrin hormone secretion, this gastrin enhance gastric HCl secretion.
3) NaHCO3 : Alkalosis, acid rebound effect, pepsin inactivation
4) Al(OH)3 : Constipation and Mg(OH) 2 : loose stool/diarrhoea. Aluminium salt produces constipation
where as magnesium salt produces purgation, so generally combination of both is used.
eg. Gelucil® contains magnesium trisilicate and aluminium hydroxide
6) Ca(CO)3 : Constipation, alkalosis, acid rebound effect
Sodium bicarbonate: (Baking soda)
● Stable in dry air but decomposes in moist air.
● Because of its high water solubility it is immediately effective in neutralizing gastric pH and increase
pH towards alkaline side. But NaHCO3 has acid rebound effect, means after decreasing pH, it again
increases pH (antacid like Ca(CO)3 also show acid rebound effect)
Mechanism: NaHCO3 liberates CO2 which accumulates and produce distension of gastric mucosa
because of this there is reflex secretion of gastric acid resulting in acidity again.
MOA :
1) Increases gastric pH to 4
2) Neutralizes prefound acid
NaHCO3 + HCl NaCl + H2O + CO2

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
3) Rapid antacid action, short duration due to absorption. 1 gm NaHCO3 neutralizes 12 meq HCl.
Side effects :
1) Sodium bicarbonate changes the pH value of gastric and intestinal contents so pepsin function is
inhibited.
2) It has acid rebound effect.
3) CO2 production causing discomfort, risk of ulcer production.
4) Metabolic alkalosis
5) Na+ retention in Chronic Heart Failure.
Drug interactions:
It influences absorption and excretion of many drugs.
1) Increases absorption of levodopa, valproic acid
2) Increases absorption of Ca2+
3) Decreases absorption of antimuscarinic drugs, H2 antagonist, tetracycline, iron products.
4) Increases excretion of weakly acidic drugs.
Doses: Cattle: 50 gm, P/O, BID or TID Horse: 30 gm, P/O, BID or TID
Sodium citrate:
● It does not produces CO2
● 1 gm sodium citrate neutralizes 10 meq HCl
Aluminium hydroxide:
● Al (OH)3 + 3 HCl AlCl3 + 3 H2O.
● Aluminium hydroxide also decreases phosphate absorption.
● It is good adsorbent (adsorb toxins)
Dose:Cattle: 30 gm, Cat: 50-100 gm, Dog: 100-200 gm.
Magnesium hydroxide : (milk of magnesia)
● Prompt and prolong action
● Control rise in pH beyond 7.0
● Also exert laxative property.
Side effect: After long therapy: renal dysfunction or retention of magnesium.
Doses: Dog: 1-2 ml, Cat: 1-5 ml, Cattle: 60-100 ml
Calcium carbonate:
● Calcium carbonate (e.g. Tums, Os-Cal) is less soluble and reacts more slowly than sodium bicarbonate
with HCl to form carbon dioxide and CaCl2.
● Excessive doses of calcium carbonate with calcium-containing dairy products can lead to
hypercalcemia, calciurea, hypophosphataemia, constipation, renal insufficiency, and metabolic alkalosis
(milk-alkali syndrome).
● Shows gastric acid rebound effect.
16. Purgatives:
Purgatives: Drugs that promote defecation by enhancing its frequency or by increasing faecal volume
or consistency.
Laxatives: The cause mild purgation/ smooth evacuation of bowel; also known as aperients
Cathartics : They are potent or super purgatives which cause severe/drastic purgation
Uses:(a) Constipation; (b) Elimination of toxicants; (c) To prevent straining while defecation in case of
advance pregnancy; (d) Before gastrointestinal surgery

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 Contraindication:
● Should not given in advanced pregnancy (causes abortion)
● Should not given in obstruction in GIT (causes rupture of intestine)
● Should not given in lactating animals (if given causes young one diarrhoea)
Classification:
i. Bulk forming purgatives
ii. Osmotic purgatives
a) Saline osmotic purgatives
b) Carbohydrate osmotic purgatives
iii. Irritant/stimulatory purgatives
a) Direct irritant purgative : Anthraquinone derivatives/emodines, diphenylmethanes (DPM)
b) Indirect irritant purgative : Vegetable oils
iv Lubricating/emollient purgatives
v. Neuromuscular purgatives
vi. Drastic purgatives
vii. Faecal softeners/stool surfactant agents
i. Bulk forming purgatives: Bulk-forming laxatives are indigestible, hydrophilic colloids that absorb
water, forming a bulky, emollient gel that distends the colon and promotes peristalsis. eg.Methylcellulose,
carboxy methylcellulose, psyllium (Isabgul), Agar, Acacia, Polycarbophil (Synthetic fibers) compounds.
Mechanism of action:
Hydrophilic colloids/fibre foods Cellulose/hemicelluloses in the vegetable fibres

Not absorbed in the intestine Digested /fermented by bacteria

Draw water and sweets providing bulk to intestinal Release fatty acid
contents
Hygroscopic in nature
Distension of intestine
Bulk formation
Stimulate intestinal motility in reflex

ii. Osmotic/saline purgatives: The colon can neither concentrate nor dilute fecal fluid: fecal water is
isotonic throughout the colon. Osmotic purgatives are soluble but non-absorbable compounds that
result in increased stool liquidity due to an obligate increase in faecal fluid. eg. Nonabsorbable Salts
like MgO, Mg(OH) 2 , MgSO4 and Na2SO4, Nonabsorbable sugars like Sorbitol and Lactulose, Balanced
Polyethylene Glycol
Mechanism of action:
Inorganic salts particularly of magnesium ions into intestine

Draw water into intestinal lumen due to their osmotic pressure

Water retention increases that the form bulk of contents

There must be free access to water otherwise it may cause dehydration or haemoconcentration.

Magnesium salt also stimulate cholecystokinin (CCK) which further increases GIT motility

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 Dose:
Cattle: 250-400 gm foal/calf: 25-50 gm
Horse: 50-100 gm Dog: 5 gm
Cat: 2-5 gm Sheep, goat, swine: 25-100 gm
iii. Irritant/stimulatory purgatives:
a) Anthraquinone derivatives/emodine purgatives: Glycosides derivatives of 1,8-dihydroxy
anthraquinone.They are also known as contact purgatives. eg.
● Natural emodines : Aloe (leaf powder of Aloe vera and Aloe chinensis), Senna (leaflet of Casia
acutifoia), cascara, sagrada, rhubarb
● Synthetic emodines eg. danthrone, dose: Cattle: 20-40 gm, Horse: 15-45 gm, Sheep: 2-5 gm
MOA:
After oral administration

Glycosides are hydrolysed into emodines by colon bacteria

This increases peristalsis by stimulating neural plexus

Increased purgation

Diphenylmethane (DPM) purgatives: eg. Phenophtheline, bisacodyl, Bisacodyl should not be used
in obstructive impaction. Its onset of action duration is 6 to 8 hours after per oral and 15 minute to 1
hour after rectal administration.
b. Indirect irritant purgatives : eg. Vegetable oils (castor oil, linseed oil). These oils after digestion in
small intestine provide linolenic acid (fatty acid) and cause formation of irritant soap with bile
(saponification) and leads to irritation to intestine and purgation
Use : (a) Prolapse/advance pregnancy; (b) Post-operative GIT surgery; (c) Dog and cat, in anal leakage
iv. Lubricating/emollient purgatives: eg. Mineral oil (liquid paraffin), soft paraffin, glycerin suppository,
Mineral oil (liquid paraffin) : It decreases water absorption from the feces and act as emollient
purgatives. Its chronic use causes the deficiency of fat soluble Vitamins A, D, E, K)
Dose: Dog: 2 mg/kg, Cat: 10-15 mg/kg
v. Neuromuscular purgatives: eg. Carbachol : Horse and cattle - 2.5 mg/kg, S/C, Sheep - 0.25-0.50
mg/kg, S/C, Physostigmine : Cattle - 30-45 ml/kg, S/C, Neostigmine : Cattle - 0.001-0.02 ml/kg, S/C
vi. Drastic purgatives: Not used clinically, used for malafied intension. eg. Croton oil, jatropha oil, barium
chloride.
vii. Faecal softeners/stool surfactant agents: These agents soften faecal material, permitting water
and lipids to penetrate. They may be administered orally or rectally. eg. docusate (oral or enema)
Docusate is anionic surface agent with wetting and emulsifying property. It reduced surfacetension
and does allow water / fat to penetrate the ingesta.
17. Emetics: In emesis the stomach empties in a retrograde manner. The pyloric sphincter is closed while
the cardia and esophagus relax to allow the gastric contents to be propelled orally by a forceful,
synchronous contraction of abdominal wall muscles and diaphragm. Closure of the glottis and elevation
of the soft palate prevent entry of vomitus into the trachea and nasopharynx.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
The reflex mechanism of vomition: Vomiting is regulated centrally by the emetic centre and the chemoreceptor
trigger zone (CTZ), both located in the medulla. The CTZ is sensitive to chemical stimuli and is the main site
of action of many emetic and antiemetic drugs. The blood-brain barrier in the neighbourhood of the CTZ is
relatively permeable, allowing circulating mediators to act directly on this centre. The CTZ also regulates
motion sickness (eg. hill travelling) a condition caused by conflicting signals arising from the vestibular apparatus
and the eye. Impulses from the CTZ pass to the emetic centre which reulates the vomiting.
Classification:
i. Central emetics: Stimulate emetic centre via CTZ and vestibular apparatus (in motion sickness) eg.
xylazine, apomorphine
ii. Local acting / reflex emetics: They act locally by irritating gastric mucosa. eg. NaCl, Na2SO4, CuSO4,
ZnSO4, H2O2 etc. H2O2 is used in dogs and cats to induce vomition in the case of recent oral toxicoses
Contraindication for reflex emetics:
● Should not give in corrosive poisoning
● Should not give in opium poisoning
● Should not give in CNS stimulant toxicity
● Should not use in the unconscious animal
iii. Mixed emetics: eg. Ipecacuanha (Syrup of ipecac) : it is obtain from plant Carapichea Ipecacuanha.
It act by local irritation of gastric mucosa as well as centrally by stimulation of CTZ.
18. Antiemetics: Drugs which suppress the vomition or nausea (feeling of vomition). They are commonly
used in simple stomach animals like dogs and cats (monogastrics).
Classification :
i. Local acting antiemetics
a. Anticholinergics or muscarinic receptor antagonists
eg. Glycopyrronium, methcopolamine, propantheline
b. Local anaesthetics like benzocaine and prokinetics like domperidone also helps prevent emesis
c. Demulcent, protectant, gastric antacids may also act as local acting antiemetics.
ii. Centrally acting antiemetics
a. H1 Antihistamines: eg. Piperazine derivatives, Ethanolamine derivative, phenothiazine derivatives
● Piperazine derivatives : These drugs are useful in motion sickness induced emesis or
inner-ear disease induced emesis where vestibular apparartus is affected. All antimotion
drughs are effective when taken half to one hour prior to journey eg. Cyclizine, meclizine,
cinnarizine. Meclizine and cyclizine are longer acting drugs and used in dogs and cats.
● Ethanolamine derivative eg. diphenhydramine,
● Phenothiazine derivatives (tranquilizers): eg. Acepromazine, chlorpromazine,
prochlorperazine
b. Antidopaminergic: eg. D2 receptor antagonists like metoclopramide is useful in emsis caused
by uraemia or viral enteritis.
c. 5HT3- antagonists/antisecretory agents: eg. Ondansetron, Granisetron, cyproheptadine etc.
Ondensetron and granisetron are drug of choice in cancer therapy induced vomition. They are
also useful in controlling post-operative vomition.
d. Miscelleneous:
● Glucocorticoids liike dexamethosone
● Sedative and anxiolytic like diazepam is used as adjunct to metoclopromide or ondansetron to
control pyschogenic or behavioural vomiting.
● Nabilone is a synthetic cannabinol derivative which supresses CTZ.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER - 12
CVS PHARMACOLOGY
Contents:
1. Cardiotonics and Myocardial stimulants
2. Anti-arrhythmic drugs
3. Anti-hypertensive drugs and Vasodilators
4. Haematinics (Haemopoietic drugs)
5. Haemostatics (Blood coagulants)
6. Antihaemostatics
1. Cardiotonics and Myocardial stimulants
● Cardiotonics is a general term used for the drugs which increase the functional capacity of cardiac
muscles without increasing the O2 demand.
● Term ‘myocardial stimulant’ is specifically used for the drugs which increase the force of contraction
of myocardium muscles and thus increases cardiac output.
● Cardiac glycosides have property of both cardiotonics and myocardial stimulant.
● They possess only positive inotropic effect whereas other cardiotonics have both positive inotropic
(force of contraction) as well as positive chronotropic effect (rate and rhythm of contraction of heart).
Classification of myocardial stimulants:
i. Cardiac glycosides (Digitalis)
ii. PDE inhibitors e.g. Xanthine derivative (theophylline, aminophylline etc), Amrinone
iii. α-adrenoceptor agonist (Sympathomimetic drugs) e.g. Adrenaline, dopamine, dobutamine,
isoprenaline.
iv. Miscellaneous e.g. CaCl2 (10% solution), calcium borogluconate (CBG)
Cardiac glycosides:
● The whole group is also referred as ‘digitalis’ as their prototype member was obtained from leaf
of plant Digitalis purpurea (Purple Fox Glove).
● Their cardiac effects were described by William Withering (1775). About 200 years ago cardiac
glycosides were used in the treatment of dropsy.
● Cardiac glycosides contain two parts: Glycon (Sugar) responsible for solubility and membrane
permeability functions and aglycon responsible for its pharmacological activity.
Cardiac glycosides and their sources:
Plant name Plant part Glycoside
Digitalis pupurea Leaves Digitoxin, Gitoxin, Gitalin, Gitaloxin
Digitalis lanata Leaves Digitoxin, Gitoxin, Digoxin, Lanatoside-C
Strophanthus gratus Seed Ouabain (Strophanthin-G)
Note: Ouabain is most potent cardiac glycoside.
MOA of cardiac glycosides:
● They bind to the extracellular side of Na+-K+ ATPase at K+ binding site of enzyme and thus reversibly
inhibit Na+-K+ pump.
● Due to failure of pump, intracellular conc. of Na+ increases which further favour inflow of Ca2+ in
exchange of Na+. Then intracellular rise in Ca2+ leads to increase in the myocardial contraction.
Pharmacological effects on heart:
● Positive ionotropic effect results in improved cardiac output, reduced diastolic pressure and
reduction in size of dialated heart. These effects are more pronounced in dysfunctional heart
rather than in normal heart.
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● Negative chronotropic effect by direct as well as indirect way. Directly, it acts on AV node which causes
decrease in conductivity and increase in refractory period. Indirectly it acts by vagal nerve stimulation.
Extra-cardiac effects:
● Increase colloid osmotic pressure of blood and increased renal blood flow results in diuretic effect.
So, decrease oedema in CHF (Congestive Heart Failure) cases.
● Higher dose may stimulate CTZ (vomition).
Digitalisation:
● It is a procedure to be followed for administration of the digitalis e.g. digoxin in CHF.
● It consists of administration of loading dose of digitalis leading to production of desired cardiac activity.
● Methods of digitalization:
i. Slow digitalization: In mild CHF, 1/5th of total dose is to be given at 10 hours interval within 2 days
ii. Rapid digitalization: In moderate CHF, 3 equally divided doses are given at 6 hours interval
iii. Intense digitalization: In severe CHF and emergency, 1/2th of total dose at a time, 1/4th of total
dose after 6 hours, 1/8th of total dose at 4 to 6 hours interval
● Signs and symptoms of digitalization: Relief in coughing, Diuresis / decreased body
weight, Improved ECG changes
Dose rates in dogs:
(a) PO: Loading dose: 0.02 – 0.06 mg/kg o.i.d.; maintenance dose: 0.01 -0.02 mg/kg. (Half life of
digoxin in dogs = 24-55 hours)
(b) Rapid IV: 0.01-0.02 mg/kg in divided doses (in pattern of intense digitisation at interval of 1-2 h)
Toxicity of digitalis:
● They have narrow margin of safety with therapeutic index of only 1.5 to 3.0.
● Their dosage should be calculated on lean body weight. Obese and ascites mass should not be
taken into consideration.
● Therapeutic drug monitoring should be done and serum digoxin concentrations should be
maintained below 2.5 ng/ml.
● Common toxicities are anorexia, nausea, dyspnoea, palpitation, cardiac arrhythmia and necrosis
of myocardium.
Clinical indications:
● In congestive heart failure (CHF), especially in dilated cardiomyopathy (DCM).
● In cardiac arrhythmia (Supraventricular tachycardia like artrial fibrillation)
PDE inhibitors
● PDE (Phosphodiesterase) inhibitors inhibit PDE enzymes responsible for degradation of cAMP in
heart and other organs. Thus, they cause increase in intracellular cAMP concentration which
gives positive inotropic effects.
● Methylxanthines like theophyllin and aminophyllin are non-selective inhibitors of PDE enzyme.
● Drugs like amrinone and milrinone are selective blockers of cardiac PDE-III enzyme.
α -adrenoceptor agonists
● Sympathomimetic drugs having beta adrenergic agonist effect, with or without dopaminergic
agonistic property, have positive inotropic and vasodilator properties.
● Adrenaline (á and â) and isoprenaline (â1 and â2) are non-selective adrenoceptor agonist whereas
dobutamine selectively stimulates â1-adrenoceptor.
Miscellaneous
● Calcium gluconate and calcium chloride (CaCl2) may be used carefully by slow infusion for
stimulation of heart.
● Glucagon hormones found to has positive inotropic effect.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
2. Anti-arrhythmic drugs
● These are cardiac depressant drugs, used in the treatment of cardiac arrhythmia.
● They are mainly used to control abnormal fast cardiac rhythms i.e. tachyarrhythmias.
Classification of anti-arrhythmic drugs (Vaughan Williams and Singh, 1969):
Class I : Sodium channel blockers
Class II : Beta (â1) adrenoceptor antagonist
Class III : Potassium channel blockers
Class IV : Calcium channel blockers
Class I: Drugs that block voltage-sensitive Na+ channels
● These are membrane stabilizer drugs (exerts like local anesthetic effect)
● Reduces rate of depolarization
● Harrison (1979) proposed sub-classification of class I drugs based on their main
electrophysiological action while blocking sodium ion channel:
❖ Class IA: Shows intermediate dissociation, e.g. Quinidine, Procainamide, Disopyramide
❖ Class IB-: Shows fast dissociation, e.g. Lignocaine (Lidocaine), Phenytoin
❖ Class IC: Shows slow dissociation, e.g. Flecainide
Class II: α1-adrenoceptor antagonists
● Inhibits sympathetic activity of heart by inhibiting â1-adrenergic receptor. e.g. Propranolol, Esmolol,
Atenolol, Sotalol
● Sotalol prolongs repolarization by blocking potassium channels; hence, it is also included in class
III drugs.
Class III: Potassium channel blockers
● These drugs that prolong the repolarization and increases duration of cardiac action potential and
refractory period.
● They do not affect resting membrane potential.
● They are used in ventricular and supra-ventricular tachyarrhythmias. e.g. Amiodarone, Bretylium
Class IV: Drugs inhibiting voltage sensitive calcium channel
● Decreases calcium influx into cardiac cells (L-type calcium channels)
● Shortens plateau phase of action potential
● Slows AV conduction which depends on calcium current. e.g. Verapamil, Diltiazem, Nifedipine,
Amlodipine
● Verapamil>Diltiazem>Nifedipine (effect on calcium channels of cardiac cells)
● Diltiazem is preferred over verapamil for long term therapy as it has less negative inotropic effect.
● Dihydropyridine (‘dipines’) derivatives like nifedipine and amlodipine have more affinity to calcium
channels in vascular smooth muscles than heart. Thus, they have more vasodilator effects than
anti-arrhythmic effect.
3. Anti-hypertensive drugs and Vasodilators
● Antihypertensive agents are drugs which are used to lower the elevated blood pressure in systemic
hypertension.
● Vasodilators are drugs which cause dilation of blood vessels due to the relaxation of vascular
smooth muscles.
● Vasodilators reduce myocardial workload, promote cardiac output, and reduce blood pressure.
Thus, they are primarily used as anti-hypertensive drugs.
Classification of antihypertensive drugs:
i. Centrally acting sympatholytic drugs (α2-stimulation in CNS). e.g. Clonidine, Methyldopa
ii. Adrenergic Neurone blockers
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 ● These drugs lower blood pressure by preventing release and storage of nor-epinephrine from
postganglionic sympathetic neurons e.g. Reserpine, Guenethidine
iii. Adrenergic blockers
a. β-adrenoceptor blockers e.g. Atenolol, Metoprolol
b. Selective α1 blockers e.g. Prazosin
c. β plus α blockers e.g. Carvediol, Labetalol
iv. Diuretics e.g. Thiazides, Furosemide, Spironolactone, Amiloride
v. Vasodilators
a. Arteriolar vasodialtors e.g. hydralazine, diazoxide, minoxidil and calcium channel blockers
like Nifedipine, Amlodipine
b. Mixed (Arterial and Venous) vasodilators e.g. Nitroprusside, Glyceryl trinitrite (nitroglycerine):
These drugs are better known as anti-anginal drugs. They increase the release of nitrous
oxide and the concentration of cGMP. They increase guanylyl cyclase activity. This causes
vasodilation by relaxation of vascular smooth muscles by nitrous oxide pathway.
vi. Drugs acting on Renin-Angiotensin System (RAS)
a. Renin inhibitors e.g. Aliskiren, Remikiren
b. Angiotensin-Converting Enzyme (ACE) Inhibitors e.g captopril, enalapril, lisinopril,
ramipril, fosinopril etc. All ACE inhibitors are pro-drugs except captopril and lisinopril.
Enalapril is pro-drug of enalaprilat. ACE is also known as kininase II enzyme and
involved in metabolism of bradykinin. Side effects of ACE inhibitors include dry cough
and angioedema due to increased bradykinin level.
c. Angiotensin antagonist (AT1 receptor blockers) e.g. Losartan, Telmisartan etc. Like
ACE inhibitors losartan produces peripheral vasodilation and blocks aldosterone
secretion but do not increase kinin level.

4. Haematinics (Haemopoietic drugs):

● These drugs promote haemoglobin synthesis and/or erythropoesis (synthesis of RBCs) and are used
in the treatment of anaemia (anti-anaemic drugs).
● Anaemia may occur due to deficiency of Fe, Cu, Co, vitamin B12, folic acid and erythropoietin.
Classification:
i. Nutraceuticals (minerals and vitamins)
● Iron deficiency: Ferrous sulphate and ferrous gluconate (oral forms), Iron dextran and iron
sorbitol (parenteral injection)
● Copper deficiency: Copper sulphate, Copper glycinate, Copper heptonate
● Cobalt deficiency: Cobalt sulphate, cobalt chloride and cobalt oxide. Cobalt is needed by
ruminal microflora for synthesis of vitamin B12, hence is important for erythropoiesis.
● Vitamin B12 deficiency: It causes pernicious anaemia. Cyanocobalamine is used at dose rate
of 2-5 µg/kg/day, I/M.
● Folic acid deficiency: It causes megaloblastic and macrocytic anaemia. Dietary supplement
is main source of folic acid.
ii. Haematopoietic growth factors
Erythropoietin (epoetin):
● It is glycoprotein hormone produced by peri-tubular renal cells, essential for normal erythropoiesis.
● It is secreted during hypoxia which occurs in anaemia. Hypoxia is sensed by renal peritubular
cells and they release erythropoietin.
● This erythropoietin act on bone marrow and increase formation of Hb and erythroblast
maturation.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 iii. Anabolic steroids : e.g. Nandrolone:- Testosterone like structure, they stimulate production of
erythropoietin.
5. Haemostatics (Blood coagulants)
● They promote blood clotting and used to prevent haemorrhage (hemostasis) or blood oozing
from minute blood vessels.
● Based upon their use, they can be classified into topical and systemic haemostatics.

Topical haemostatics: These agents are applied directly to bleeding surface to prevent superficial
capillary or minute blood vessels bleeding. Following agents are used as topical haemostatics:
i. Clotting factors. e.g. Thromboplastin, fibrinogen, thrombin
ii. Occlusives. e.g. Fibrin foam, calcium alginate, cellulose, gelatine sponge
iii. Vasoconstrictors. e.g. adrenaline
iv. Styptics (Astringents). e.g. Alum, tannic acid, silver nitrate, ferric sulphate, ainc chloride etc.

Systemic haemostatics: These agents are administered by IV, IM or oral routes to prevent internal
haemorrhages. It includes drugs vitamin K analogues, blood components (platelets, fibrinogen),
fibrinolytic inhibitors like aminocaproic acid and tranexamic acid, other agents like protamin sulphate,
adrenochrome monosemicarbazone, ethamsylate etc.

6. Antihaemostatics
● They prevent haemostatis by interfering blood-coagulation process, lyses formed thrombi, inhibit
thrombi formation or platelet functions and accordingly classified into three broad classes: i)
anticoagulants, ii) thrombolytics (fibrinolytics) and iii) anti-thrombotics (anti-platelet) drugs.
● Anticoagulants
❖ In vitro anticoagulants: They are used for laboratory or blood transfusion purpose. e.g. Oxalate
mixture, sodium fluoride, EDTA, heparine, ACD etc.
❖ Oral in vivo anticoagulant: They are slow acting systemic anticoagulants. e.g. Dicoumarol, warfarin,
ethylbiscoumacerate etc.
❖ Parenteral in vivo anticoagulant: They are fast acting systemic anticoagulants. e.g. Heparin, orgaran
♦ Thrombolytics and Fibrinolytics. e.g. Streptokinase, urokinase, streptodornase, alteplase.
❖ Streptokinase and streptodornase are derived from streptococcus bacteria and act as plasminogen
activator. Urokinase and alteplase are derived from cell culture of human kidney cells and melanoma
cells, respectively.
♦ Antithrombotics (Antiplatelets)
❖ They inhibit platelet activation and aggregations. They do not dissolve existing thrombi but prevent
their growth and reoccurrence. So, they are mainly used for prophylaxis of thromboembolic disorders.
eg. Aspirin (used in canine heartworm and feline cardiomyopathy), dipyrimidole, dazoxiben

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER-13
RESPIRATORY PHARMACOLOGY
Contents :
1. Antitussive drugs
2. Expectorants (Mucokinetics)
3. Mucolytics
4. Bronchodilators
5. Analeptics (Respiratory stimulants)
6. Nasal decongestant
1. Antitussive drugs: Drugs which help in suppressing or relieving cough.
Cough is a protective reflex that removes foreign material and secretions from the bronchi and
bronchioles. Cough is of two types: (a) Productive cough: It is always associated with removal of
mucous from respiratory tract & considered as protective mechanism. (b) Unproductive cough: It is
always painful, stressful & exhaustive. In certain cases unproductive cough is to be suppressed.
Indications : Antitussive drugs are indicated for unproductive coughs.
Classification :
A. Pheripheral acting drug : eg. benzonatate (Mucosal Anaesthetic) and demulcents like honey, syrup,
glycerine, liquorice etc.
B. Centally acting drug:
i. Opoid or narcotic : Codeine, butorphanol and hydrocodon
ii. Non-narcotic : Pholcodine, dextromethorphan and noscapine
Codeine:
● Direct acts on medulla oblongata (depresses cough centre)
● It is methyl morphine (natural as well as semi-synthetic opiate alkaloid).
● It posses lesser analgesis, respiratory depressent and constipation properties than morphine.
Pholcodine:
● Longer duration of action as compared to codeine
Dextromethorphan:
● It is d-isomer of levorphanol (a codeine analouge)
● Directly suppress cough centre, increases cough threshold
● Used in both human and veterinary medicine because of non-addiction property
Butorphenol:
● Opiate partial agonist
● Potent analgesic & antitussive action (100 times more potent than codeine)
Hydrocodon:
● More potent than codeine
Noscapine:
● It produces relaxation of smooth muscles in bronchi & also cause histamine release in large dose
but is having excellent antitussive action.
● It is bronchodialator.
2. Expectorant: Drug which increases the fluidity & volume of bronchopulmonary secretion & promote
the productive coughing.
● Also used to remove the inflammatory debris during pneumonia & bronchitis.
● Also called as mucokinetics drugs.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 Classification:
A. Inhalant expectorant:
E.g. menthol, turpentine, benzoin, water steam
B. Secretory expectorant :
● Act by stimulating mucous membrane secretion in respiratory tract.
● Their expectorant property is very less as compared to inhalant.

Sub-classes of secretory expectorant :

i. Saline expectorant : eg. (NH4) CO3, NH4Cl, KI
ii. Reflex acting expectorant : eg. Syrup, balsum of tolu, onion, ipecac, sulphur compounds, volatile
ammonia.
Syrup has mainly soothing demulcent action on mucosa.
iii. Direct acting stimulant expectorant : eg. eucalyptus oil, turpentine oil, guaiacol, guaiphenesin
iv. Anodyne expectorant : Reflexly acting having Antitussive as well as pain relieving action & increase
repiratory secretion 400 times. eg. camphorated tincture of opium

3. Mucolytics : Drugs which reduce the viscosity of mucous secretion in the respiratory tract & facilitate
the expectoration.
Examples includes :
● 10-20% solution of sodium acetyl cysteine as nasay spray
● Bromhexine : It is synthetic derivative of vasicine, an active principle obtained from Adhatoda
vasica plant (Ardusi)
● Ambroxol : It is active metabolite of bromhexine.

4. Bronchodilator:
● These agents dilate bronchioles and used in asthma, general broncho-pneumonia, chronic
bronchitis, tracheo-bronchitis, COPD (Chronic Obstructive Pulmonary Disease) in various species.
● In asthma there is constriction of bronchiole muscle or reduction of air passage volume.
● Acute asthma is always related with hyperparasympathomimetic activity & liberation of
prostaglandins, histamine, 5-HT etc.

Classification:
A. Sympathomimetics:
● Selective β 2 adrenoreceptor agonists are preferred for treatment of asthma to relieve
bronchoconstriction and bronchospasm. eg. Salbutamol, terbutaline, clenbuterol, fenoterol.
● Clenbuterol is long acting selective β2 receptor agonist.
● They antagonize the bronchospasm of any course & also inhibit release of histamine, PG2,
TNF-α & PAF.
● In addition, they also posses mucolytic action i.e. increase ciliary action in clearing mucous.
● In case of hypersensitivity allergy & anaphylaxis, non selective β2 adrenoreceptor agonist like
adrenaline (epinephrine) and isoprenaline can be used as life saving drug as there is profuse
vasodilation in these conditions & these drug prevent this.

B. Methylxanthine derivatives :
● They exert direct relaxant action on bronchiole muscle through inhibition of phosphodiesterase
(PDE) enzyme which than result in increase in cGMP and cAMP, thus produces relaxant
effect on smooth muscles. eg. theophylline, theobromine, caffeine.
● Increase cAMP also inhibit release of histamine and SRS-A (Slow Reacting Substance of
Anaphylaxis)
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 C. Parasympatholytics (Muscarinic receptor antagonist) : For bronchodilation, eg. Atropine (Used
in horse to treat pneumonia), glycopyrrolate, ipratropium etc.
Dose of hetropine : 0.02-0.04 mg/kg, IM, SC, or IV
D. Anti-histamine: eg. Promethazine, diphenhydramine, ephedrine
E. Mast Cell stabilizers: eg. Cromolyn (cromoglycate) and nedocromil
● Bronchiole relaxant
● Act through inhibition of histamine & leucoriene release
● Also inhibit release of PAF
F. Leukotrienes receptor inhibitors : These have bronchiole dilation effect by preventing action of
leukotrienes.eg. Zafirlukast and Montelukast
G. Anti-inflammatory agents : Corticosteroids and NSAIDs.
eg. Beclomethasone, Budesonide, Flunisolide, Fluticasone (used as Inhalor), Mometasone,
Triamcinolone, Prednisolone (used in horse) for relief from COPD.

5. Analeptics (Respiratory stimulants): Drugs which stimulate the respiration & they are used to relieve
the respiratory depression especially due to overdose of anaesthesia or due to toxicity of other CNS
depressant drugs. Example includes :
a) Doxapram :
● It direct excites neurons of medullary respiratory center.
● It also act indirectly by reflex activation of carotid and aortic, chemoreceptor
● Causes transient increase in respirotary rate and volume.
Dose : Horse: 0.5-1.0 mg/kg, I/V
Dog and cat: 1.0-5.0 mg/kg, I/V
Foal: 0.02-0.04 mg/kg, I/V
b) Nikethamide
Dose: 2-4 mg/kg, P/O or I/M or I/V
c) Methyl xanthine: Stimulate the medullary respiratory centre. eg. caffeine
d) Bemegride: General CNS stimulant with wide margin of safety. It is non-specific barbiturate
antagonist.

6. Nasal decongestant : It is used in allergic and viral rhinitis to reduce swelling and oedema of nasal
passage. It is not used commonly in veterinary medicine. eg. Ephedrine, phenylnephrine (α1
adrenoreceptor agonists).

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER- 14
RENAL PHARMACOLOGY
CONTENTS :
1. Diuretics
2. Urinary Alkalizers
3. Urinary Acidifiers
4. Urinary Antiseptics
1. Diuretics : Diuretics increase the excretion of Na+ and water. They decrease the reabsorption of Na+ and
Cl- from the filtrate, increased water loss being secondary to the increased excretion of NaCl (natriuresis).
Indication : (a) Oedema (eg. pulmonary oedema in congestive heart failure) (b) Hypertension
(c) Renal disorders (d) Liver cirrhosis
Classification:
i. Low efficacy diuretics
a) Osmotic diuretics
b) Carbonic anhydrase inhibitors
c) Potassium sparing diuretics
d) Xanthine diuretics eg. theophylline
ii. Moderate efficacy diuretics
a) Thiazide diuretics (low ceiling diuretic)
iii. High efficacy diuretics
a) Loop diuretics (high ceiling diuretic)
b) Mercurial diuretics
i. Low efficacy diuretics:
a) Osmotic diuretics:
Osmotic diuretics are pharmacologically inert non-electrolyte substances that are filtered in the
glomerulus but not reabsorbed by the nephron eg. Mannitol, sorbitol, glycerine.
Site of action: Mainly proximal tubule, descending limb of the loop of Henle, distal tubules.
MOA : Water passive reabsorption is reduced by the presence of non-reabsorbable solute (Osmotic
diuretics) within the tubule; so a larger volume of water remains within the proximal tubule. So, more
amount of water is excreted and along with it minor increasing in Na+ excretion (secondary) occurs.
INDICATIONS:
1. Used in cerebral oedema to decrease intracranial pressure (eg. mannitol is choice of fluid therapy
in CNS toxicities).
2. To decrease intraocular pressure and to maintain urinary flow in tubules
3. Used to increase GFR and to enhance urinary excretion of toxins
Side effects:
1. IV injection may increase the osmolarity of plasma, so water is allow to move into plasma from
extravascular compartment so expansion of the extracellular fluid volume (hypervolemia).
2. Hyponatraemia and Hyperkalemia
Contradictions: Dehydration, Pumonary oedema and Progressive renal failure
ii. Carbonic anhydrase inhibitor:
● Carbonic anhydrase is an enzyme, mainly present in PCT, where it catalyzes the H2CO3 (carbonic
acid) and produces free H+ ions which are used for NA+-H+ exchange.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 ● Clinically CA inhibitors have limited usefulness as diuretics because they are much less efficacious
than thiazides and loop diuretics By blocking carbonic anhydrase, these inhibitors block Na+
reabsorption and cause diuresis. eg. acetazolamide, methazolamide, diclophenamide
● Acetazolamide loses its effect after one month because cell will adopt for alternate source of H+
i.e. it has a self limiting action. It is also used for treatment of glaucoma and metabolic acidocis. It
is also used as urinary alkalizer
Side effects : Hyponatremia,hypokalaemia and renal crystalluria
ii. Potassium sparing diuretics:
● These diuretics prevent K+ secretion by antagonizing the effects of aldosterone in the principal
cells of collecting tubules.
● Inhibition may occur by antagonism of mineralocorticoid (aldosterone) receptors (eg. antagonist
like spironolactone, canrenone) or by inhibition of Na+ influx through ion channels in the epithelial
cells (Na+ channel blockers like amiloride, triamterene).
MOA:
Aldosterone antagonists: They binds to aldosterone receptors and prevent synthesis of AIPs
(aldosterone induced proteins). So, Na+ channel remains in dormaint stage. Also, Na+ absorption is
inhibited and along with it K+ are not excreted in the tubular lumen. Hence retain the K+ instead of
wasting it (natriuresis and K retention results).
Sodium channel blockers: direct inhibitors of Na+ influx (block Na+ channels) in the principal cells of distal
collecting tubules of nephron causes natriuresis and indirectly inhibits K+ excretion, thus K+ retention results).
Spironolactone:
Indications:
1. In primary hyperaldosteronism (Spironolactone is drug of choice) eg. adrewnal adenomas
2. Used as adjuncts with thiazide or loop diuretics to prevent hypokalaemia.
3. Refractory oedema associated with hepatic cirrhosis and nephritic syndrome
Contraindications: Metabolic acidosis, hyperkalemia, acute renal disease and anuria
Adverse Effects:
1. Electrolutic imbalance like Hyperkalemia and hyponatremia (Two potassium sparing diuretics are
not used concurrently as it causes severe hyperkalaemia).
2. Gynecomastia, impotence, decreasedc libido (because these drugs are synthetic steroids)
ii. Moderate efficacy diuretics/ Thiazide diuretics
● These are also called “Low ceiling diuretics” or “Na+-Cl- symport inhibitors”
● They are sulphonamide derivatives and have similar structure to sulpha-drugs.
● Some derivatives are pharmacologically similar like thiazides but structurally different and knoen
as thiazide like diuretics.
Short acing thiazides: eg. Hydrochlorothiazide (HCTZ), chlorothiazide sodium (earlier it was
categorized under carbonic anhydrase inhibitors class), benzothiazide, and xipamide (thiazide like).
Long acting thiazides: eg. Methylchlorthiazide, bendrofluazide, Polythiazide.
Metalozone, Dopamine and Indapamide are thiazide like long acting drugs.
MOA:
● Thiazides act on DCT (luminal side) and block Na+/Cl- cotransporter (an enzyme) and thus, prevents
Na+ resorption. Function of this enzyme is modulated or changed by thiazides.
● Thiazides also produce vasodilation (so used in hypertension), K+ loss and hyperglycaemia.
● Thiazides also called as “low ceiling diuretics” because if thiazides are given in high dose, the
volume of urine remains same i.e. not increase.
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 ● Out of total Na+ reabsorption, about upto 95% reabsorbtio already occur in PCT before urine
mass reaches to DCT where only 5% reabsorption occurs for Na+.
Indications:
1. Hypertension
2. Cardiac or hypoproteinaemic oedema
3. Diabetes insipidus
4. Nephrolithiasis (because produce hypocalcinuria) i.e. calcium oxide uroliths.
5. Osteoporosis (because produce hypercalcemia)
6. Post-parturiient udder oedema in dairy cattle.
Contraindication:
1. Cardiac arrhythmia
2. Renal failure with anuria
3. Hypotension
4. Diabetes mellitus
Side effects:
1. Hypokalemic and hypochloraemic metabolic alkalosis
2. Hypokalemia (more common than with “loops diureics”), So, give K+ supplementation or use it in
adjunct with K+-sparing diuretics.
3. Hyponatremia
4. Hyperuricemia (gout)
5. Hyperglycemia
6. Hyperlipidemia (except indapamide)
7. May cause sulpha-drug hypersensitivity like skin reactions.
iii. High efficacy diuretics
a. Loop diuretics:
● Most potent group of diuretics with maximal natriuretic effect.
● Loop diuretics selectively inhibit Na+/Cl- reabsorption in the Thick Ascending Loop of Henle (TALH).
● Due to the large Na+/ Cl- absorption capacity of this segment and the fact that the diuretic action of
these drugs is not limited by development of acidosis, as seen with the carbonic anhydrase
inhibitors, loop diuretics are the most efficacious diuretic agents. eg. Furosemide (or frusemide),
ethacrynic acid, bumetanide, torsemide, piretanide, mazolamine
MOA:
● They block the Na+ / K+ / 2Cl- symporter in luminal side of TAHL. Ion symport is inhibited by binding
with chloride binding site. So there is no Na+, K+, Cl- reabsorption, hence there is loss of Na+, K+, Cl-
along with H2O.
● Also reduces aldosterone secretion.
Pharmacological Effects of Furosemide:
1. Decreases ECF and decreases B.P (Reduces central venous presssure)
2. Produce dehydration
3. Produce Hypokalemic metabolic alkalosis
4. Produce hypocalcemia
5. Produce hypomagnesemia
6. Posses weak CA inhibitory action (but ethacrynic acid do not have this property)
Pharmacokinetics:
1. Oral bioavailability is excellent.
2. Extensive protein binding.
3. Half life in dogs is 1-1.5 h and duration of action is 4-6 h
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 Indications:
1. Pulmonary oedema
2. Mammary oedema: occur during the large stage of pregnancy due constriction of mammary vein
by foetus.
3. Brisket oedema, hydrothorex ascites and non-specific oedema
4. Hyperkalemia
5. Acute renal failure
6. Anion overdose: treating toxic ingestions of bromide, fluoride, and iodide.
Contraindication:
1. Hepatic cirrhosis
2. Borderline Renal failure
3. Pre existing electrolytic imbalance
Side effect :
1. Hypokalemic and hypochloraemic metabolic alkalosis : increase K+ and H+ loss
2. Hyperuricemia: Gout
3. Ototoxicity in cats (also increases ototoxicity of aminoglycoside antibiotics). Ototoxicity is more
seen with use of ethacrynic acid.
4. Hypomagnesemia
5. Hypocalcemia
6. Allergic reactions (except for ethacrynic acid as it do not have sulpha like structure): skin rash,
eosinophilia, haemolytic effect.
Misuse: Furosemide is used in dopping in horses during horse shows because it reduces ECF so
clear cut demarcation of muscles is there. In race horses, it is believed to diminished incidences of
epitaxis by reducing central venous pressure.
2. Urinary alkalizers
● Produces alkaline urine
● These are metabolized to produce cations which are excreted with bicarbonate and produces
alkaline urine. eg. NaHCO3, potassium citrate, potassium acetate
Indications:
i. To reduce toxicity of sulphonamide and paracetamol
ii. To promote excretion of weakly acidic drugs like salicylate, barbiturates.

3. Urinary acidifiers
● Produces acidity in urine. eg. ammonium chloride, ascorbic acid, methionine, sodium acid
phosphate
Indications:
i. To enhance the excretion of basic substances
ii. To increase the antibacterial activity in urinary tract

4. Urinary antiseptics
● Drugs which are used to produce antiseptic effect in part of urinary tract
● For action of urinary antiseptics, urine is required to become acidic. eg. sulphonamide, gentamicin,
ciprofloxacin, methanamine, hexamine
Methanamine : It is converted into NH3 and formaldehyde and this released formaldehyde acts as antiseptic
at acidic pH. At pH 5 about 20 % formaledhyde is released where as at pH 6 it is only 6 %. Addition of
mandelic acid or hippuric acid to methamin helps to acidify the urine, and thus enhance its pH depended
antibacterial activity.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER- 15
REPRODUCTIVE PHARMACOLOGY
Contents:
1. Aphrodisiacs
2. Anaphrodisiacs
3. Ecbolics (uterotonics)
4. Oxytocics
5. Tocolytics
6. Abortificients
1. Aphrodisiacs : Agents that increase the sexual desire. eg. yohimbine
2. Anaphrodisiacs : Drugs that decrease the sexual desire. eg. coriander, salix, mashua
3. Ecbolics : Drugs that stimulate the non-pregnant uterus motility and tonicity. These are used for the
purpose of cleaning effect in the atonic uterus. eg. oxytocics, prostaglandins, ergot alkaloids
4. Oxytocics: Drugs that induce or facilitateds birth by stimulating the contraction of uterine muscles at term.
Classification : A) Natural oxytocics B) Ergot alkaloids C) Prostaglandins
A. Natural oxytocics: eg. oxytocin
Oxytocin : It is synthesized in supraoptic nuclei of hypothelemus and stored in the posterior pituitary.
It is nona peptide. One USP unit of oxytocin is equivalent to 2-2.2 mcg of pure oxytocin.
Pharmacological Actions of Oxytocin:
i. On uterus: Oxytocin act on myometrium and contract the pregnant mammalian uterus and expel
the foetus. It is sensitive to pregnant uterus. It can only stimulate non pregnant uterus if given at
very high doses.
ii. On mammary gland: It causes the contraction of myoepithelial cells causing letting down of milk
but does not have any effect on the synthesis of milk.
iii. Sperm transport: oxytocin facilitates the sperm transportation in the female vagina after coitus.
iv. It is having weak ADH like action and it is contraindicated in heart patient and kidney disease.
Pharmacokinetics :
i. Oxytocin is not administered orally because it is peptide and digested by digestive enzymes, So,
it is given IV in normal saline because it has ultrashort half life, but when mixed with saline it
continuous available to uterus and metabolize continuously.
iii. Onset of action : IV : 1-2 minutes, IM : 5-10 minutes,
iv. Duration of action:IV : 3-5 minutes, IM : 60 minutes
Indications :
i. Secondary uterine inertia
ii. Speeding up expulsion of foetus unless foetal presentation and position is normal.
iii. To facilitate the uterine involusion in post partum retained placenta and metritis cases.
iv. In case of retained placenta.
v. To facilitate letting down of milk in agalactia.
Note : Epidosine is an example of synthetic oxytocin
Doses of oxytocin:
Species IM route IV route
Cow and mare 10-40 IU 2.5-10 IU
Ewe, doe and sow 2.5-10 IU 0.5-2.5 IU
Bitch 01-10 IU 0.5 IU
Queen 0.5-5.0 IU
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
2) Ergot alkaloids:These are obtained from fungus Claviceps purpurea. eg. ergometrine, ergotamine
● Ergometrine is having rapid and long acting vasoconstriction and oxytocic effect. Control post-
partum haemorrhage.
● Ergot is itself not used because it produces spasmodic contraction.
● Ergot alkaloids particularly methylergometrine cause prominent uterine contraction (increases
force, frequency and duration of contraction).
● A gravid uterus and puperial uterus is more sensitive for ergot alkaloids.
● Vasoconstrictor and uterotonic activity of ergot alkaloid is due to partial agonist action of 5-HT receptor.
● It is used in the active management of 3rd stage of labour.
Indications :
i. Uterine atony
ii. Uterine inertia
iii. Metrorrhagia: after abortion uterine discharge of blood and exudate
iv. Post-partum haemorrhage control
v. Sub involution of uterus: means retain normal size and shape
Dose of methylergometrine : Cow and mare, 10-20 mg, Sow :0.5-1.0 mg, Bitch : 0.2-1.0 mg
3) Prostaglandins: eg. PGE2 (Dinopristone) and PGF2α (Dinoprost)
● These are synthetic analogue of prostaglandin.
● These cause cervical relaxation of muscles due to direct relaxant effect and contraction of uterine body.
● It is not drug of choice because it induces prolong uterine contraction.
● Luteolytic effect : It lyses corpus luteum after parturition, after it reproduce cyst under control of
oestrogen and cycle rotate again and if cycle persist then progesterone continuously liberated
and oestrous cycle not repeated.
Commonly used PGs in veterinary practice: Carboprost (synthetic PG analogue of 15-methyl
PGF2α), Germeprost (synthetic PG analogue of PGE1), dinoprost
5. Tocolytics (Uterine sedative) :
● Drugs which suppress the premature labour by relaxation of uterine muscles are called as tocolytics.
● These are also called as anti-contraction or labour depressant or uterine relaxant or uterine
sedatives or uterine spasmolytics.
Example includes :
i. Magnesium sulphate (MgSO4 ) : It is muscle relaxant so inhibit the uterine contraction by inhibiting
the myosin light chain
ii. Ethyl alcohol : Inhibit the uterine motility
iii. Ca+2 channel blockers : eg. nifedipine.
● Produce the relaxation of myometrium
● It delays the parturion for 4-27 days
iv. α 2
–adrenoreceptor agonist : eg. retodrin, terbutaline
● Used to delay premature labour/ threaten abortion.
● To reduce the foetal stress during transport of mother to hospital during preparation for
operative delivery of foetus.
v. Relaxin
● It is decapeptide secreted by corpus luteum, placenta and uterus when the animal approach
parturition.
● Its physiological role in the parturition is to induce softening/relaxation of cervix and pelvic ligament.
6. Abortificients : Drugs that induce the abortion before completion of term. eg. Mifepristone.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER - 16
PHARMACOTHERAPEUTICS OF HORMONES AND VITAMINS
Sr Hormone Use Species Dose and Administration
No.
1 Gonadotropin releasing a. Cystic ovaries Cow 0.1 mg/kg IM or IV
hormone (GnRH)
2 Thyrotropic hormone (TSH) a. Acanthosis nigricans Dog 1-2 U/Kg I/M For five days
3 Leutinizing hormone (LH) a. Stimulation of follicles Cattle & 25 mg I/V; repeat after 1-4 weeks
or interstitial cell stimulating b. Ovulation Horse, 5 mg2.5 mg1 mg
hormone (ICSH) c. Cystic ovaries Sheep,
d. Increase testosterone Swine,
production Dog
4 FSH-P a. Folliculogenesis and Cow 5 mg/each 12 hr for a total dose of
superovulation 40 mg I/M on cycle days 10-14+
40mg PGF2α I/M 48 hr after first
FSH injection.
5 Pregnant mare serum a. Oestrus Cattle/ 1000-2000 U S/C, I/M or I/V100-
gonadotropin (PMSG) b. Stimulation of follicles Horse 500 U200-800 U25-200 U25-100 U
c. ovulation Sheep
Swine
Dog/Cat
6 Human chorionic a. stimulation of ovaries Cattle/ 1000-2000 U I/V, 10,000 U I/M400-
gonadotropin (HCG) b. cystic ovaries Horse 800 U I/V500-1000 U I/V100-500 U
c. cryptorchidism Sheep I/V100-500 U I/V( I/M for lyeding cell
d. IC stimulation Swine stimulation)
Dog/ Cat
7 Testosterone propionate a. Sterility Stallion & 100-250 mg S/C or I/M for three
(in oil) b. Hypogonadism Bull times.20-25 mg5-15 mg
c. Reduced libido Ram
d. Aspermia Dog
8 Diethylstilbesterol (DES) a. Misalliance Dog 0.5-1 mg/kg/day orally
b. Urinary incontinence Dog 0.5 mg/kg orally on fifth day of
c. Anal oedema
d. Prostrate hypertrophy
9 Metranol a. Misalliance mating
10 Estradiol cypioate a. Uterine atony Cow & 10mg I/M
b. Poor uterine discharge Mare
c. Abortifacient in early
pregnancy
11 Progesterone (in oil) a. Prevention of Mare & 50-100mg I/M
embryonic death cow
Ewe 10-15 mg
Swine 10-20 mg
Dog/Cat 2.5-5 mg
12 Megestrol a. Oestrus suppression Dog 2 mg/kg I/M for 8 days during
prooestrus
0.6 mg/kg I/M for 30-32 days
during anoestrus.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
13 Melengestrol a. Increase weight gain Feedlot 0.2-0.5 mg/heifer/day orally
b. In crease feed heifers (withdraw 48-72 hr before
efficiency slaughter)
c. Suppres oestrus
14 Pregnant mare serum a. Superovulation Cow 1500 IU on 15th or 16th day of
gonadotropin (PMSG) oestrus
Ewe 700-1400 IU I/M on any day from
4-13 days of oestrus
Goat 1000-15000 IU I/M on day 16, 17
or 18 of oestrus
15 PMSG and PGF2 alpha a. Superovulation Cow PMSG 2000 IU I/M on any day
between 9-12 days of oestrus
followed by (48 hr) 750-1000
micro g of PGF2 alpha I/M
16. PGF2 alpha a. Synchronization of Cow 25-30 mg I/M on any day of
oestrus oestrus between 8-12 days or 30
mg I/M with a 10 day gap
Sheep 10-15 mg I/M on any day from 5-
and Goat 14 days of oestrus
Vitamins
Vitamins Deficiency signs/disease Therapy
Fat soluble Keratinization of epithelial surfaces, night Farm animals : 100-200 units/kg/day
vitamins blindness, low sperm quality, foetal resorption, i.e. 1-2 g/day.
Vitamin A nutritional roup, low egg production and poor
egg hatchability in poltry. Poultry : 0.07-022 g/kg feed/day.
Vitamin D Rickets in young animals and osteomalacia in Cattle : 50-100 IU/kg/day.
adults. Horses, Sheep and Pig
chicks : 150-300 IU/kg/day
Dogs : 200-400 IU/kg/day
Vitamin A Muscular dystrophy in young animals (cattle, All young : 25 mg/kg s/c or i/m stock
sheep, dog, pig and goat). White muscle disease Calves and lambs: 40 mg/kg/day orally
of stiff lamb disease in sheep. Pig : 500 mg/day orally
Dog : upto 300 mg/kg orally
Cat : 30 mg/kg/day
Poultry : 390 mg/bird
Vitamin K Delayed clotting and spontaneous haemorrage in Warferin poisoning in all species :
all the species (more in poultry) Menaphtone or Menadione @ 5mgi/m.
Sweet clover poisoning : Menaphtone
@1.1 mg/kg i/m.
Deficiency: Small animals 2-10 mg/kg
orally.
Large animals: 100-400 mg/kg orally.
Poultry: Menaphtone@1-2 g/ton of feed

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 Water soluble vitamins
Vitamins Deficiency signs/disease Therapy
Thiamine Nervous signs, vomition and diarrohoea. Certain Horse = 100 mg s/c or i/m or oral
(B1 or plants contain antihistaminase like Equistem spp., Calf = 100 mg s/c or i/m or oral
Aneurine) bracken rhizomes, whose ingestion causes Pig = 2.5-15 mg s/c or i/m or oral
thiamine deficiency. Cat = 1-5 mg/kg s/c or i/m or oral
Dog = 1-10 mg/kg s/c or i/m or oral
Riboflavin Curl toe paralysis in young chicks. Anaemia, Horse : 40 mg daily in feed
(B2) dermatitis and scours in calves. Slow growth, Pig: 5 mg orally
low fertility, eye discharge, irritation and
photophobia in horses and pigs.
Pyridoxin Acrodynia (dermatitis characterized by Same as thiamine antidote to cyanacet
(B6) hyperkeratitis and acanthosis of skin) in dogs. hydrazide or dictycide overdose.
Degeneration of spinal and demeyelination of
peripheral nerves.
Nicotinic Pellagra in man. Calf : 25 mg/day s/c
acid and Black tongue or brown mouth in dog. Pig: 0.1-0.3 g s/c or 0.2-0.9 g orally
niacin Rough scaly skin, oral and GI ulceration and Dog and: 5-10 mg/kg i/m
(pellagra diarrhea in pig. Perosis , dermatitis and Cat: 10-30 mg/kg orally
preventing inflammation of tongue in chgicks.
factor)
Hydro- Antipernicious anaemia factor Dog and cat : 2-4 mg/kg/day i/m.
xycobala- In ruminants due to cobalt deficiency (bush
mine (B12). sickness, nakuruitis or grand taverse disease)
Hind limb weakness or incoordination, loss of
wool, stunted growth etc. in all anim als.
Biotin Fatty liver and kidney syndrome in broiler 100 ug/chick orally
(vitamin H, chicken fed entirely on wheat ration. Egg white
bis 11b, contains an antibiotic : avidine
coenzyme
R)
Choline Perosis (slipped tendon in poultry). Fatty liver Dog : 544 mg/kg/day orally
ana ataxia in dogs, cats, pigs etc. Cat : 25-50 g orally or s/c also used in
milkfever or ketosis.
Vitamin C No definite signs are described. Horse: 2-4 g s/c
Bull: 1-2 g s/c every 3-4 days up to 6
weeks.
Cow : 1-2 g i/v and 2 g s/c before mating
or 2 g s/c once or twise a week
for up to 6 doses.
Dog : 25-75 mg orally or s/c per day

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER - 17
DERMATO-PHARMACOLOGY
Contents :
1. Demulcents 2. Emollients 3. Dermal protectants
4. Astringents 5. Counter-irritants 6. Caustics (corrosive)
7. Escharotics 8. Keratolytics 9. Keratoplastics
10. Anti-seborrhoeics 11. Topical Antiseptics
1. Demulcents:
● Inert agents which act as soothing agent on inflamed or denuded mucosa or abraded skin and
lessen the irritation.
● They are substances of high molecular weight which are water soluble i.e. hydrophilic colloidal nature.
● They form a coating layer over the mucous membrane.
● Act as vehicle for many skin medicinal preparations. eg. Glycerine, Propylene glycol, PEG
(polyethylene glycol), gum acacia, glycyrrhiza etc.
2. Emollient:
● Like demulcents, it acts like soothing agent on abraded skin and mucous membrane and forms
an occlusive film layer.
● Emollients are fatty or oily in nature and this term is mainly used for skin applications.
● Additionally, they posses humectant property i.e. they prevent moisture loss and increases water
holding capacity of the dermis.
● Used as base for skin ointments. eg. Arachis oil, linseed oil, cocoa butter, lanolin, soft & hard
paraffin, bee-wax etc.
3. Dermal Protectants:
● They are insoluble, finely grounded, inert solid substances applied topically over skin or mucous
membrane to provide protection or to prevent friction.
● They generally posses adsorbent property and protect skin from toxins or irritants. e.g. Hydrated
magnesium silicate (talc powder), zinc stearate, bentonite, calamine, starch, zinc oxide etc.
Note : By function, demulcent, emollient and dermal protectants all are protective agents.
4. Astringent:
● These are substances which precipitate surface cellular protein and reduce cell membrane
permeability, mechanically toughen the skin or mucosa and promote the healing.
● They do not penetrate the skin.
e.g. salts of zinc and aluminum like zinc sulphate, aluminium acetate, alum, tannic acid.
● Astringents that used to stop local bleeding by promoting coagulation are known as styptics.
5. Counter-irritants:
● These are locally applied agents on intact skin to produce local hyperaemia (increases blood
circulation) and hasten the process of inflammation to varying degree.
● They are used to relieve pain or to facilitate healing of underlying tissue. eg. Turpentine oil, eucalyptus
oil, wintergreen oil (methyl salicylate), menthol, camphor, ammonia, ammonium hydroxide, red
iodide of mercury.
● Depending upon their concentration used, and various degree of irritation produced by them,
these agents can be classified into:-
❖ Rubefacients: Mild counter-irritants that produce local hyperaemia or erythema.
❖ Irritants: Produce hyperaemia as well as inflammation; have sensory component.
❖ Vesicants (Blisters):- strong conuter-irritants that produce vesicles or blisters (alter capillary
permeability and accumulate fluid under the epidermis).

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
6. Caustics (corrosives):
● These are topical agents which cause destruction of tissue at the site of application.
● Used to destroy warts, granulation tissues, keratoses etc.
● Used as disbudding agent in calves destroy warts. e.g. silver nitrate, antimony trichloride, phenol,
glacial acetic acid, trichloroacetic acid.
7. Escharotics (cauterizant):
● Agents which facilitate the formation of scab and scar are known as escharotics.
● Many caustics act as escharotics.
8. Keratolytics:
● They soften & dissolve the intracellular cementing substances of horny layer (stratum corneum)
of skin.
● They increase hydration of keratinocytes and desquamation process of epidermal cells.
● Used as anti-hyperkeratosis agents eg. In cases of warts, psoriasis, cornified skin etc. e.g. Salicylic
acid, benzoic acid, sulfur, benzoyl peroxide, urea etc.
9. Keratoplastics:
● They normalize the cornification (keratinisation) process by slowing epithelial turnover
● Inhibits basal cell prolification by inhibiting DNA synthesis.
● Prevents skin scaling and hypertrophy. e.g. Coal tar, salicylic acid, sulfur etc.
Note : Most of keratoplastic agents have keratolytic and anti-seborrhoeic property.
10. Anti-seborrhoeics:
● Drugs which decrease sebum secretion from sebaceous glands of skin.
● Useful in seborrhea which causes oily skin, dandruff and itching. eg. selenium sulfide, benzoyl
peroxide etc.
11. Topical antiseptics:
● Topical antiseptics are the agents which inhibit growth of micro-organisms from living surfaces
like skin.
● May or may not be irritating.eg. Povidone iodine (as skin scrub for surgery), chlorhexidine, hydrogen
peroxide (sporocide on clostridial spores), benzalkonium chloride, cetrimide etc.

BIOENHANCER : Bioenhancers are molecules, which do not possess drug activity of their own but promote and augment the
biological activity and/or bioavailability when used in combination therapy. Synergism in which the action of one biomolecule
is enhanced by another unrelated chemical has been the hallmark of herbal bioenhancers. The concept for bioenhancers
of herbal origin can be tracked from the ancient knowledge of Ayurveda.‘Trikatu’ is a traditional Ayurvedic herbal
formulation consisting of three herbs in equal ratio. It includes Long Pepper (Piper longum), Black pepper
(Piper nigrum), and Ginger (Zingiber officinale). Active phytomolecule in both Piper longum and Piper nigrum, which is
responsible for bioenhancing effect, is piperine. Herb ingredients are effective bioenhancer at very low doses. They are
safer compounds than synthetic one, cost effective and easily available.Nutritional deficiency due to poor gastrointesti-
nal absorption is an increasing problem worldwide. Nutritional herbal bioenhancers provide an alternative method for
improving nutritional status by increasing bioavailability of nutrients due to better GIT absorption. They can be used as
animal and bird feed supplement.Herbal bioenhancers have several mechanisms of action. These include mainly,
increase in gastrointestinal blood supply, decrease in gastric emptying and gastrointestinal transit time, non competitive
inhibition of drug metabolizing enzymes, increase in bioenergetic processes, suppression of first pass metabolism and
elimination of drugs.Herbal bioenhancers are effective for number of drug classes such as antibiotics, anti-tuberculous,
antiviral, antifungal, anticancerous drugs etc. Combinations which have potential application in veterinary therapeutics
include rifampicin plus piperine, oxytetracycline plus piperine, ciprofloxacin plus piperine, ampicillin plus niaziridin and
taxol plus glycyrrhizin. Newer herbal bioenhancers includes Niaziridin (Moringa oleifera), Glycyrrhizin (Glycyrrhiza glabra),
Cuminum cyminum extracts, Carum carvi extracts, Allicin (Allium sativum), Lysergol (Ipomoea muricata), Aloe vera, and
Rosewater. Their development is to be targeted for drugs which are poorly bioavailable, given for longer period of time,
highly toxic and expensive. For example, formulation with Rifampicin in reduced dose plus Piperine has gone through
clinical trials up to phase III under anti-TB drug development. Further, research should be carried out to evaluate clinical
application of herbal bioenhancers in modern veterinary therapeutics.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER - 18
BIO-ENHANCER
Bioenhancers are molecules, which do not possess drug activity of their own but promote and augment
the biological activity and/or bioavailability when used in combination therapy. Synergism in which the
action of one biomolecule is enhanced by another unrelated chemical has been the hallmark of herbal
bioenhancers.

The concept for bioenhancers of herbal origin can be tracked from the ancient knowledge of Ayurveda.
‘Trikatu’ is a traditional Ayurvedic herbal formulation consisting of three herbs in equal ratio. It includes
Long Pepper (Piper longum), Black pepper (Piper nigrum), and Ginger (Zingiber officinale). Active
phytomolecule in both Piper longum and Piper nigrum, which is responsible for bioenhancing effect,
is piperine. Herb ingredients are effective bioenhancer at very low doses. They are safer compounds
than synthetic one, cost effective and easily available.

Nutritional deficiency due to poor gastrointestinal absorption is an increasing problem worldwide.

Nutritional herbal bioenhancers provide an alternative method for improving nutritional status by
increasing bioavailability of nutrients due to better GIT absorption. They can be used as animal and
bird feed supplement.

Herbal bioenhancers have several mechanisms of action. These include mainly, increase in
gastrointestinal blood supply, decrease in gastric emptying and gastrointestinal transit time, non
competitive inhibition of drug metabolizing enzymes, increase in bioenergetic processes, suppression
of first pass metabolism and elimination of drugs.

Herbal bioenhancers are effective for number of drug classes such as antibiotics, anti-tuberculous,
antiviral, antifungal, anticancerous drugs etc. Combinations which have potential application in
veterinary therapeutics include rifampicin plus piperine, oxytetracycline plus piperine, ciprofloxacin
plus piperine, ampicillin plus niaziridin and taxol plus glycyrrhizin.

Newer herbal bioenhancers includes Niaziridin (Moringa oleifera), Glycyrrhizin (Glycyrrhiza glabra),
Cuminum cyminum extracts, Carum carvi extracts, Allicin (Allium sativum), Lysergol (Ipomoea
muricata), Aloe vera, and Rosewater. Their development is to be targeted for drugs which are poorly
bioavailable, given for longer period of time, highly toxic and expensive. For example, formulation
with Rifampicin in reduced dose plus Piperine has gone through clinical trials up to phase III under
anti-TB drug development. Further, research should be carried out to evaluate clinical application of
herbal bioenhancers in modern veterinary therapeutics.

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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 CHAPTER-26
CNS STIMULANTS
CNS STIMULANTS
These are the drugs which stimulates the CNS.They are classified in threencategories:
(1) Cortical stimulator
(2) Medullary stimulator / Direct CNS stimulator
(3) Spinal stimulator : Nicotine, ammonia and lobelin are indirect or reflexly CNS stimulator
(clinically not used)
(1) Cortical stimulator
A.Xanthine derivatives: These are alkaloid obtained from tea & coffee. Basically, there are
three alkaloids.
Caffeine: It is chemically 1,3,7-trimethylxanthine, obtained from coffee seed (Coffee arabica)
It affects CNS & cardiovascular system.
Mechanism: It acts via four mechanisms as given bellow.
(1) It releases Ca+2 from the sarcoplasmic reticulum (skeletal and cardiac muscle). It also blocks
the adenosine receptors.
(2) Phosphodiestrase inhibition and release of Ca+2. This is probably observed at concentrations
much higher than the therapeutic plasma concentration, while adenosine receptors blockade.
(3) cAMP is metabolized by enzyme phosphodiestrase, it causes inhibition of phosphodiestrase
enzyme. More cAMP is available. So there is more steroid synthesis and release of hormones.
(4) This caffeine causes stimulation of â-adrenergic receptors so it causes cardiac stimulation.
Caffeine acts on adenosine receptors and block them & due to this blockage there is inhibition
of depression of cardiac pacemaker.
Clinical uses:
l Given orally or I/M, when given I/M sodium-benzoate is added in caffeine which increases
solubility of it.
l It is generally used in severe case of narcotic depression or sedation.
l Dose:
Horse and cattle : Total dose 4 mg
Sheep and goat : Total dose 1 - 1.5 mg
Cat and dog :
Total dose 100 - 500 mg
l In general, there is wide margin of safety but in heavy dose lead to convulsion.
Theobromine: It is 3,7-dimethylxanthine, obtained from cocoa seeds (Theobroma cacao)
it produces mild effect on CNS, mainly affect cardiovascular system & diuresis.
Theophylline:
l 1,3-dimethylxanthine, obtained from tea leaves (Thea sinensis).
l Aminophylline is a semisynthetic derivative and used clinically.
l It has less CNS stimulant activity but more bronchodialator activity.
l It increases cardiac activity and has diuretic effect.
l It is more commonly used in respiratory depression like “asthma” etc.
l It is used in congestive heart failure.
l It is commonly used in condition in horses called as “Broken wind”
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Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
 l Dose:
Dog : Total dose, 50mg
Horse/other species : 1-2mg/kg, orally or I/M or I/V
l In human it is used as spray (Asthalin spray contains aminophylline/salbutamol)
l Out of above three, theobromine is not used clinically.
B. Sympathomimetics:
l Commonly used drugs are amphetamine andephedrine
l They are powerful pressure drugs and increase B.P as well as cardiac output.
l Amphetamine occurs as dextrorotatory (CNS stimulation) & leavorotatory (cardiovascular
drug) form.
l Dextrorotatory form causes temporary stimulation of nervous system which increases mental
and physical activity. So it is drug of abuse for dopping (in horses)
l It has got effects like anorexigenic effect which causes anorexia (loss of appetite), so it is
used as anti-obesity effect.
l Dose: 3-4mg/kg, S/C or I/M
l Ephedrine? similar to amphetamine, given orally, 3-4mg/kg
(2) Medullary stimulator : These are mainly respiratory stimulant & also called analeptics.
Clinical uses:
1) They are used in post anaesthetic depression and asphyxia
3) Also employed in neonate asphyxia.
4) They are also used to stimulate respiration in case of drowning
5) They also stimulate depressed respiration in barbiturate poisoning
6) They are used as tretment for heat and electric shock.
7) They are used in chronic hypoventilation with CO2 retention.
Doxapram:
l It stimulates medullary respiratory centre and it acts on chemo-receptors present in carotid
arteries and aortic arch.
l It stimulates respiration and also increase the B.P.
l It is considered as most superior respiratory stimulant, it has got very short duration of action.
l It is used as an antidote of thiopentone toxicity.
l Dose:
Dog : 1 - 2 mg/kg, I/V
Cattle and buffalo : 0.5 mg/kg, I/V
Leptazol, metrazol:
l It causes stimulation of medullary respiratory centre.
l It also causes stimulation of vasomotor centre leading to increased blood supply.
l It causes Inhibition of GABA and there by leads to stimulation.
l It acts very rapidly but is has very low margin of safety.
l Dose:
Dogs and cats : Total dose, 50 -100 mg, I/M
Horse and cattle : Total dose, 0.5 -1mg, I/M
l It is also given in case of extensive barbiturate depression.

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 Nikethamide: (Coramine)
l It is derivative of the nicotinic acid and action is similar to doxapram.
l It initially causes stimulation and lately depression.
l It is commonly used in barbiturate and morphine depression.
l It is available oral formulation and mainly given in small animals
l Dose:
Dog and cat : 22mg/kg, orally or I/V or I/M or S/C
Picrotoxin: (cocculin)
l Natural compound obtained by seeds of plant Anamirta cocculus.
l It cause effect on medulla as well as spinal cord.
l It is non-competitive antagonist of GABA.
l Margin of safety is less.
l As it stimulates spinal cord, it causes convulsion. Clnically not used.
Bemigride: (antagonist of barbiturate)
l Clinically used in barbiturate poisoning.
l Dose: 20mg/kg, I/V
CO2: (physiological analeptic)
l When CO2 concentration increase in blood? it stimulate respiratory centre.
l CO2 can be given eternally & causes respiratory stimulation.
l It causes severe acidosis when given externally.

(3) Spinal stimulants

Strychnine
l It is alkaloid derived from seed of plant Strychnos nux-vomica.
l It is commonly available as”nux vomica powder”.
l It basically acts on spinal cord.
l In brain “reinshow cells” are present. It does not allow impulse to pass continuously (motor
impulse). This strychnine blocks reinshow cells and give exaggrated response. This leads to
continous discharge of motor impulses.
l Strychnine causes inhibition of these GABA (brain) and Glycine (spinal cord). This will cause
exaggrated response and lead to condition “hyperaesthesia”
l It causes severe convulsion and muscular spasm.
l Clinically, it is used very rarely. It used as nervine tonic to stimulate ruminal motility.
Dose:
Horse and cattle : 15-16mg
Sheep and goat : 10 -15mg
Pig : 5.0 - 8.0 mg always orally
Dogs : 0.5 -1.0 mg
Cats : 0.1- 0.5mg
Strychnine is available as powder. It is dissolved and solution is used orally.

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 CHAPTER-27
LOCAL ANAESTHETICS
Local anaesthetics
l Drugs on topical / local aaplication causes reversible loss of sensations in a restricted area of
body is termed as local anaesthetics.
l Agents applied locally to skin / mucosa for reversible blockade of the nerve impulses – they
effectively block the somatic sensory, somatic motor and autonomic nervous system.
l Initially, in 1860 cocaine was isolated from Erythroxylum coca – numbing of tongue (Niemann).
l Koller introduced it into surgery (1884).
l It is not used now because of known toxicity and addictive potential.
Ideal properties of a LA
l It should produce reversible paralysis.
l It should be non addictive.
l It should be readily soluble and stable in water.
l It is non irritant to the skin.
l It is compatible with epinephrine.
l It is slowly absorbed to have long duration of action.
l It is inexpensive.
l It does not induce hyperesthesia.

Common mechanism of actions? basically 3 mechanisms

1) They act as membrane stabilizing agent: They reduce the permeability of membrane. The local
anaesthetic has amino group which combines with polar group of cell membrane, it affects Na+-K+
pump. The transmission of nerve impulse is impeded.
2) Effect on membrane Ca+2: The calcium whenever present decreases threshold potential, so local
anaesthetic act on Ca+2 in such a manner that threshold potential gets increase.
3) Local anaesthetics bring deformities in Na+ channels: Sometime Na+ channels get closed & Na+-K+
exchange do not take place. This blocks the impulse transmission.
Absorption pattern & systemic effects of local anaesthetics
l Absorption: The minimum absorption in to blood circulation is desired. For this purpose, adrenaline is
added along with local anaesthetics. Epinephrine cause local vasoconstriction leading to lesser
absorption and longer persistence of local anaesthesia at site. The adreanline is used at ratio of 1:
100000 or 1: 50000 along with local anaesthetics.
l Addition of hylouronidase with local anaesthesia increases the penetration of local anaesthetics into
surrounding tissues. Whenever given S/C, it cause diffusion of local anaesthesia over large area and
increase area of desensitization. Adverse effects; If local anaesthesia is absorbed into systemic circulation
due to over dose or faulty injection site, It may precipitate nervous and cardiovascular reactions.
(1) CNS – It causes initially stimulation, tremor, restlessness, convulsions and death. Higher doses
may lead to depression. Low non-seizure dose is used for euphoria in man and to enhance
performance in horses
(2) CVS: It decreases myocardial contractility, rate and force of conduction. It causes dilatation of the
arterioles. Renal and hepatic blood flow is reduced. This lower the metabolism and excretion of
local anaesthetics and cocurrently admnistered drugs.
Different compounds used as local anaesthesia
Cocaine: Cocaine is alkaloid obtained from plant Erythroxylon cocoa. This cocaine is first local anaesthesia to
be used and is regarded as or mother of all local anaesttics. It does not affect intact skin (not topically used) o If
given orally than destroyed in gastric pH. It is potent local anaesthetic, given through sub cutaenous injection.
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Mechanism
l It reduces/blocks the uptake of catecholamines, so epinephrine remain at the site, it itself cause the
vasoconstriction. So epinephrine is not required in addition with cocaine as vasoconstriction. Cocaine
causes pupil dilatation, so very good anaesthesia for ophthalmic observation.
l It is mainly used for observation of eyes.
l It cause of dilation of pupil & constriction of blood vessels locally, so very good for conjunctivitis.
l It is very good anaesthetic for nasal, buccal cavity, larynx & pharynx.
Procaine
l It is first synthetic local anaesthetic introduced by Einhorn in 1905.
l It has an added advantage over coccaine that it is not addictive in nature.
l It is not potent as cocaine, but less toxic.
l It has got very short half-life of 25 minutes, so It increase its life (duration of action) epinephrine is
added & decrease absorption.
l It is metabolized to PABA, so it cannot be used along with sulfonamides.
l It cause severe vasodilatation & it is commonly used as antihypertensive drug. In this procaine is not
used but procaine amide is used.
l It is not used in shock.
l Dose: 1-2% for infiltration, 3-4% for nerve block.
Lignocaine (lidocaine)
l Most commonly used local anaesthetic.
l It is twice potent than than procaine & not cause tissue irritation.
l Quick onset of action & duration of action is twice longer than procaine.
l It is quickly absorbed, hence epinephrine is added.
l Also used as surface anaesthetic/topical.
l Dose:0.5-1% for infiltration, 2-5% for nerve block
Lignocaine like compounds newer compounds
i) Bupivacaine
ii) Mepivacaine
iii) Prilocaine
iv) Cinchocaine
l Among these bupivacaine is most potent (7 times) having 1-12 hours duration of action.
l Mepivacaine is 2-3 times more potent than procaine. The duration of action is 2 hours. It is
commonly used in horses.
Some rarely used local Anaesthetics:
i) Ethanol
ii) Phenol
iii) Chlorbutol
iv) Menthol
v) Benzyl alcohol
Surface anaesthesia:
Ethyl chloride (spray): It has freezing effect locally, so it causes numbness. It is also used as inhalant
anaesthesia.
Amethocaine (tetracaine): It is used for ophthalmic purpose, also for infiltration. It is 10 times potent than
cocaine. For topical purpose, 0.5-1% and for infiltration, 1-2%. Other surface anaesthetics are lidocaine,
dibucaine, benzocaine and oxythazine. Repeated application of surface anaesthetics can cause skin allergy.

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 CHAPTER-28
MUSCLE RELAXANTS AND ANTIDEPRESSANTS
MUSCLE RELAXANTS
All these agents cause muscle paralysis, so used in convulsion and extreme contration. They either
cause flaccid or spastic paralysis. These terminology more used for neuromuscular blockage. These
are divided into two main groups; (1) Centrally acting and (2) peripherally acting.

(1) Centrally acting:

They act on brain, but not cause anaesthesia.
They expected to control muscle contraction.
They are known as skeletal muscle spsmolytics.
E.g., Diazepam, mephensin, guiafenensin, baclofen,

Diazepam:
It acts via GABA receptors. It antagonizes convulsions induced by picrotoxin and nikethamide.
It is used commonly to control muscle spasm, muscle stiffnees and convulsions.
Dose:
Dog : 0.5 - 1.0 mg/kg IV or IM
Cat : 2.5 - 5.0 mg/kg PO TID

Mephenesin:
l It is specific centrally acting muscle relaxant and least effect on CNS.It is a gycine agonist.
So antagonise strychnine or tetanus convulsions, but not of picrotoxins.
l It is not used clinically, due to various adverse reactions (it causes thrombosis & haemolysis).
l It acts on both skeletal and smooth muscle.

Guaifenesin:
l Commonly used muscle relaxant.
l Common irritant added in cough syrup.
l It causes flaccid type of paralysis.
l It acts as glycine agonist
l It acts on monosynaptic & polysynaptic motor nerve.
l It has got wide margin of safety.
l It is used as cough syrup.
l It can control convulsion due to strychnine poisoning and tetanus convulsion.
l But not used against GABA induced convulsions.
l If given via I/V route, it causes haemolysis, so lways gaiven orally mostly.
Dose:
Dog : 45-90 mg IV
Large animal : 60 - 120 mg IV

Baclofen:
l It has GABA like activity, so it can be used in reduce spasticity in neurological disorders.

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 Methocarbamol:
l Its mechanism is not clear.
l It is used in dog, cat and horse as muscle relaxant.
l Dose:
Dog and cat : 40 mg/kg, orally
l Horse : 5 - 20 mg/kg, I/V

Dantrolene:
l It is directly acting skeletal muscle relaxant.
l It inhibits release of Ca+2 from sarcoplasmic reticulum.
l It has also some effect on brain.
l It is only specific and effective treatment for malignant hyperthermia, a life-threatening disorder
triggered by general anaesthesia.
l Dose:
Dog : 2.5 mg/kg, I/V
Horse and pig :1 -3 mg/kg, I/V

(2) Peripherally Acting/Skeletal Muscle Relaxant/Neuromuscular Blockers

They are act on neuromuscular end plate and so called as neuromuscular blockade.
They are given by IV route only.
They are categorised into two groups namely (1) Competitive neuromuscular blockers and
(2) Non competitive neuro muscular blockers.
The comparison of both types of neuromuscular blockers
COMPETITIVE BLOCKER NON-COMPETITIVE BLOCKER
(1) Non-depolarizing (1) Depolarizing
(2) Reversible blocker (2) Irreversible blocker
(3) Flaccid paralysis (Curariform effects) (3) Tonic / Spastic paralysis
(4) Antagonised by AchE inhibitors (4) Produces synergistic effecst with AchE inhibitors

Competitive neuromuscular blockers

I. Natural compounds : eg. d-tubocurarine (obtained from plant, Chondrodendron tomentosum)
á-toxin present in venom of poisonous snake like cobra
II. Synthetic compounds : eg., gallamine, pancuronium, alcuronium, atracuronium, They acts by
competitive antagonism of acetylcholine for nicotinic receptors at neuromuscular junction. They
do not allow acetylcholine to cause depolarisation of muscle cells. They are thus known as Non
depolarising blockers.They produce curariform effects characterised by flacid paralysis.
Following drugs potentiate the curariform effecst of non competitive neuromuscular blockers.
(1) Quinidine,
(2) Ananesthetics (baribiturates, halothane, methoxy furane, ether),
(3) Aantibiotics (aminoglycoside, oxytetracycline, polymixin, lincosamide).

Following drugs antagonises the curariform effecst of non competitive neuromuscular blockers.
(1) Anti AchE compound like physostigmine, neostigmine and edrophonium.
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Non competitive neuromuscular blockers: E.g., Succinylcholine (suxamethonium),
decamethonium They acts through persistant depolarisation of post syneptic muscle fibers. Muscle
fibers becomes non responsive to acetylcholine. They do not competete for nicotinic receptors at
motar end plate. Organophosphate compounds potentiate the action of non competitive
neuromuscular blockers.Both of these groups have antagonistic effect, if given together so
combination has no effect at all.

Pharmacological effects of neuromuscular blockers:

Effect on Cardiovascular system:-
it causes severer vasodilatation and fall in B.P.
Most of these agents when given rapid I/V injection, release histamine which causes
anaphylactic reaction, severe bronchoconstriction leads to shock and death.
They are always given slowley in diluted form.

Clinical uses:
1) As preanaesthesia for inducing skeletal muscle relaxation.
2) As anti convulsant.
3) Capturing the wild animals (Curariform drugs)
4) For orthopedic surgical manipulation (Diazepams and methocarbamol)
5) Adjunct therapy in acute muscle injury (centrally acting drugs are used)
6) Prevention or treatment of malignant hyperthermia or rhabdomyolysis in horse

Dose:
1) d–tubocurarine: Cat, dog and pig : 0.4 - 0.5 mg/kg Small ruminants? 0.06mg/kg
2) Gallamine: Dog and cat: 0.1 mg/kg, Other:0.5 mg/kg
3) Succinylcholine: Dog & cat :0.5 -1 mg/kg, Cattle, buffalo and horse: 0.04 - 0.05 mg/kg

ANTIDEPRESSANT (MOOD ELEVATORS)

Used in human in case of depression. Also called as thymoleptics/antidepressant.

Types of antidepressents:
1) Selective serotonin reuptake inhibitors (SSRIs) : E.g. citalopram, fluoxetine, fluvoxamine
etc.
2) Selective serotonin reuptake enhancers (SSREs) : e.g. tianeptine
3) Serotonin-norepinephrine reuptake inhibitors (SNRIs): e.g. duloxetine, milnacipran,
venlafexine
4) Tricyclic antidepressant (TCAs) : e.g. imipramine, desimipramine, trimipramine,
amitriptyline, clomipramine
5) Monoamine Oxidase inhibitors (MAO-inhibitors)/MAOIs : e.g. selegiline, iproniazid,
isocarboxazid, moclobemide, mitheum chloride Moclobemide? reversible inhibitor of
monoamine Oxidase A (RIMA).

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 SECTION III : EXERCISE FOR OBJECTIVE QUESTIONS
Q-I. Fill in the blanks appropriately:
1. __________________ deals with post marketing surveillance and reporting of ADR of drug.
2. Decreasing response to a drug on repeated or prolong administration is termed as
______________________.
3. __________________ is the medicinal system based on the principle of “Like Cures Like”.
4. ___________________ is the medicinal system based on principle “Equilibrium among three elements
of Vatt, Kapha, and Pitta”.
5. CDRI is abbreviation for _____________________________________________________.
6. NIPER is abbreviation for _________________________________________________.
7. _____________ is worshiped as a God of Medicine or Health in Indian System of Medicine.
8. _____________ founded the first pharmacology laboratory at Estonia, University of Dorpet.
9. First pharmaceutical company established in Gujarat is _____________________________.
10. _________ name of drug gives the precise information regarding chemical structure of drug.
11. Drug included in Pharmacopoeias is termed as ______________________ drug.
12. ________________________________ is an anti malarial drug obtained from plant source.
13. ______________________________ is an example of alkaloid drug obtained from plants.
14. The oldest known source of drug is ______________________.
15. _______________________________ is an example of drug obtained from animal sources.
16. ____________________________ is an example of drug obtained from microbial origin.
17. DCGI stands for ________________________________________________________.
18. _______________________________ is an example of drug obtained from soil.
19. An agent, which stimulates gastric acid secretion and digestion, is known as ____________.
20. An agent, which induces vomiting, is termed ____________________________________.
21. An unethical use of drug to increase physical endurance during sport events is known as
__________________.
22. ___________________ form of drug is lipophili C.
23. ___________________ form of drug is hydrophili C.
24. If pH > pK then Ionized fraction of drug __________________ unionized fraction of drug.
25. If pH = pK then Ionized fraction of drug _________________ unionized fraction of drug.
26. An agent, which induces deep sleep, is termed as ________________________________.
27. An agent, which promotes growth of rumen microbes and digestion, is known as
______________________________.
28. If pH < pK then Ionized fraction of drug _________________ unionized fraction of drug.
29. The time taken by the drug to enter in to the solution phase is known as ______________.
30. ________________ is a saturable process of drug transport across the biological membrane.
31. Higher the value of Volume of distribution, longer is ____________________________.
32. _______________________________is an example of drug obtained by biosynthetic tool.
33. Higher the plasma protein binding, lesser is ___________________________.
34. Enzyme assembly responsible for drug metabolism is known as _____________________.
35. _______________________ is the science that deals with genetic variation of drug response in
individuals.
36. Agent which is pharmacologically inert but, sometimes given to simulate impact of medication in
patients is known as _______________.
37. Atropine is used for pre-anaesthetic medication for its __________________ property.

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38. Barbiturates are derivatives of ___________________.
39. Basic drugs bind to_______________ fraction of plasma proteins.
40. All substances are poison, there is none, which is not poison. The right dose differentiates poison and
remedy. This famous quotation was given by _____________________.
41. ___________________________ is regarded as the Father of Indian Pharmacology.
42. Pethidine in U.K. is same as _____________________ in U.S. A.
43. _____________ is an agent, which stimulates sexual urge and desire.
44. _____________ is an agent, which induces sleep.
45. _____________ is an agent which promotes growth of ruminal microbes.
46. The time taken by the drug to enter in to the solution phase is known as _____________ .
47. Paracetamol and ________________ has the tendency to accumulate in the liver.
48. An unusual response to drug is known as ___________________.
49. _____________________ consists of testing of drug in small group of healthy volunteers.
50. ___________________________deals with study of economics of drug used and derived benefits /
effects.
51. Dosage regimen includes ____________, _____________ & _____________________.
52. __________________________________is roman god of health for whom Rx is use D.
53. Captopril act by inhibiting ____________________ enzyme.
54. Norepinephrine is metabolized by ______________ and _____________enzymes.
55. H2 antagonists are used in the treatment of _______________________.
56. Dobutamine is a selective _____________ receptor agonist.
57. Screening of drug for one or two pharmacological properties is known as _____________.
58. Full form of NF is______________________.
59. Bioavailability is 100% following _____________ administration.
60. Succinylcholine is a ________________________ type of muscle relaxant.
61. The inert substance administered to satisfy the patient psychologically is referred
as_________________.
62. Pigs are deficient in _________________ metabolic pathway.
63. Cats are deficient in _______________ synthetic phase of metabolism.
64. The pharmacokinetic parameter that describes the extent of distribution of a drug
is____________________.
65. ________________was the first alkaloid to have been isolated from the plant source.
66. Excretion of acidic drugs is promoted in __________________ urine.
67. _______________ was the first Professor of Pharmacology in Indi A.
68. Dose- Response curve shifts to ___________________ in presence of antagonist.
69. Non-responsiveness of the previously responsive tissue following repeated drug administration is
called as ______________________.
70. _______________ is the most potent among all cardiac glycosides.
71. Omeprazole inhibits gastric acid secretion by inhibiting ______________________.
72. Ondansetron acts on ______________________ to produce antiemetic effect.
73. International Pharmacopoeia (Ph.I.) is published by _______________________________.
74. The drugs that are neglected for inclusion in the drug development program owing to their limited use
are termed as _______________________.
75. Drug induced diseases are termed as _______________________ diseases.
76. Therapeutic index = ______________
77. Study of drug in relation to dose and dosages is termed as __________________.
78. The structural components of glycosides are _________________ & ________________.

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79. Apomorphine is _____________________ acting emeti C.
80. Tyramine is _________________________ acting sympathomimeti C.
81. Aminophylline and theophyliline increases intracellular concentration of __________________ while
inducing bronchodilatation.
82. eCG ( PMSG) is the source primarily of ____________________________.
83. Bromhexine is classified as ____________________ expectorant.
84. __________________ is a cholinergic alkaloid obtained from a mushroom.
85. Two main types of adrenergic receptors are _________ and ________, while that of cholinergic
receptors are ______________ and ____________.
86. Higher the potency of a drug, _________ will be its dose required for treatment.
87. __________________ is a bacterial toxin of which diminishes release of Acetylcholine.
88. ________________ is the neurotransmitter at the post-ganglionic parasympathetic fiber.
89. ____________________ is an intraneuronal enzyme oxidizing catecholamines.
90. ____________________ is an anticoagulant used in vitro and in vivo.
91. _____________________ is also referred as antiarrythmic of intensive cardiac care units.
92. The agent that increases bile secretion from hepatocytes is called as _____________.
93. The agents that contract uterus are termed as _______________________.
94. _______________________________ purgatives are the fastest acting purgatives.
95. Deficiency of vitamin ______________ produces ‘curled toe paralysis’ in chicken.
96. ________________ is drug of choice in toxicity of d-tubocurarine.
97. _________________ agents are used for painless killing of animals.
98. __________________ is the active metabolite of chloral hydrate.
99. Acetazolamide inhibits_________________ enzyme.
100. Metformin is used as ______________ agent.
101. Insulin is secreted by _________________ cells of Islets of Langerhans.
102. Hexamine exerts antiseptic effect in ____________________________ urine.
103. Aspirin used in treatment of coagulopathies due to its _________________ effect.
104. The agents inhibiting bacterial fermentation in stomach are referred as ________________.
105. ____________ is the most potent vasoconstrictor agent formed from renin.
106. ____________ is used in angina pectoris and is administered by ________________route to avoid
first pass effect and it releases ______________________in body.
107. Drugs which increase force of heart contractions are termed as __________.
108. Nikethamide has ____________ action on CNS.
109. Non-steroidal anti-inflammatory drugs act by inhibiting ___________ enzyme.
110. Nystagmus is noticed in the horse in stage ______ of anaesthesi A.
111. Organophosphate insecticides act by irreversible inhibition of __________ enzyme.
112. Phenobarbital is ________________ of hepatic microsomal enzyme system.
113. Shape of curve in graded log-dose response plot is ______________________.
114. Study of qualitative and quantitative evaluation of drugs is known as ___________________.
115. ___________________and ___________________are used to dissolve extravascular and
intravascular clots, respectively.
116. ______________________, produced in spoiled sweet clover, has _____________________ action
by inhibiting _______________.
117. It is advisable to give __________ to piglets before iron therapy.
118. ________________ and ______________ are bitter principles present in Nux vomica and they act
as ____________________.
119. Excess of ______________ in food decreases absorption of copper.
120. Histamine and Dopamine are synthesized from amino acids ___________________ and
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 ________________ respectively.
121. _____________________________ is a direct acting emeti C.
122. Xylazine is a _________________________ acting emetics.
123. _______________ are drugs which promote gastric motility and facilitate gastric emptying.
124. Cardiac gylcosides __________________ heart rate and increases force of contraction.
125. _________________________________ is an example of calcium channel blockers.
126. ________________________ is an antagonist of heparine.
127. __________________________ is an anticoagulant from leech and it can be used in vivo.
128. Terburtaline is ____________________________ agonist.
129. _______________________ causes mainly water diuresis with low degree of natriuresis.
130. ____________________________ are the drugs which relax the uterine myomatrium.
131. White muscle disease in sheep occurs due to deficiency of _______________________.
132. __________________________ is an enzyme associated with destruction of acetylcholine.
133. ____________________________________ is an alkaloid from Nicotiana tabacum.
134. Syrup of ipecae contains _____________ alkaloid, which has _____________action.
135. Dilatation of bronchi is medicated by ________________type of adrenoceptors.
136. Source of pilocarpine and arecoline are _________________and __________________, respectively.
137. _______________________ is an example of ganglionic blocker agent.
138. GABA stands for _____________________________________________________.
139. Sympathomimetic drugs causes _________________________ of bronchial smooth muscle.
140. _______________ is a histaminergic receptors involved in regulation of gastric acid secretion.
141. _________________________________ is a precursor of 5-hydroxytryptamine
142. Amphetamine is ______________________________ acting adrenomimetics.
143. ____________________ decreases the fluidity and volume of saliv A.
144. _______________ is a synthetic analogue of Prostaglandin (PGE1) used in gastric ulcers.
145. ____________________ is a non buffering antacid suitable for IV use.
146. Cardiac glycosides produce positive inotropic effects by inhibiting _______________.
147. ____________________ releases nitrous oxide and produces powerful vasodilatation.
148. ____________________ is an antagonist of leukotrine receptors.
149. Salbutamol is____________________ agonist.
150. Drug which decreases viscosity of naso-pulmonary secretion to facilitate expectoration is known as
____________________.
151. Hexamine in acidic urine liberates ammonia and ___________________ which produces antiseptic
effects.
152. Site of action of loop diuretics is ____________________.
153. ______________ is an alkaloid from Claviceps purpurea, having uterine stimulant effects.
154. ____________________ are the agents which dissolve keratinized layers of skin.
155. ____________________ is a diuretic which induces hyperglycemia in patients.
156. ____________________ is an anticoagulant known as physiological anticoagulant.
157. Dopamine is synthesized from amino acids____________________.
158. _____________ are solutions or suspensions of soothing substances to be applied to the skin without
friction.
159. _____________ is an active metabolite of phenylbutazone.
160. _____________ is term for inactive drug which is convertible to pharmacologically active form in vivo.
161. ________________ administration of drug is subjected to first pass effect.
162. ______________ is drug which has both local anesthetic and anti-arrhythmic action.
163. _______________ is drug which has both antiepileptic and antiarrythmic action.
164. Reserpine causes depletion of ____________________ levels in adrenergic neurons.
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165. ________________________ is an example of nasal decongestant.
166. Adrenaline is the drug of choice for the treatment of type _____ hypersensitivity reactions.
167. ____________________ is an example of fish derived toxin which block axonal action potential by
inhibiting voltage gated sodium ion channel.
168. ___________________________ is an example of mast cell stabilizers.
169. Major pre-ganglionic neurotransmitter in both sympathetic as well as parasympathetic nervous
system is __________________.
170. Gastric and pancreatic glands receive supply of _________________ nervous system only.
171. Estimation of drug concentration or potency by measuring its biological response in intact animals or
isolated preparations is known as _______________.
172. ______________ isolated morphine from opium.
173. _______________ are the drugs that cause expulsion of gases from stomach.
174. ___________________ is most important means by which drugs enter the body and their distribution
occurs across cell boundaries.
175. _______________________ is the study of physiologic and biochemical effects of drugs and how
these effects relate to the drugs mechanism of action.
176. A drug that has both affinity as well as efficacy is termed as ________________.
177. Aspirin affects prostaglandin synthesis by inhibiting _____________ enzyme.
178. Atropine has ______________ effect on pupil of eye.
179. Diazepam produces anticonvulsant effect by antagonizing _______________ in CNS.
180. Drug that produce profound sleep with marked depression are termed as _____________.
181. Drugs which have ability to induce parturition before full term are known as _______________.
182. Surgical operations are performed generally in stage_________ of general anesthesi A.
183. ________________________________ is regarded as Father of Modern Pharmacology.
184. Tannins have _____________________ action on the mucous membrane.
185. All conjugative reactions are catalyzed by non-microsomal enzymes except ____________.
186. In ______________ order kinetics, constant fraction of drug is eliminated per unit time.
187. Half life of the drug is not constant and depends on drug concentration in ___________ order kinetics.
188. A __________________ is the macromolecule component of body tissues with which a drug interacts
to produce pharmacological effects.
189. ______________________ is an example of inverse agonist or negative antagonist.
190. Receptors remained unoccupied (free) by agonists are known as _____________ receptors.
191. Four variables of dose-response curve are ______________, ________________, ___________,
and _______________.
192. Ratio of LD1 and ED99 is known as __________________________________.
193. Pirenzepine and telenzepine are selective antagonists of ____________ receptor.
194. Type of muscarinic receptors which predominant in heart is __________.
195. Interaction, in which a drug with no effect of its own but increases effect of another drug, is known as
_____________________________.
196. ______________ is a non-selective â antagonist which undergo significant first-pass effect.
197. ________________, a reversible anticholinesterase, is used for differential diagnosis of myasthenia
gravis and cholinergic crisis.
198. Dantrolene sodium, a direct acting muscle relaxant, interferes with release of _____________ from
sarcoplasmic reticulum of voluntary muscles.
199. Species like _______________ can tolerate large dose of atropine without any toxic effects.
200. Zafirlukast and montelukast are ______________________ receptor antagonists used to treat allergic
respiratory disease.

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Q-II: Select the most appropriate answer:
1. Following is a H2 blockers:
A. Omeprazole
B. Ondansetron
C. Domperidol
D. Ranitidine
2. Asafoetida (heeng) is:
A. Oleoresin
B. Gum-resins
C. Waxes
D. Plant derived fixed oil
3. Order of duration of action for a drug given by different routes will be:
A. SC > IM > IV
B. IM > SC > IV
C. IM > IV > SC
D. SC > IV > IM
4. Following are non-pharmacological or type B adverse drug effect except:
A. Hypersensitivity
B. Intolerance
C. Idiosyncrasy
D. Photosensitization
5. Acetazolamide acts on:
A. Loop of Hinle
B. Glomerulus
C. PCT
D. DCT
6. Which is true for misoprostol?
A. Induces ulcers
B. Stimulates gastric acid secretion
C. Reduces mucus secretion
D. Synthetic prostaglandin (PGE1) analogue
7. Pharmacologically inert substance which does not produce any therapeutic effect:
A. Placebo
B. Psychotropic agent
C. Anti-psychotic drug
D. Psychosomatic drug
8. Which one is an in vivo as well as in vitro anti-coagulant?
A. Sodium citrate
B. Heparine
C. Sodium chloride
D. EDTA
9. Following cause primarily water diuresis:
A. Mannitol
B. Acetazoalmide
C. Amiloride
D. Hydrochlorthiazide

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10. Drug which helps propelling mucus secretion in respiratory tract:
A. Mucokinetics
B. Mucolytics
C. Prokinetics
D. Gastrokinetics
11. Dose of drug that produces mortality or lethality in 50% of exposed population is:
A. LD50
B. ED50
C. Toxic dose
D. Lethal dose
12. Following drug is obtained from soil:
A. Atropine
B. Caffeine
C. Morphine
D. Magnesium
13. Science that deals with study of mechanism of action of drug is known as:
A. Pharmacokinetics
B. Pharmacodynamics
C. Pharmacometrics
D. Pharmacovigilance
14. “Pen Tsao” is a material medica written in the language of:
A. English
B. Chinese
C. Arabic
D. Urdu
15. Following drug acts by blocking calcium channel and causes fall in blood pressure:
A. Phentolamine
B. Propanol
C. Amlodipine
D. Labetalol
16. Caffeine acts on which part of CNS?
A. Medulla
B. Cortex
C. Spinal cord
D. All of above
17. Following is a naturally occurring alkaloid obtained from Chinese shrub Ephedra vulga:
A. Atropine
B. Ephedrine
C. Digitalis
D. Digitoxin
18. Which is the competitive neuromuscular blocker?
A. d-tubocurarine
B. Pancuronium
C. Gallamine
D. All of above
19. Which is true for balanced anaesthesia?
A. Irreversible loss of consciniousness.
B. Irrevesible loss of sensation.
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 C. Muscle relaxant
D. Both (A) and (C)
20. Adrenaline does not have the following effect:
A. Increase heart rate
B. Increases blood glucose
C. Increase cardiac output
D. Miosis
21. The antagonist of diazepam is:
A. Lorezapam
B. Flumazenil
C. Atropine
D. Thiophenate
22. Which of following is most potent inhalant anaesthetic?
A. Ether
B. Halothane
C. Methoxyfurane
D. Isofurane
23. Which of the following inhibits uptake of acetylcholine into vesicles?
A. Vesamicol
B. Cobra toxin
C. Bungarotoxin
D. Botulinum toxin
24. Which of following is used in the treatment of myasthenia gravis:
A. Dopamine
B. Neostigmine
C. Atropine
D. Benzodiazepam
25. Which of following is used for relief of heaves in horse?
A. Oxytocin
B. Atropine
C. Methanol
D. Frusamide
26. Which of following drug increases blood pressure, heart rate and force of contractions?
A. Epinephrine
B. Atropine
C. Labetolol
D. Pindalol
27. Post operative urinary bladder atony can be treated with:
A. Atropine sulphate
B. Dopamine
C. Bethanechol
D. Pilocarpine
28. Following is not a pharmacokinetics process:
A. Absorption
B. Distribution
C. Metabolism
D. Dissolution

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29. Pharmacovigilance does not include:
A. Screening
B. Adverse drug reaction
C. Drug toxicity in patients
D. Extra label use of drug
30. Which drug is metabolized by sulphoxidation:
A. Malathion
B. Phenylbutazone
C. Albendazole
D. Quinidine
31. Drug which reduces viscosity of mucus secretion in respiratory tract:
A. Mucokinetics
B. Mucolytics
C. Prokinetics
D. Gastrokinetics
32. Dose of drug that produces mortality or lethality is:
A. LD50
B. ED50
C. Toxic dose
D. Lethal dose
33. Following drug is not obtained from soil:
A. Atropine
B. Caffeine
C. Morphine
D. All of above
34. ‘All or none’ response is related to:
A. Quantal dose response curve
B. Graded dose response curve
C. Drug excretion
D. Drug metabolism
35. The recommended route of administration for oxytocin is:
A. IV and Oral
B. IM and Oral
C. IV and IM
D. IV and Local
36. Conversion of nicotinic acid to nicotinamide leads to:
A. Increases toxicity
B. Decreased toxicity
C. No change in toxicity
D. None of above
37. Which is a sign of digitalization:
A. Dyspnoea
B. Nausea
C. Relief in coughing
D. Palpitation
38. Science that deals with drug dosage determination is known as:
A. Posology

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 B. Pharmacy
C. Pharmacometrics
D. Metrology
39. Following is not a dissociative anaesthetics:
A. Ketamine
B. Tiletamine
C. Phencyclidine
D. None of above
40. Chlorpent anaesthesia include:
A. Chloral hydrate
B. Magnesium sulphate
C. Phenobarbitone
D. All of above
41. Following is a beta receptor blocker which is used as bronchodilator:
A. Terbutaline
B. Salbutamol
C. Caffeine
D. Both (A) and (B)
42. Propanolol blocks:
A. â1
B. â2
C. â3
D. â1 and â2
43. Verapamil acts by:
A. blocking potassium channel
B. blocking L type calcium channel
C. blocking sodium channel
D. blocking ATPase
44. Following is an action of H1 blockers:
A. CNS sedatives
B. Anti-emetics
C. Local anaesthetics
D. All of above
45. Following is an anti-cholinergic pre-anaesthetic:
A. Atropine
B. Sumatropine
C. Promethazine
D. Chloral hydrate
46. Chloral hydrate is converted to:
A. Diethyl ether
B. Trichloromethane
C. Trochloroethanol
D. Dichloromethane
47. Which is not true for aspirin:
A. It is NSAIDs
B. It has strong analgesic and antipyretic activity
C. Prolong use leads to gastric bleeding

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 D. It inhibits phospholipase
48. The source of opium alkaloids is:
A. Papaver somniferum
B. Digitalis purpurea
C. Claviceps purpurea
D. Urgenia maritime
49. Paracetamol has following characteristics:
A. Strong analgesic
B. Strong anti-inflammatory
C. Sedative
D. Selective COX-2 inhibitor
50. Following is an á1 blocker:
A. Pentazocin
B. Pentaprazole
C. Prazocin
D. Penylephrine
51. All of following except one is not a NOT a natural drug:
A. Atropine
B. Quinine
C. Digitalis
D. Paracetamol
52. Which is true for ondansetron?
A. 5 HT3 analogue
B. 5 HT3 agonist
C. 5 HT3 antagonist
D. 5 HT3 reactivator
53. Which one is an in vivo as well as in vitro anti-coagulant?
A. Sodium citrate
B. Heparine
C. Sodium chloride
D. EDTA
54. Following is a tocolytic drugs?
A. Emodine
B. Naloxane
C. Oxytocin
D. Acetycholine
55. Physostigmine acts on which receptors?
A. Alpha
B. Beta
C. Muscarinic
D. Dopamine
56. Which of following has no action on nicotinic receptors?
A. Acetylcholine
B. Carbachol
C. Methacholine
D. Muscurine
57. Which of following represents parasympathetic part of ANS?

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 A. Lumbo-sacral
B. None of above
C. Thoraco-lumber
D. Cranio-sacral
58. Acetylcholine is metabolized by following enzyme:
A. Ach-e
B. ACE
C. Adenyl cyclase
D. ATPase
59. Following is NOT a â2 receptor agonist:
A. Salbutamol
B. Salmetrol
C. Terbutaline
D. Dobutamine
60. Which of following is á-2 adrenoceptor antagonist?
A. Yohimbine
B. Atropine
C. Atenolol
D. Clenbuterol
61. Following is an precursor of histamine:
A. Tyrosine
B. Tyrptophane
C. Histidine
D. Renitidine
62. Metoserpate is an synthetic analogue of:
A. Xylocaine
B. Tetracaine
C. Reserpine
D. Lidocaine
63. Following is an MAO inhibitor:
A. Imipramine
B. Desipramine
C. Amitriptyline
D. All of above
64. Which of following is major process responsible for termination of action of thiopentone?
A. Metabolism
B. Redistribution
C. Excretion
D. Absorption.
65. Stage IV of general anesthesia is also known as:
A. Delirium
B. Analgesia
C. Surgical anaesthesia
D. Medullary paralysis
66. Alkalization of urine promotes action of following antibacterials:
A. Fluoroquinolones
B. Penicillins

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 C. Aminoglycosides
D. Macrocyclics
67. Following is an example of caustics:
A. Copper sulfate
B. Zinc sulfate
C. Salicylic acid
D. Bentonite
68. The pharmacological activity of cardiac glycoside is a function of:
A. Aglycon
B. Gylcon
C. Both (A) & (B)
D. None of above
69. Drug(s) which gets inactivated in rumen:
A. Chloramphenicol
B. Digitalis
C. Trimethoprim
D. All of above
70. Action of cholinergic agonist on GIT smooth muscle is:
A. Increased motility
B. Decreased motility
C. Causes no effects
D. Induces paralysis
71. Following is a precursor of histamine:
A. Tryptophan
B. Histidine
C. Tyrosine
D. Dopamine
72. Fluoride has a tendency to accumulate in which of following tissues:
A. Kidneys
B. Liver
C. Teeth of young animals
D. Spleen
73. Hypoprotinaemia has direct impact on:
A. Drug solubility
B. Drug disintegration
C. Drug distribution
D. None of above
74. Following is NOT an in vitro anticoagulant:
A. Sodium oxalate
B. Sodium citrate
C. K2 EDTA
D. Dicoumarol
75. Amphetamine acts by:
A. Releasing noradrenaline
B. Releasing dopamine
C. Both (A) & (B)
D. None of above

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76. Caffeine acts on which part of CNS via:
A. Blocking adenosine action in cortex
B. Blocking adenosine action in medulla
C. Blocking adenosine action in spinal cord
D. All of above
77. Strychnine causes one of following:
A. CNS stimulantation
B. Severe spinal convulsion
C. Inhibition of gylcine
D. All of above
78. Which of following synthetic opioid has anti-diarrhoeal activities?
A. Dicyclomine
B. Loperaminde
C. Domperidole
D. Hydroxycodeine.
79. Which is not a phenothiazine tranquilizer?
A. Acepromezine
B. Chlorpromezine
C. Triflupromezine
D. Cetrizine
80. Following is angiotensin receptor blocker:
A. Losartan
B. Enalapril
C. Ketanserin
D. Ondansetron
81. Following is an example of endogenous opioid:
A. Endorphins
B. Epinephrine
C. Ephedrine
D. All of above
82. All opioid receptors belong to following type of receptors:
A. G protein coupled
B. Ligand gated ion channels
C. Enzymes linked
D. None of above
83. What determines the degree of movement of a drug between body compartments?
A. Partition constant
B. Degree of ionization
C. pH
D. All of the above
84. Which of the following is considered the brand name?
A. Paracetamol
B. Crocin
C. Acetaminophen
D. Antipyretics
85. Pharmacokinetics is the effect of the ____ & pharmacodynamics is the effect of the _____.
A. Drug on other drug; Body on the drug

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 B. Body on the drug; Drug on other drug
C. Drug on the body; Body on the drug
D. Body on the drug; Drug on the body
86. Which of the following process is NOT an action of the body on a drug?
A. Distribution
B. Target binding
C. Synthetic conjugations
D. Biliary excretion
87. Which of the following is the amount of a drug absorbed per the amount administered?
A. Bioavailability
B. Bioequivalence
C. Drug absorption
D. None of above
88. For intravenous (IV) dosages, what is the bioavailability assumed to be?
A. 0%
B. 1%
C. 50 %
D. 100 %
89. Which of the following is NOT a pharmacokinetic process?
A. Alteration of the drug by liver enzymes
B. The drug is readily deposited in fat tissue
C. Movement of drug from the gut into general circulation
D. The drug causes dilation of coronary vessels
90. Which of the following has least side effects?
A. Paracetamol
B. Aspirin
C. Meloxicam
D. Nimesulide
91. Most drugs are either _______ acids or _______ bases.
A. Strong; Strong
B. Strong; Weak
C. Weak; Weak
D. Weak; Strong
92. Weak acids and bases are excreted faster in ________ and ________urine, respectively.
A. Acidic; Alkaline
B. Alkaline; Acidic
C. Neutral; Neutral
D. Neutral; Alkaline
93. Organ responsible “first pass effect” is:
A. Brain
B. Heart
C. Kidney
D. Liver
94. Which of the following enteral administration routes has the largest first-pass effect?
A. Sublingual
B. Buccal
C. Rectal

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 D. Oral
95. Which of the following would receive drug slowly?
A. Brain
B. Fat
C. Muscle
D. Kidney
96. What type of drugs can cross the blood-brain barrier (BBB)?
A. Large and lipid-soluble
B. Large and lipid-insoluble
C. Small and lipid-soluble
D. Small and lipid-insoluble
97. Which of the following is NOT a phase II substrate?
A. Glucuronic acid
B. Sulfuric acid
C. Acetic acid
D. Alcohol
98. Which of the following reactions is phase II and NOT phase I?
A. Reductions
B. Conjugations
C. Deaminations
D. Hydrolyses
99. The goal of the Cytochrome - P450 system is:
A. Metabolism of xenobiotics
B. Detoxification of xenobiotics
C. Absorption of xenobiotics
D. (A) & (B)
100. Generally, following is in the correct order regarding doses:
A. ED50 < LD50 < TD50
B. ED50 < TD50 < LD50
C. LD50 < TD50 < ED50
D. LD50 < ED50 < TD50
101. Which of the following is considered the therapeutic index?
A. T.I. = LD25 / ED75
B. T.I. = LD50 / ED50
C. T.I. = ED25 / LD75
D. T.I. = ED50 / LD50
102. Following causes inhibition of aggregation of platelets
A. Aspirine
B. Urokinase
C. Thromboxane A2
D. Streptokinase
103. Most appropriate anticoagulant used for collection of blood for blood glucose estimation:
A. Sodium EDTA
B. Sodium fluoride
C. Heparin
D. Sodium oxalate
104. Agar acts as:

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 A. Cathartics
B. Emollient purgative
C. Bulk purgative
D. Osmotic purgative
105. Acid rebound effect is observed with:
A. Sodium bicarbonate
B. Sodium citrate
C. Sodium chloride
D. Potassium iodide
106. An antagonist has:
A. Efficacy only
B. Affinity only
C. Both efficacy and affinity
D. Neither efficacy nor affinity
107. Isaphgula husk acts as:
A. Bulk purgative
B. Osmotic purgative
C. Emollient purgative
D. Cathartics
108. The stage(s) of anaesthesia which is induced by ketamin is:
A. Stage I only
B. Stage II only
C. Stage I and II only
D. Stage II and III only
109. Antiemetic action of domperidone is mediated by inhibition of receptors:
A. Opoid receptor
B. Muscarinic receptor
C. Dopamine receptor
D. 5-HT receptor
110. Pharmacological effects of oxytocin:
A. Contraction of myoepithelium of mammary alveoli
B. Contraction of uterus
C. Both (A) & (B)
D. None of the above
111. High plasma protein binding of drugs results in increased:
A. Volume of distribution
B. Plasma half-life
C. Clearance
D. Rate of metabolism
112. The therapeutic index of the drug indicates:
A. Potency
B. Efficacy
C. Safety
D. Toxicity
113. In hepatocytes, the seat of drug-metabolizing enzymes is:
A. Cell membrane
B. Ribosomes

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 C. Smooth endoplasmic reticulum
D. Rough endoplasmic reticulum
114. Bioavailabilty of a drug is calculated by formula:
A. 0.693/â
B. Dose/AUC x â
C. AUC (extravascular)/ AUC (intravenous)
D. AUC (intravenous)/ AUC (extravascular)
115. Most potent local anaesthetic among the following
A. Lignocaine
B. Mepivacaine
C. Bupivacaine
D. Procaine
116. Most potent inhalant anaesthetic having lowest MAC:
A. Methoxyflurane
B. Halothane
C. Isoflurane
D. Enflurane
117. Which one of the following is a rate limiting step in adrenaline synthesis?
A. Tyrosine to DOPA
B. DOPA to Dopamine
C. Dopamine to Nor-adrenaline
D. None of the above
118. Magnesium sulphate has following properties EXCEPT:
A. Euthanizing agent
B. Purgative
C. Muscle relaxant
D. Analeptic
119. Which one of the following has maximum natriuretic effect?
A. Spironolactone
B. Frusemide
C. Mannitol
D. Acetazolamide
120. Which one of the following is an example of physical antagonism?
A. Use of activated charcoal in poisoning cases
B. Use of antacids to neutralize gastric acidity
C. Use of atropine in organophosphate poisoning
D. Use of yohimbine in xylazine overdose
121. In simple terms, pharmacokinetics is study of effect of:
A. Drug on another drug
B. Drug on body
C. Body on drug
D. All of the above
122. Reserpine, an anti-hypertensive alkaloid is obtained from medicinal plant:
A. Ocimum sanctum
B. Adhatoda vasica
C. Leptadenia reticulate
D. Rauwolfia serpentina

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123. Half-life of a drug is calculated by formula:
A. 0.693 / â
B. AUC (P.O.) / AUC (I.V.)
C. Dose / AUC x â
D. F x dose / AUC
124. Drug metabolism involving conjugation through acetylation is absent in:
A. Horse
B. Dog
C. Cat
D. Pig
125. Drug reducing anxiety with little sedation without affecting consciousness is:
A. Narcotics
B. Ataratics
C. Soporifics
D. Sedatives
126. An injection of local anaesthetic into CSF within subarachnoid space is called:
A. Topical anaesthesia
B. Nerve block anaesthesia
C. Infiltration anaesthesia
D. Spinal anaesthesia
127. Replacement of oxygen by =NH group at carbon 2 of barbituric acid:
A. Increase potency
B. Increase duration of action
C. Decrease potency
D. Destroy activity
128. Antagonism between heparin and protamine is an example of:
A. Functional antagonism
B. Competitive antagonism
C. Chemical antagonism
D. Physiological antagonism
129. Most effective drug for induction of sedation in ruminants:
A. Diazepam
B. Medetomidine
C. Triflupromazine
D. Xylazine
130. Potentiation of local anesthesia can be achieved by co-administration of:
A. Atropine
B. Adrenaline
C. Acetylcholine
D. All of the above
131. Irritant and non-isotonic drug solutions are injected by:
A. Intravenous route
B. Intramuscular route
C. Subcutaneous
D. Intraperitoneal route
132. Sudden death due to chloral hydrate anesthesia in horses occurs due to:
A. Cardiac failure

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 B. Renal failure
C. Respiratory failure
D. Hepatic failure
133. Death in chloroform anesthesia occurs due to:
A. Respiratory failure in acute over dosage.
B. Cardiac arrest during induction.
C. Hepatotoxicity
D. All of the above.
134. Following has ultra-short duration of anesthetic action:
A. Phenobarbital sodium
B. Thiopentol sodium
C. Amobabbital sodium
D. Pentobarbital sodium
135. Terms related to drugs acting on digestive system except:
A. Antacids
B. Anticarminative
C. Analeptics
D. Antizymotics
136. Species which is most sensitive to sedative action of xylazine:
A. Dog
B. Cat
C. Horse
D. Cow
137. Droperidol – fentanyl citrate is combined in the ratio of:
A. 1:5
B. 5:1
C. 1:50
D. 50:1
138. More selective COX-2 inhibitor is:
A. Meloxicam
B. Aspirin
C. Paracetamol
D. Phenylbutazone.
139. Most potent mu, kappa, and delta opioid receptor agonist is:
A. Morphine
B. Etorphine
C. Naltrexone
D. Fentanyl
140. Drug which interfere with uptake and binding of norepinephrine in storage vesicles:
A. Reserpine
B. Gaunethidine
C. 6-hydroxydopamine
D. Bretylium
141. A selective â2 agonist is:
A. Tyramine
B. Dobutamine
C. Salbutamol

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 D. Clonidine
142. Immediate precursor of Norepinephrine is:
A. Tyrosine
B. Dopamine
C. Adrenaline
D. DOPA
143. A selective á-1 receptor antagonist is:
A. Yohimbine
B. Atenolol
C. Pindolol
D. Prazosin
144. Effects of stimulation of muscarinic receptors on cardiovascular system:
A. Vasodilation
B. Positive chronotropic and ionotropic
C. Decrease in cardiac output
D. All of the above
145. Drug of choice in Anaphylactic shock:
A. Isoproterenol
B. Norepinephrine
C. Carbidopa
D. Epinephrine
146. Followings are pharmacological effects of Atropine EXCEPT:
A. Decrease GIT motility
B. Miosis
C. Relaxation of bronchial smooth muscles
D. Reduce salivary secretions
147. A proton pump inhibitor used to treat gastroesophageal reflux disease (GERD) is:
A. Ondansetron
B. Fomatidine
C. Domperidone
D. Omeprazole
148. Antagonist of Nm receptor is:
A. Tubocurarine
B. Hexamethonium
C. Trimethaphan
D. All of the above
149. Following drug produces prokinetic effect:
A. Cimetidine
B. Metaclopramide
C. Prochlorperazine
D. Ameprazole
150. The drug of choice to treat status epilepticus in dogs is:
A. Acepromazine
B. Phenobarbitone
C. Diazepam
D. Potassium bromide

100
Deparment of Pharmacology & Toxicology College of Veterinary Sci. & A. H., SDAU
Class Notes- VPT 321

ANS PHARMACOLOGY
Brain
Central Nervous
System
Spinal Cord

Nervous System
Sympathetic
Nervous System
Autonomic
Nervous System
Peripheral Parasympathetic
Nervous System Nervous System
Somatic Nervous
System

Term ANS given by LANGLEY (1908) as ANS supplies nerve fibres to visceral organs
which have some autonomicity.
Autonomic Nervous System: (Autonomic=Visceral=vegetative)
Controls involuntary functions of the body.
It supplies it’s fibres to all organs except skeletal muscles
[Auto= self, Nomos= Governing]
So self regulating the functions of visceral organs thereby maintains the homeostasis or vital
functions of the body like thermoregulation, blood pressure, cardiac function, digestion,
urination, defecation.
Comparison of autonomic and somatic nervous system:

Particular Autonomic Nervous System Somatic Nervous System

Supply All peripheral structures except Skeletal system
1
skeletal muscles
2 Synapse Outside CNS Within CNS
3 Ganglion Contain Ganglion No any Ganglion
Formation of Many Autonomic fibres form Absent
4
plexus plexus/network
Type/nature of Preganglionic Myelinated All are Non-myelinated
5
fibre Postganglionic Nonmyelinated
Nerve Organs does not undergo Complete paralysis & atrophy
6
degeneration atrophy of skeletal muscle
7 Neurotransmitters Acetylcholine or adrenaline Acetylcholine
8 Nature of work Involuntary Voluntary

Divisions of Autonomic Nervous System:

Divided into 2 main divisions: sympathetic & parasympathetic.
Two divisions differ from each other: Anatomically, physiologically,
pharmacologically.

By Dr. H. B. Patel & Satyajeet Singh ~2~

Class Notes- VPT 321

Organs with both Sympathetic & Heart, Intestinal smooth muscles

Parasympathetic supply
Organs with only Sympathetic supply Many Blood vessels, sweat gland, Haair
follicles
Organs with only Parasympathetic supply Ciliary muscle, Gastric & Pancreatic gland

General considerations about ANS:

All Autonomic fibres have 2 neurons. I.e. Preganglionic & Postganglionic.

Cell body (cyton) of Preganglionic fibres are located within CNS i.e. Cerebrospinal
Axis.
Axon of Preganglionic neurons forms synapse with cell body of Postganglionic nerve
fibres outside CNS within Autonomic Ganglions.
Autonomic ganglion is specialised nodular structure comprising neurons (>1,00,000).
It occurs outside the Cerebrospinal Axis.
Neurons that are before the autonomic ganglion are called as Preganglionic Neurons
and which are after autonomic ganglion are called as Postganglionic Neurons.
After forming synapse with Preganglionic neurons, the Postganglionic neurons travels
and innervates effector organs (e.g. smooth muscles, heart) called effectors.
Junction of pre and postganglionic nerve fibres is called as Synapse. There is always a
gap of 200-400A° between two neurons. This gap is known as Syneptic Cleft.
Junction of Postganglionic nerve fibres to its effector organ is known as Neuroeffector
Junction/Neuromuscular Junction.
Nerve membrane/terminal prior to the synapse is known as Pre Synaptic Membrane.
Nerve membrane after synapse is known as Post Synaptic Membrane/Post Junctional
Membrane.
Passage of nerve impulse along the axon is electrical in nature, called as Conduction.
Passage of nerve impulse across the synapse is known as Neurotransmission.
Nerves that release the Acetylcholine (Ach) as a neurotransmitter are called as
Cholinergic Nerves.
Nerves that release the Nor-adrenaline or Adrenaline are called as Nor-adrenergic or
Adrenergic Nerves.

General functions of Autonomic Nervous System:

Sr. Sympathetic Nervous System Parasympathetic Nervous System

No
1 Functions mainly for:
Not essential for life under
laboratory conditions. Organised/localised discharge
But in case of stress condition the Not for mass response
function of Sympathetic Nervous Conservation/restoration of energy.
System is essential.

By Dr. H. B. Patel & Satyajeet Singh ~3~

Class Notes- VPT 321

2
Absorption of nutrients.

3
This occurs in conditions whenever In Rest & Digest conditions
there is a threat to life/stress. Prepare
body for fight or flight response

4 Anabolic function (Conservation of

Catabolic function (Expenditure of energy)
energy)
5 Heart Rate
Heart Rate
6 Blood pressure
Blood Pressure
7 Constriction of pupil.
Dilatation of Pupil
8 Constriction of Bronchi.
Dilatation of Bronchi.
9
Peristalsis & Tone (so Constipation) Peristalsis & Tone (so Diarrhoea)

10
Salivation (so Dryness in Mouth) Salivation

11
Sweat secretion Sweat secretion

12
Respiration Respiration

13
Urinary Output Urinary Output

14
Blood supply to skeletal muscle Blood supply to skeletal muscle

15
Blood supply to visceral organs Blood supply to visceral organs

16
It has Ganglion close to spinal cord. The Ganglia are far away from the
spinal cord & close to or within the
effectors.

17
Blood supply shifted from peripheral
organs to heart, brain, lung, skeletal
muscle.

By Dr. H. B. Patel & Satyajeet Singh ~4~

Class Notes- VPT 321

18
More blood supply/RBCs to general
circulation from spleen.

19. Release of glucose

(Hyperglycaemia).

The neurotransmitter of the

Preganglionic sympathetic neurons
is Acetylcholine (ACh) Neurotransmitter is only the
The neurotransmitter released by the Acetylcholine on both pre and
20.
Postganglionic sympathetic neurons postsynaptic parasympathetic
is Noradrenaline. there is one ganglion.
exception: the sympathetic post-
ganglionic neurons of the sweat
glands release acetylcholine
In general the functions of sympathetic and parasympathetic nervous system are viewed as
Antagonist but there are some exceptions:
1) Independent & different
2) Interdependent & integrated
3) Complementary
o Antagonist: e.g. Heart/pupil
Sympathetic------ Heart Rate, Dilates Pupil
Parasympathetic--- Heart Rate, Constricts Pupil

o Complementary/Interdependent: e.g. Male sex organ

Parasympathetic----- Erection of penis
Sympathetic--------- Ejaculation

o Independent: e.g. Blood Vessels

Control of Blood Pressure Peripheral Vasoconstriction is through Sympathetic
system (No Parasympathetic system)

Neurotransmitter: Chemical substance that releases in synapse and carry the impulses.
Depending upon receptors and transmitters there may excitation or inhibition of post synaptic
neuron. If receptors are excitatory then excitation and if receptors are inhibitory then
inhibition of post synaptic neuron will occur. Two important NTs of Autonomic Nervous
System are Acetylcholine (Ach) & Nor-adrenaline.

Conduction Neurotransmission

Require physical media for propagation Propagation without any physical media

No requirement of nerves, requirement of

Require nerves
chemical

By Dr. H. B. Patel & Satyajeet Singh ~5~

Class Notes- VPT 321

Neuromodulators Neurotransmitter
Chemical substances transmit nerve
Nerves participate in the transmission of
impulses across the synapse.
nerve impulses.
Chemical substance on reaching post
synaptic membrane excites or inhibits
They control the release of
post synaptic membrane and cause
Neurotransmitters.
transmission of nerve impulses.
Process is very fast.
Process is slow.
E.g. acetylcholine, adrenaline.
E.g. prostaglandins.

Neuromodulators: Chemical substances produced by cells but

Not participate into Neurotransmission directly.
Control release of NTs.
Produced by non-synaptic site.
Process is slow & involves cascade of intercellular processes and messengers.
E.g. Prostaglandins (PGs), peptides, Adenosine, Arachidonic acid

Neuromediators: Enhance the postsynaptic response of specific NTs. E.g. cAMP, cGMP,
DAG

Co-Transmitters: when neuron releases more than one Neurotransmitters/Neuromodulators,

both are required to produce effects, then NTs are called as co-Transmitters.

----------------------------------------------------------------------------------------------------------------

Neurotransmissions:

Passage of nerve impulse across the synapse is known as Neurotransmission.

Steps in Neurotransmission (6 steps in sequences)

1. Axonal conduction
2. NT release
3. Receptor events
4. Post synaptic Response
5. Destruction of NTs.
6. Non electrogenic activities.

By Dr. H. B. Patel & Satyajeet Singh ~6~

Class Notes- VPT 321

1. Axonal Conduction: passage of impulse along on Axon is known as Axonal

Conduction.
Steps in Axonal Conduction:
a) Resting Membrane Potential= -70mV
b) Due to stimuli RMP become zero due to movement of Na+ inside.
(positivity/Depolarization)
c) Rapidly K+ move out followed by Na+ move out so again negativity (-ve) so
Hyperpolarization.
d) Gradually K+ re-enters in cells & re-established RMP.

In this way Action Potential is generated at the point of stimulus

So local part of Neuron /nerves get excited

This excited part conducts the Action Potential to adjacent parts

In this way impulse conduction occurs.

Tetradotoxin:(Puffer fish poison) it will cause blockage of Axonal conduction by blocking

the Voltage sensitive Na channels, so blocks entry of Na+ thus inhibit generation of Action
Potential.

Bratrachotoxin :(an alkaloid toxin from south American frog) it causes increase Na+ entry
into the nerve causing persistant Depolarization and Axonal conduction.

2. Neurotransmitter Release:
o Action Potential arrives at nerve terminals
o Depolarization of nerve membrane at terminals
o Ca++ enter into cell from ECF
o Ca++ causes fusion of vesicles to Axoplasmic Membrane.
o Release of contents of vesicles (NTs/Enzymes/proteins) into Synaptic Cleft by
process of exocytosis.

NTs are synthesized by cells using enzymes and stored in Granules or Vesicles inside the
cells/neurons in inactive or bound forms. This process is Ultrafast/Supersensitive.

3. Receptor Events:
Once NT released, it diffuse across the Synaptic Cleft/junctional Tissues and combines
with receptors located on Post synaptic membrane.
This interaction of NT & Receptor may initiates two types of effects i.e. Excitatory
[Excitatory Post Synaptic Potential (EPSP)] and Inhibitory [Inhibitory Post Synaptic
Potential (IPSP)].

4. Post Synaptic Response: Depending upon EPSP & IPSP (Receptor-NT interaction), it
may produce excitation or inhibition on cells/effector organs.

By Dr. H. B. Patel & Satyajeet Singh ~7~

Class Notes- VPT 321

If EPSP-- reaches Post Synaptic Membrane in neurons or skeletal muscle or cardiac

muscle (Effector organ) there is muscle contraction, muscle tone, secretion of glands
in periphery.
If IPSP-- no initiation of Action Potential, so no excitation in effector organs and
inhibitory effect is observed

5. Destruction of Neurotransmitter: For rapid action of NT, its action must be

terminated.
3 ways to terminate the action of NT:
I. Metabolic Degradation: Some specific enzymes inactivate the NTs. These
enzymes are produced by Pre synaptic membranes or by synaptic tissues. For
e.g.
o Ach hydrolysed by Acetylcholinesterase (AchE).
o Nor-adrenaline hydrolysed by COMT & MAO.
COMT= Catecholamine o-methyl transferase (causes extraneural hydrolysis)
MAO= Monoamine Oxidase (causes intraneural hydrolysis)
End product of Nor-adrenaline oxidation by MAO is VMA (Vanillylmandelic Acid).

II. Reuptake: Certain NTs after their release are taken back into Pre Synaptic
Membrane by specific carrier. E.g. Nor-adrenaline reuptake by nerve cells
terminates its action at synapse.
III. Diffusion: Small amount of NTs are diffused by surrounding tissues &
metabolised locally. E.g. Peptide NTs & Peptidase enzyme.

6. Non Electrogenic function: During resting stage small quantity of NTs is released
continuously but not sufficient to initiate the EPSP & IPSP but require maintaining the
physiological responsiveness of cell/stimuli.
-------------------------------------------------------------------------------------------------------

Cholinergic Transmission

Neurons that release the Ach are known as cholinergic transmission. Or

Neurotransmission by Ach is known as cholinergic transmission.

Sites where Ach acts as NT:

Autonomic ganglion both Sympathetic & Parasympathetic.

Adrenal medulla
Somatic nerves of skeletal muscles.
CNS
Preganglionic Sympathetic Nerve Fibres
Pre & Postganglionic Parasympathetic Nerve Fibres

By Dr. H. B. Patel & Satyajeet Singh ~8~

Class Notes- VPT 321

Biosysnthesis/Storage/Release of Ach:

Acetic acid + ATP Acetyl AMP

Acetyl AMP + CoA Acetyl CoA

Choline Acetyltransferase (CAT or ChAT)
Acetyl CoA + Choline Acetylcholine + CoA

Choline is supplied from Vitamine-B complex from extraneural sources.

ATP is derived from Carbohydrate.
CoA is derived from minerals & proteins.

Ach synthesis occurs in axon.

Acetyl CoA is synthesized in Neurons. (Hemicholium & Triethylcholine blocks
Choline transferse)
After synthesis, Ach is stored into storage vesicles.
When Action Potential/Nerve Impulse arrives at the nerve terminals

Ca++ Channels Open

Increase Influx of Ca++

Increased concentration of Ca++ causes fusion of vesicles with cell membrane

Exocytosis of vesicles occurs

Discharge of Ach into synapse

Vesamicol: inhibit uptake of Ach into vesicle leading to empty vesicles fusing with neuron
membrane. It is Cholinergic Antagonist. It does not act at Post synaptic Ach Receptors.

Botulinum & Bungarotoxin: it inhibits release of Ach into synaptic cleft. Bungarotoxin is a
snake venom of krait(Bungarus multicinctus).
α-Bungarotoxin: Binds irreversibly & competitively to Ach Receptor.
β-Bungarotoxin: Target is Pre Syneptical Terminal where it cause exhaustion of Ach stores
by binding to actin protein.

Black widow spider & Ciguatoxin: initially increase release of Ach and later
decrease release of Ach. Black widow spider is the common name of some spiders in
the Genus latrodactus. Ciguatoxin is fish poison which causes Ciguatera.

Receptor Events:

By Dr. H. B. Patel & Satyajeet Singh ~9~

Class Notes- VPT 321

Released Ach diffuse across synapse & combines with receptors located on Post
Synaptic Membrans/Pre Synaptic Membrane.
Interaction with receptors initiates the biological events depending upon the nature of
receptors.
After their action with receptors (Action of Ach with Receptor lasts only for 2
mSecond.), dissociated or hydrolysed into Choline & Acetyl CoA by enzyme
Acetylcholinesterase.
Acetylcholinesterase (AchE)
Acetylcholine (Ach) Acetyl CoA + Choline

Two types of AchE enzyme: (on Enzyme Specificity)

Pseudo/Non Specific /Butyryl
True/Acetylcholinesterase cholinesterase
Enzyme
All body tissues, RBCs. Blood, Plasma, Liver, Urine.
1.
AchE hydrolyses Ach at faster BchE hydrolyses Bch & Benzylcholine
2. rate. at faster rate.
Not hydrolyses Bch & Slowly hydrolyses Ach.
3. Benzylcholine.

Organophosphorus compounds: inhibits AchE & BchE enzyme.

Neostigmine/Physostigmine: inhibits AchE enzyme

Cholinergic transmission

Acetylcholine (ACh) synthesis:

o Requires choline, which enters the neuron via carrier-mediated transport
o Requires acetylation of choline, utilising acetyl coenzyme A as source of acetyl groups, and
involves choline acetyl transferase, a cytosolic enzyme found only in cholinergic neurons.
ACh is packaged into synaptic vesicles at high concentration by carrier-mediated transport.
ACh release occurs by Ca2+-mediated exocytosis. At the neuromuscular junction, one presynaptic nerve
impulse releases 100-500 vesicles.
At the neuromuscular junction, ACh acts on nicotinic receptors to open cation channels, producing a
rapid depolarisation (endplate potential), which normally initiates an action potential in the muscle
fibre. Transmission at other 'fast' cholinergic synapses (e.g. ganglionic) is similar.
At 'fast' cholinergic synapses, ACh is hydrolysed within about 1 ms by acetylcholinesterase, so a
presynaptic action potential produces only one postsynaptic action potential.
Transmission mediated by muscarinic receptors is much slower in its time course, and synaptic
structures are less clearly defined. In many situations, ACh functions as a modulator rather than as a
direct transmitter.

Main mechanisms of pharmacological block: inhibition of choline uptake, inhibition of ACh release,
block of postsynaptic receptors or ion channels, persistent postsynaptic depolarisation

By Dr. H. B. Patel & Satyajeet Singh ~ 10 ~

Class Notes- VPT 321

Adrenergic Transmission

Transmission mediated by Nor-adrenaline or Nor-epinephrine at Postganglionic

Sympathetic Nerve Terminals (except Sweat gland in mare & dogs) is known as
Adrenergic Transmission.
Or
Transmission mediated by Nor-adrenaline & Dopamine is known as Adrenergic
Transmission.

Site of action is Postganglionic Sympathetic Nerve Fibres.

3 Steps:
1) Synthesis of Nor-adrenaline.
2) Storage & Release of Nor-adrenaline.
3) Disposition/Destruction of Nor-adrenaline.

1) Synthesis of Nor-adrenaline:
Site: Adrenergic nerves
Precursor: Phenylalanine (Taken up from ECF)
Phenylalanine

Phenylalanine hydroxylase

Tyrosine

In Axoplasm (Rate limiting step) Tyrosine hydroxylase

DOPA (Dihydroxy Phenylalanine)

Dopa decarboxylase

Dopamine

Dopamine β-hydroxylase

In synaptic vesicle Nor-epinephrine

Phenylethanolamine N-methyl transferase

Epinephrine

o Phenylalanine essential amino acid- converted into tyrosine in LIVER

o DOPA decaboxylase- Histamine, 5-HT synthesis also require

By Dr. H. B. Patel & Satyajeet Singh ~ 11 ~

Class Notes- VPT 321

o Synthesis upto Dopamine occur in Axoplasm.

o Dopamaine enter into vesicles & converted into Nor-adrenaline by Dopamine
β-hydroxylase.
o α-methyl tyrosine inhibits tyrosine hydroxylase & block Epinephrine/Nor-
epinephrine synthesis.
o Carbidopa Dopa decrboxylase inhibited- used in the treatment of
Parkinson disease.
o α-methyldopa analogue to Dopa forming methylnephrine which is
false transmitter of Nor-epinephrine so loss of functions.

2) Storage & release of Nor-adrenaline:

o In nerve cells, Nor-epinephrine is stored in Synaptic Vesicles along with ATP.
(in Adrenal medulla Chromaffin Cells)
o Action potential arrives, Ca+2 inflow is enhanced so granules release Nor-
epinephrine by exocytosis in synaptic cleft.
o There is a self regulatory/Feed Back mechanism in Nor-epinephrine release.
o Other Neuromodulators, Ach, Nor-epinephrine (NE), Epinephrine, 5-HT, PGE,
Histamine, Dopamine, & ATP decreases Nor-epinphrine release through
various specific responses.

Autoregulation how it occurs?

NE released in Synapse combines with Presynaptic α-2 Receptor no formation of
cAMP closing of Ca+2 gated channels & resultant failure of exocytosis.

3) Destruction/Disposition of Nor-adrenaline:
Enzymes:
In mitochondria Liver & Intestinal epithelium

MAO (intracellular)
Axoplasmic degradation in Adrenergic Nerve Terminal

COMT (extracellular) neural and Non-neural tissues (circulatory degradation)

Pheocytochroma:- Tumour of Adrenal gland

MAO Antidepressent action

Termination of action of NE is mainly by reuptake of NE into Presynaptic Vesicles. From

where
a. 60% reuptake into vesicles (as it was)
b. 20% reuptake into Extraneural tissues & enzymatic breakdown by COMT
c. 5% bind with receptors
d. 15% metabolised by MAO.

By Dr. H. B. Patel & Satyajeet Singh ~ 12 ~

Class Notes- VPT 321

Noradrenergic transmission

Transmitter synthesis involves the following.

o L-tyrosine is converted to dihydroxyphenylalanine (dopa) by tyrosine hydroxylase
(rate-limiting step). Tyrosine hydroxylase occurs only in catecholaminergic neurons.
o Dopa is converted to dopamine by dopa decarboxylase.
o Dopamine is converted to noradrenaline by dopamine β-hydroxylase (DBH), located
in synaptic vesicles.
o In the adrenal medulla, noradrenaline is converted to adrenaline by
phenylethanolamine N-methyl transferase.
Transmitter storage: noradrenaline is stored at high concentration in synaptic vesicles,
together with ATP, chromogranin and DBH, all of which are released by exocytosis.
Transport of noradrenaline into vesicles occurs by a reserpine -sensitive transporter.
Noradrenaline content of cytosol is normally low due to monoamine oxidase in nerve
terminals.
Transmitter release occurs normally by Ca2+-mediated exocytosis from varicosities on the
terminal network. Non-exocytotic release occurs in response to indirectly acting
sympathomimetic drugs (e.g. amphetamine), which displace noradrenaline from vesicles.
Noradrenaline escapes via uptake 1 (reverse transport).
Transmitter action is terminated mainly by transporter-mediated reuptake of noradrenaline
into nerve terminals (uptake 1). Uptake 1 is blocked by tricyclic antidepressant drugs and
cocaine.
Noradrenaline release is controlled by autoinhibitory feedback mediated by α2 receptors.
Cotransmission occurs at many noradrenergic nerve terminals, ATP and neuropeptide Y
being frequently coreleased with NA. ATP mediates the early phase of smooth muscle
contraction in response to sympathetic nerve activity

Receptors of ANS

1. Cholinergic Receptor (Cholinoreceptor)

2. Adrenergic Receptor (Adrenoreceptor/sympathetic Receptor)

By Dr. H. B. Patel & Satyajeet Singh ~ 13 ~

Class Notes- VPT 321

1. Cholinergic Receptors

Cholinergic
Receptor

Muscarinic Nicotinic

Muscle
M1 M2 M3 M4 M5 Type (Nm) Neuronal
Type (Nn)
-on
Skeletal - on
muscle Neuronal
tissues

o Muscarinic Muscarine (alkaloid obtained from mushroom Amontia

muscaria)
o Nicotinic Nicotine (alkaloid obtained from leaves of Nicotiana tabacum)
o Muscarinic receptors (mAChR) are G-protein Coupled Receptors (M1. M3,
M5 activates Gs while M2, M4 activates Gi)
o Nicotinic receptors (nAChR) are Ligand Gated Ion Channels, activation of
which results in depolarization & excitation.
o G-protein coupled receptors (GPCRs) also called 7TM (7 Transmembrane
receptor) is the family of Transmembrane Receptors.

I. Nicotinic Receptors: (nAChR)

Mechanism of action of Nicotinic Receptors:

Nicotinic Receptors combine with Ligand Gated Ion Channels

Ach binding induces conformational changes in Receptor proteins

Pore is created

Na+ enters via pores

Depolarization

Contraction of skeletal muscle

Stimulation of Postganglionic Nerve
Secretion of Adrenaline from adrenal medulla
Usually these Nicotinic Receptors do not respond to low dose of Ach.
Nicotinic Receptor produces effect exactly like consumption of Nicotine.

By Dr. H. B. Patel & Satyajeet Singh ~ 14 ~

Class Notes- VPT 321

Nicotinic Receptor
Agonist Antagonist
type
d- Tubocurarine
Acetylcholine
Pancuronium
Carbachol
Nm
Atracuronium
Suxamethonium
α-Bungarotoxin
Decamethonium
Trimethaphan
Acetylcholine
Mecamylamine
Carbachol
Nn
Hexamethonium
Cobeline

Cytisine(Baphitoxin/Sophorine)

II. Muscarinic Receptors: (mAChR)

Five types:
Nature
of Location Effect
Receptor
o Autonomic ganglion,
M1 o Gastric glands, Adrenaline & HCl secretion
excitatory
o CNS
o Heart, Heart rate,
M2 o GIT, Force of contraction,
inhibitory
o CNS NE release
o contraction of
bronchiole & GIT but
o Smooth muscles of viscera exception in blood
(Bronchi, GIT, Urinary vessels where relaxation
M3 excitatory tract & Blood vessels) i.e. dilatation
o Glands o stimulate salivary,
bronchial, lacrimal &
sweat gland
o Lungs
M4 inhibitory o CNS
o Eyes
M5 o Salivary glands
excitatory
o CNS

Mechanism of Action of M1, M3, M5:

By Dr. H. B. Patel & Satyajeet Singh ~ 15 ~

Class Notes- VPT 321

M1, M3, M5 stimulate the GPCRs (Gs)

Activation of Phospholipase C

Increase in the concentration of

Inositoltriphophate (IP3)

Increase in the concentration of Diacyl Glycerol (DAG)

( Conc. Of DAG Ca+2 concentration contraction of smooth muscles
secretion of gland)

Activation of Protein Kinase C

Further biological response

Mechanism of Action of M2, M4:

M2 & M4 stimulate the GPCRs (Gi)

Inhibit Adenylcyclase

K+ channels become activated

Ca+2 channels blocked

Negative effect on the heart rate & contraction

G-Protein Coupled Receptors
Agonist + Receptor ------ Binding

Phospholipase C

Phospholipids Phospholipase C IP3 + DAG

( Ca+2 releases from ER) (Stimulate protein
Kinase C)

Agonist Antagonist

Acetylcholine
Pirenzepine
M1 Oxotremorine

By Dr. H. B. Patel & Satyajeet Singh ~ 16 ~

Class Notes- VPT 321

Gallamine
M2 methacholine
Himbacine
M3 Bethanechol

Acetylcholine receptors

Main subdivision is into nicotinic (nAChR) and muscarinic (mAChR) subtypes.

nAChRs are directly coupled to cation channels, and mediate fast excitatory synaptic
transmission at the neuromuscular junction, autonomic ganglia, and various sites in the
central nervous system (CNS). Muscle and neuronal nAChRs differ in their molecular
structure and pharmacology.

mAChRs and nAChRs occur presynaptically as well as postsynaptically, and function to

regulate transmitter release.

mAChRs are G-protein-coupled receptors causing:

o activation of phospholipase C (hence formation of inositol trisphosphate and

diacylglycerol as second messengers)

o inhibition of adenylyl cyclase

o Activation of potassium channels or inhibition of calcium channels.

mAChRs mediate acetylcholine effects at postganglionic parasympathetic synapses (mainly

heart, smooth muscle, glands), and contribute to ganglionic excitation. They occur in many
parts of the CNS.

Three main types of mAChR occur.

o M1 receptors ('neural') producing slow excitation of ganglia. They are selectively

blocked by pirenzepine.

o M2 receptors ('cardiac') causing decrease in cardiac rate and force of contraction

(mainly of atria). They are selectively blocked by gallamine. M2 receptors also
mediate presynaptic inhibition.

o M3 receptors ('glandular') causing secretion, contraction of visceral smooth muscle,

vascular relaxation.

M4 and M5, occur mainly in the CNS.

All mAChRs are activated by acetylcholine and blocked by atropine.

2. Adrenergic Receptors

2 types and many subtypes

By Dr. H. B. Patel & Satyajeet Singh ~ 17 ~

Class Notes- VPT 321

Adrenergic Receptor

α β

α1 α2 β1 β2 β3

α2-inhibits Adenylcyclase
all β subtypes stimulates Adenylcyclase (producing cAMP & protein kinase- A)

Recept
Agonist antagonist Location Effect
or

Smooth
Vasoconstriction
muscles of
Blood vessels, Constriction of
Uterus
Bronchi,
Uterus Relaxation of GIT
muscle
α1 Phenylephrine Prazosin Sphincter
muscle of GIT Constriction of
Urinary Bladder
Sphincter
muscle of Secretion of Gland
urinary system Constriction of Iris
Iris Radial Radial muscle
muscle
Relaxation of GIT
muscle
Constriction of
GIT smooth vascular smooth
muscles muscle
Blood vessels Decrease insulin
α2 Clonidine Yohimbine secretion from β-
β cells of
cells of pancrease.
pancrease
Inhibition of NT
Brain stem
release
Platelets
Produce platelet
aggregation

Heart
Increase Heart Rate
Salivary
β1 Dobutamine Metoprolol Increase Rennin
glands
secretion.
JG cells of
kidney

By Dr. H. B. Patel & Satyajeet Singh ~ 18 ~

Class Notes- VPT 321

Bronchodialation
Vasodilation
Bronchi Relaxation of GIT
Blood vessels Relaxation of uterus
β2 Terbutaline Butoxamine GIT & urinary bladder
Uterus Hepatic
Urinary glycogenolysis
bladder Inhibition of
Histamine release
β3 Lipolysis
Adipose tissue

Note: β-blockers are used to reduce performance related anxiety. E.g. Diazepam (β-
blocker)

All α-Receptors are : Excitatory (except in GIT)

All β-Receptors are : Inhibitory (except in Heart)

Classification of adrenoceptors

Main pharmacological classification into α and β subtypes, based originally on order of

potency among agonists, later on selective antagonists.
Adrenoceptor subtypes:
o two main α-receptor subtypes, α1 and α2, each divided into three further subtypes
o three β-adrenoceptor subtypes (β1, β2, β3)
o All belong to the superfamily of G-protein-coupled receptors.
Second messengers:
o α1-receptors activate phospholipase C, producing inositol trisphosphate and
diacylglycerol as second messengers
o α2-receptors inhibit adenylate cyclase, decreasing cAMP formation
o All types of β-receptor stimulate adenylyl cyclase.
The main effects of receptor activation are as follows.
o α1-receptors: vasoconstriction, relaxation of gastrointestinal smooth muscle, salivary
secretion and hepatic glycogenolysis
o α2-receptors: inhibition of transmitter release (including noradrenaline and
acetylcholine release from autonomic nerves), platelet aggregation, contraction of
vascular smooth muscle, inhibition of insulin release
o β1-receptors: increased cardiac rate and force
o β2-receptors: bronchodilatation, vasodilatation, relaxation of visceral smooth muscle,
hepatic glycogenolysis and muscle tremor

o β3-receptors: lipolysis

By Dr. H. B. Patel & Satyajeet Singh ~ 19 ~

Class Notes- VPT 321

Non-peptide Mediators: 5-Hydroxytryptamine, Dopamine, GABA, NO

Peptide Mediators: Neuropeptide, VAP (Vaso active peptides), GnRH, substance-P,

CGRPb (Calcitonin Gene Related Peptide beta), Opoid peptides.

----------------------------@@@@@@-------------------

Some Toxins act Ion Channels.

Channel Types Mode of Toxin Action Source

Voltage-gated
Sodium channels
Tetrodotoxin (TTX) Blocks channel from outside Puffer fish
Batrachotoxin (BTX) Slows inactivation, shifts activation Colombian frog
Potassium channels
Apamin Blocks "small Ca-activated" K Honeybee
channel
Charybdotoxin Blocks "big Ca-activated" K channel Scorpion
Calcium channels
Omega conotoxin ( -CTX- Blocks N-type channel Pacific cone snail
GVIA)
Agatoxin ( -AGA-IVA) Blocks P-type channel Funnel web spider
Ligand-gated
Nicotinic ACh receptor
α-Bungarotoxin Irreversible antagonist Marine snake
GABAA receptor

Picrotoxin Blocks channel South Pacific

plant
Glycine receptor
Strychnine Competitive antagonist Indian plant
AMPA receptor
Philanthotoxin Blocks channel Wasp

By Dr. H. B. Patel & Satyajeet Singh ~ 20 ~

Class Notes- VPT 321

Autonomic drugs

Sympathetic Nervous Parasympathetic

System Drugs Nervous System Drugs

Sympathomimetic Sympatholytic
Drugs Drugs
or or
Adrenomimetic Antiadrenergic
Drugs Drugs
or or
Adrenergic Drugs Adrenoreceptor
antagonist Drugs
or
or
Adrenergic agonist
Drugs Adrenergic
antagonist Drugs
or
or
Sympathoplegic
drugs

Parasympathomimetic
Drugs Parasympatholytic
or Drugs
Cholinomimetic Drugs or
or Cholinolytic
Cholinergic agonist Drugs
Drugs or
or Cholinergic
Cholinergic Drugs antagonist Drugs
or or
Cholinoreceptor agonist Anticholinergic
Drugs Drugs

By Dr. H. B. Patel & Satyajeet Singh ~ 21 ~

Class Notes- VPT 321

Sympathomimetic Drugs

Drugs which mimic the action of sympathetic nervous system are called as
sympathomimetics.
They produce effect similar to epinephrine or norepinephrine on animal body.
These drugs mediate their action through adrenoreceptors (α & β) so they are called
as adrenergic drugs.
These adrenergic drugs are classified into 3 categories:
1. Direct acting
2. Indirect acting
3. Mixed acting

1. Direct acting
Drugs which directly act on α & β receptors. These are classified as
1) α- Agonist
2) β- Agonist
3) Mixed Agonist

1) α- Agonist: Drugs which selectively act on α- Receptor.

It includes:

a) α1 Agonist:
E.g. Phenylephrine
Methoxamine
Cirazoline
Xylometazoline
Noradrenaline
Phenylephrine & Methoxamine produce constriction of bronchiole. So used
in nasal decongestant (in cold, allergy, inflammation, pain in nasal tract) and
hypotensive crisis (severe fall in B.P).

b) α2 Agonist:
E.g. Clonidine
Xylazine
Guanafacine
Guanabenz
Detomidine
Remifidine
Oxymetazoline
These drugs are used in chronic diarrhoea to reduce frequency of diarrhoea
because in chronic diarrhoea nerves get damage so motility of GIT increases.
These drugs reduce tone and motility of GIT due to relaxation of GI smooth
muscles & constriction of sphincter.

By Dr. H. B. Patel & Satyajeet Singh ~ 22 ~

Class Notes- VPT 321

2) β- Agonist: Drugs which selectively act on β- Receptor.

It includes:

a) β1 Agonist:
E.g. Dobutamine
Isoproterenol
These stimulate heart so used in cardiac failure.

b) β2 Agonist:
E.g. Terbutaline
Salbutamol
Retodrine
Metaproterenol
Terbutaline & Salbutamol act in bronchiole & produce inhibitory effect so,
bronchiole dialates & animal get relief from cough, asthma etc. So they are
common in cough syrup.
Retodrine is used in females in premature labour. (as Tocolytic drug)

c) Mixed agonist: drugs which non selectively act on α & β receptor.

2. Indirect acting:
They act indirectly on α & β receptors.
E.g. Amphetamine
Tyramine
Amphetamine is used in hypotensive crisis.
Amphetamine is misused to reduce body weight in humans.
Amphetamine and tyramine are used in ADHD (Attention Deficit Hyperactivity
Disorder.) E.g. DYSLAXIA in which person know everything but not able to
express.

3. Mixed acting:
They can act both directly and indirectly.
E.g. Ephedrine
Mephetramine
Metraminol
Mephetramine is used in hypotensive crisis.
Relative Selectivity of Adrenoceptor Agonists

Relative Receptor Affinities

Alpha agonists

By Dr. H. B. Patel & Satyajeet Singh ~ 23 ~

Class Notes- VPT 321

Phenylephrine, methoxamine α1 > α2 >>>>> β

Clonidine, methylnorepinephrine α2 > α1 >>>>> β

Mixed alpha and beta agonists

Norepinephrine α1 = α2; β1 >>β2

Epinephrine α 1 = α 2; β 1 = β 2

Beta agonists

Dobutamine1 β1 > β2 >>>> α

Isoproterenol β1 = β2 >>>> α

Terbutaline, metaproterenol, albuterol, ritodrine β2 >> β1 >>>> α

Dopamine agonists

Dopamine D1 = D2 >> β>> α

Fenoldopam D1 >> D2

Distribution of Adrenoceptor Subtypes & Their Action

Type Tissue Actions

Most vascular smooth muscle (innervated) Contraction
Pupillary dilator muscle Contraction (dilates pupil)
α1
Pilomotor smooth muscle Erects hair
Prostate Contraction
Heart Increases force of contraction
Postsynaptic CNS adrenoceptors Probably multiple
α2
Platelets Aggregation
Adrenergic and cholinergic nerve terminals Inhibition of transmitter release

By Dr. H. B. Patel & Satyajeet Singh ~ 24 ~

Class Notes- VPT 321

Some vascular smooth muscle Contraction

Fat cells Inhibition of lipolysis
β1 Heart Increases force and rate of
contraction
Respiratory, uterine, and vascular smooth Promotes smooth muscle relaxation
muscle
β2
Skeletal muscle Promotes potassium uptake
Liver Activates glycogenolysis
β3 Fat cells Activates lipolysis

D1 Smooth muscle Dilates renal blood vessels

D2 Nerve endings Modulates transmitter release

Effect of Sympathomimetic Drugs on various systems:

1. Cardio Vascular system:

Heart rate (Positive Chronotropic effect)
Cardiac Output
Force of Contraction (Positive Inotropic effect)

2. Blood pressure:
At lower dose or slow infusion B.P

At higher dose or rapid infusion B.P

Lower dose B.P

Higher dose B.P

Above phenomenon is called as “Dale Re e al Phe e ” or

“Epinephrine Reversal”. (Epinephrine causes increase in B.P, which is followed
by decrease in B.P)
Reason of this phenomenon:
There are 2 types of receptor for the epinephrine-α & β.
α are excitatory for B.P (B.P )
β are inhibitory for B.P (B.P )
Numbers of receptors α >β
By Dr. H. B. Patel & Satyajeet Singh ~ 25 ~
Class Notes- VPT 321

Affinity of epinephrine α <β

The rise in the B.P is mediated by α-receptors as these are more in number than more
powerful & sensitive β-receptors in blood vessels. Here though β-receptors are
occupied by the drug, there effect is suppressed by activation of large number of α-
receptors.
As concentration of epinephrine is decreased by metabolism or elimination, it
dissociates first from less sensitive α-receptors. So at later stage, the numbers of
activated β-receptors remain more than activated α-receptors which causes decrease in
B.P.

If α-receptors are blocked, than B.P decreases on giving epinephrine

3. Respiratory system:
Bronchodialation by β2 receptors

4. Uterus:
By α1 & β2 receptors
Effect on uterus depends on species and stage of pregnancy.
In non pregnant uterus, it will produce the contraction.
In the last trimester of pregnancy, it will produce the relaxation of uterine muscles
that’s why it used in the treatment of premature labour. (Post partum
complication).

5. Gastrointestinal tract:
By α2 & β2 receptors
More prominent is α2
Relaxes GIT smooth muscles.
Reduces GIT motility.
Reduces gland secretion.
Facilitates contraction of sphincters.

6. Urinary bladder:
Decreases secretion due to relaxation of smooth muscles of bladder.
By Dr. H. B. Patel & Satyajeet Singh ~ 26 ~
Class Notes- VPT 321

7. Eye:
By α1 receptors
Produce dilation of pupil (mydriasis) due to contraction of radial iris muscles.
Decreases intraocular pressure especially in glaucoma

Iris Radial muscle

Iris Circular muscle

8. Effect on metabolism:
Hyperglycaemia
Hyperlipaemia
Decrease insulin secretion (α2)

9. Effect on skeletal muscles:

Increase force of contraction.
Increase thermogenesis

10. Central Nervous System:

Stimulate PNS
Restlessness
Headache
Tremor

11. Effect on other glands:

Contraction of spleen release of RBCs in circulation
Contraction of pilomotor muscle of hair follicle

Pharmacokinetics:
Though epinephrine is absorbed from the GIT, but its bioavailability is poor because it
is rapidly degraded in the intestinal wall & liver. (By MAO & COMT)

Clinical uses of adrenergic drugs:

1) For prolongation of action of local anaesthesia.
2) Used in local haemostasis.
3) Used in allergy (α1)
4) Cardiac stimulant

By Dr. H. B. Patel & Satyajeet Singh ~ 27 ~

Class Notes- VPT 321

5) Nasal decongestant. E.g. Oxymetazoline (α1)

6) In cardiac arrest. E.g. Adrenaline (β1)
7) Cardiogenic shock. E.g. Dobutamine (β1)
8) In the treatment of asthma and cough (as bronchodialator) (β2) E.g. salbutamol,
terbutaline.
9) Decrease histamine release from mast cells & help in the treatment of anaphylaxis.
E.g. sting bite
--------------------------------------------------------------------------------------------

Sympatholytic Drugs
Drugs which inhibit the effect of sympathetic neurotransmitters.
Also called adrenoreceptor blockers.
Generally known as antiadrenergic drugs.

Classification:
Mixed α1 & α2 blockers:
Phenoxybenzamine
Phentalomine
Tolazosin
Mixed β1 & β2 blockers:
Propranolol
Nadolol
Timolol
Phenbutolol

Effects:

α1 receptor blocker : B.P

α2 receptor blocker: insulin secretion
β1 receptor blocker: Heart rate
β2 receptor blocker: dilate coronary artery

By Dr. H. B. Patel & Satyajeet Singh ~ 28 ~

Class Notes- VPT 321

sympatholytics

Adrenergic Inhibition of Drug which

receptor norepinephrine Drug which interfere with
antagonist synthesis interfere with nor
nor epinephrine
e.g. epinephrine release
Metyhyldopa storage
Carbidopa
e.g. Bretylium
α-Methyltyrosine e.g. Reserpine
Guanethidine

α Blocker β Blocker

α1 antagonist
β1 antagonist

e.g.
e.g.
Prazosin
Atenolol
Terazosin
Doxazosin Esmolol
Trimazosin Metoprolol
Proctolol

α2 antagonist
β2 antagonist
e.g.
Yohimbine e.g.
Atipamezole Butoxamine

Relative Selectivity of Antagonists for Adrenoceptors

Receptor Affinity
α Antagonists
α1 >>>> α2
Prazosin, terazosin, doxazosin

α1 > α2
Phenoxybenzamine

By Dr. H. B. Patel & Satyajeet Singh ~ 29 ~

Class Notes- VPT 321

α1 = α2
Phentolamine

α2 >> α1
Yohimbine, tolazoline

Mixed antagonists
β1 = β2 ≥ α1 > α2
Labetalol

β Antagonists
β1 >>> β2
Metoprololol, atenolol, esmolol

β1 = β2
Propranolol, pindolol, timolol

β2 >>> β1
Butoxamine

Use of α receptor blockers:

Diagnosis and treatment of pheochromocytoma.

E.g. Phenoxybenzamine
Phentalomine
Tolazosin
Used in high B.P.
Use of β receptor blocker:

In hypertension, angina, cardiac arrhythmia, anxiety, tremor and glaucoma.

In treatment of hyperthyroidism.

Labetalol:

Mixed α & β receptor antagonist.

Used in hypertensive crisis

Propranolol:

Mixed β blocker
Used in ventricular fibrillation
In performance related anxiety
Dose in dog is @ 1mg/kg/day.

Methyldopa:

By Dr. H. B. Patel & Satyajeet Singh ~ 30 ~

Class Notes- VPT 321

It inhibits the conversion of dopamine to adrenaline by combining with the enzyme,

which is involving in converting dopamine to adrenaline.
Methy ldopa is used in the treatment of parkinson’s disease.

Reserpine:
It is an alkaloid obtained from Rauwolfia serpentina.
Reserpine block the uptake of catecholamines (epinephrine and norepinephrine) ,
serotonin & dopamine into synaptic vesicle by blocking the VMAT(Vesicular
Membrane-Associated Transporter) in the both CNS & PNS.
It inhibit uptake of noradrenaline or adrenaline into vesicles so, norepinephrine
remain in cytosol where it degraded by MAO.

Effects of reserpine:
It initially increases B.P then follow decrease in B.P
Used in hypertension (antihypertensive drug)
Antiserotonin, antidopamine
May cause sedation by depleting storage of catecholamines & serotonin.

Action:
Reserpine enter into neuron & break the vesicle so, no adrenaline is stored in the
vesicles.
-----------------------------------------------------------------------------
-------

By Dr. H. B. Patel & Satyajeet Singh ~ 31 ~

Class Notes- VPT 321

Parasympathomimetic Drugs
Drugs which produce Ach like action.
Generally known as cholinergic drugs

Out of two cholinergic receptors, nicotinic receptors are activated at very higher dose
while muscarinic receptors are activated at very lower dose.
Due to this reason anticholinergic drugs are often called as antimuscarinic drugs.
Antinicotinic drugs are often not used.

Cholinergic drugs

Indirect acting
Direct acting
(Act via inhibition of
(Act on N and M receptor) AChE)

Natural Reversible Agent

e.g. e.g.
Muscarine
Neostigmine
Arecoline
Physostigmine
Pilocarpine
Pyridostigmine
Nicotine
Edrophonium

Synthetic Irreversible Agent

e.g. e.g.
Acetylcholine Organophosphate
Methacholine
compounds
Bethanechol
Carbamates (malathion,
Carbachol parathion)

By Dr. H. B. Patel & Satyajeet Singh ~ 32 ~

Class Notes- VPT 321

Effect of Directly acting cholinomimetic drugs on various systems:

A. Muscarinic effect:

1. Heart/CVS:
Heart rate
Cardiac output
Blood pressure (Hypertension)
Vasodialation

2. Gastrointestinal tract:
GIT motility
Secretion

3. Respiratory system:
Bronchoconstriction
Tracheobronchial secretion

4. Urinary tract:
Contract urinary bladder & uterus & facilitate micturition.

5. Endocrine system:
Sweating
Salivation
Lacrimation

6. Eye:
Produce contraction of pupil (miosis) due to contraction in iris circular
muscles.

7. Male sex organ:

Erection of penis

8. CNS:
Muscular tremor/ fasciculations
Hypothermia
Effects of Direct-Acting Cholinoceptor Stimulants
Organ Response
Eye
Sphincter muscle of iris Contraction (miosis)

By Dr. H. B. Patel & Satyajeet Singh ~ 33 ~

Class Notes- VPT 321

Ciliary muscle Contraction for near vision

Heart
Sinoatrial node Decrease in rate (negative chronotropy)
Atria Decrease in contractile strength (negative inotropy).
Decrease in refractory period
Atrioventricular node Decrease in conduction velocity (negative dromotropy).
Increase in refractory period
Ventricles Small decrease in contractile strength
Blood vessels
Arteries Dilation (via EDRF)
Veins Dilation (via EDRF
Lung
Bronchial muscle Contraction (bronchoconstriction)
Bronchial glands Stimulation
Gastrointestinal tract
Motility Increase
Sphincters Relaxation
Secretion Stimulation
Urinary bladder
Detrusor Contraction
Trigone and sphincter Relaxation
Glands
Sweat, salivary, lacrimal, Secretion
nasopharyngeal

EDRF: endothelium-derived relaxing factor

B. Nicotinic effect:
At higher dose of acetylcholine
Stimulation of autonomic ganglia.
Stimulation of adrenaline secretion.
Increase in B.P (Hypertension)
Skeletal muscle fasciculation.
If drug persist for long time, paralysis occur.

Note: due rapid destruction & hydrolysis of Ach by endogenous esterases, it is not
used therapeutically.

By Dr. H. B. Patel & Satyajeet Singh ~ 34 ~

Class Notes- VPT 321

Behtanechol:
Structurally related to Ach.
Very little nicotinic effect.
Strong Muscarinic effect.
Not hydrolysed by AchE but not by other esterases enzymes.
Uses:
Measure effect on smooth muscle & GIT producing contraction.
Promote micturition & defaecation.

Carbachol:
Structurally related Ach.
Both Muscarinic & nicotinic effect.
Poorly hydrolysed by AchE but slowly hydrolysed by other esterase enzyme.
Uses:
It has open effect on CVS & GIT.
Produce miosis. Sometime used as ophthalmic solution (0.01%) to reduce
intraocular pressure in glaucoma.
In Intestinal colic, ruminal colic & impaction.
Note: Carbachol is very rarely used for therapeutic purpose because of high potency
& longer duration of action.

Pilocarpine:
Obtained from plant Pilocarpus microphyllus.
It has only Muscarinic effect.
It is used in treatment of wide angle glaucoma to reduce intraocular pressure
producing contraction of cilliary muscle.

Arecholine:
Obtained from seeds of Areca catechu (Beetle nut).
Both Muscarinic & nicotinic effect.
Used in the treatment of taeniasis in dog.

Muscarine:
Obtained from mushroom Amanita muscaria.
It has only muscarinic effect.

Indirectly acting cholinomimetic drugs / indirectly acting

Antiacetylcholinesterase agents:
These are indirectly acting parasympathomimetic agents.
They inhibit AchE enzyme resulting acculation of Ach at cholinergic effector site.
All of the cholinesterase inhibitors increase the concentration of endogenous
acetylcholine at cholinoceptors by inhibiting acetylcholinesterase.

By Dr. H. B. Patel & Satyajeet Singh ~ 35 ~

Class Notes- VPT 321

Indirectly acting drugs are of two types:

I.Reversible inhibitors:
They bind to the active site of the AchE enzyme reversibly to act as an alternate
substrate for AchE enzyme, this result in inhibition of hydrolysis of Ach.
E.g. Neostigmine
Physostigmine
Pyridostigmine
Edrophonium
II.Irreversible inhibitors:
They bind to the esteratic site of the AchE enzyme resulting in formation of an
irreversible (or very highly stable) complex which cannot hydrolyse Ach.
E.g. Organophosphate compounds.
Carbamates (Malathion, Parathion)
Aging of Ach:
Aging" is due to the loss of one alkoxy group, leaving a much more stable monoalkyl-
or monoalkoxy-phosphoryl-AchE & AchE enzyme become totally resistant to
hydrolysis.
This produces more stable form of AchE enzyme.
The rate of aging varies with the particular organophosphate compound. If given
before aging has occurred, strong nucleophiles like pralidoxime are able to break the
phosphorus-enzyme bond and can be used as "cholinesterase regenerator" drugs for
organophosphate insecticide poisoning. Once aging has occurred, the enzyme-
inhibitor complex become more stable and is more difficult to break, even with oxime
regenerator compounds.
Clinical uses of Anticholinesterase Agents:
1. To antagonize curare. (e.g edrophonium, pyridostigmine)
This increases strength of contraction, especially in muscles weakened by
curare-like neuromuscular blocking agents or by myasthenia gravis.
Curare:
It is a plant alkaloid which blocks Neuromuscular Junction and produce
muscular relaxation.
Earlier time used as arrow poison.

2. To treat Glaucoma:
To reduce intraocular pressure
E.g. Physostigmine (0.5-1.0% solution)
3. In Ruminal impaction:
E.g. Physostigmine (cattle= 30-45 mg S/C inj.)
4. In Myasthenia gravis:
It is muscular weakness of nervous origin
E.g. Physostigmine or Neostigmine

By Dr. H. B. Patel & Satyajeet Singh ~ 36 ~

Class Notes- VPT 321

5. In snake Bite: (especially in cobra bite)

Venom has curare like effect.
[Neostigmine+Atropine] is given to prevent respiratory paralysis.

Malicious poisoning/Organophosphate poisoning:

1. Poisoning which is performed as an act of malafied intension.
2. In this poisoning Muscarinic & Nicotinic receptors are destroyed.
Treatment:
1. Atropine sulphate
It has Antimuscarinic effect.
2. Cholinesterase Regenerator Compounds
Capable of regenerating active enzyme from the organophosphorus-
cholinesterase complex, is also available to treat organophosphorus poisoning.
These oxime agents include:
Pralidoxime (PAM),
Diacetylmonoxime (DAM),
Mono Iso Nitro Amide (MINA)

The oxime group (=NOH) has a very high affinity for the phosphorus atom,
and these drugs can hydrolyze the phosphorylated enzyme if the complex has
not "aged".
PAM is most effective in regenerating the cholinesterase associated with
skeletal muscle neuromuscular junctions. Pralidoxime is ineffective in
reversing the central effects of organophosphate poisoning because its positive
charge prevents entry into the central nervous system.
DAM, on the other hand, crosses the blood-brain barrier and, can regenerate
some of the central nervous system cholinesterase.
Monoxime are not recommended in carbamate poisoning because
carbamide inhibitor act on AchE enzyme irreversibly & are contraindicated
Dose of PAM:
Dog: 10-20 mg/kg
Horse: 20 mg/kg
Sheep & Goat: 25 mg/kg

By Dr. H. B. Patel & Satyajeet Singh ~ 37 ~

Class Notes- VPT 321

Parasympatholytics

Agents which prevent Ach from producing its characteristic effect.

These drugs inhibit the effect of Ach, mainly the Muscarinic action & other
cholinomimetic drugs.
These parasympatholytic drugs are also called muscarinolytic or
antimuscarinic drugs because they produce selective effect on Muscarinic
receptor at therapeutic dose.
Nicotinic receptor antagonist also blocks the certain action of Ach. They are
generally referred to as ganglionic blocker or neuromuscular blocker.

Parasympatholytics

Synthetic
e.g.
Natural alkaloid Glycopyrolate
Semi-synthetic
e.g. Dicyclomin
E.g.
Atropine Cyclopentamine
Homatropine
Scopolamine Isopropamide
Oxyphencyclimine
Propanetheline

Source & Chemistry:

1. Atropine (hyoscyamine) is found in the plant Atropa belladonna, or deadly

nightshade, and in Datura stramonium, also known as jimsonweed (Jamestown
weed), sacred Datura, or thorn apple.
2. Scopolamine (hyoscine) occurs in shrub Hyoscyamus niger, or henbane, as the l(-)
stereoisomer. Naturally occurring atropine is l(-)-hyoscyamine, but the commercial
material is racemic d,l-hyoscyamine.
3. The l(-) isomers of both alkaloids are at least 100 times more potent (Antimuscarinic
activity) than the d(+) isomers.

Pharmacological effects of Muscarinic receptor blocking drugs on various

systems:

By Dr. H. B. Patel & Satyajeet Singh ~ 38 ~

Class Notes- VPT 321

1. Cardio Vascular System:

At low dose of atropine decrease heart rate followed by increase heart rate.
Rapid injection of atropine increase heart rate followed by sudden fall in Heart rate
(or B.P)

2. Gastrointestinal tract:
Atropine produces sooth uscle relaxation.
Dercreases ruminal activity.
Atropine is used as antihypermitilitic drug.

3. Glands:
Decrease salivary secretion
Decrease lacrimal secretion

4. Respiratory system:
Atropine decreases bronchial secretion. Antimuscarinic drugs are
frequently used prior to administration of inhalant anesthetics to reduce the
accumulation of secretions in the trachea and the possibility of laryngospasm.
Atropine dialate bronchioles.

5. Eye:
Produce dilation of pupil (mydriasis) & cycloplegia (paralysis of ciliary muscles)
due to relaxation of circular iris muscles.

6. Urinary tract:
Atropine is used in relaxation of urinary tract muscle & slows voiding of
urine.
Useful for urinary/renal spasmolytic colic.

7. Central Nervous System:

In toxic doses, scopolamine and to a lesser degree atropine can cause
excitement (stimulatory effect), agitation, hallucinations, and coma.
Atropine at therapeutic dose, produce minimal stimulant effects on the
central nervous system & sedative effect on the brain.

8. Sweat glands:
Atropine suppresses thermoregulatory sweating. So produce anhydrotic effect
(loss of sweating) and produce hyperthermia.
These effects are not observed in horse.
In human, in adults, body temperature is elevated by this effect only if large
doses are administered, but in infants and children even ordinary doses may
cause "atropine fever."

9. Other effects:
By Dr. H. B. Patel & Satyajeet Singh ~ 39 ~
Class Notes- VPT 321

Atropine produces hyperpyrexia particularly at higher dose.

These effects are not observed in horse.

Clinical Pharmacology of the Muscarinic Receptor-Blocking Drugs:

1. Central nervous system disorders:

In parkinson’s disease
In motion sickness

2. Opthalmic examination:
Accurate measurement of refractive error requires ciliary paralysis. Also,
ophthalmoscopic examination of the retina is greatly facilitated by mydriasis.
Therefore, antimuscarinic agents, administered topically as eye drops or
ointment, are very helpful in doing a complete examination
Antimuscarinic drugs should never be used for mydriasis unless cycloplegia
or prolonged action is required. Alpha-adrenoceptor stimulant drugs, eg,
phenylephrine, produce a short-lasting mydriasis that is usually sufficient for
funduscopic examination
Homatropine is 10 times less potent than atropine sulphate and used as
mydriatic agent.

3. Respiratory disorder:
In asthma (e.g. Ipratropium, a synthetic analogue of atropine)
In COPD (Chronic Obstructive Pulmonary Disorder)

4. Gastrointestinal disorders:
Antidiarrhoeal agent in ruminants

5. Cardiovascular disorder:
In myocardial infarction

6. Urinary disorders:
In urinary colic

7. Atropine is used as preanaesthetic medication (antisialogogue)

8. In cholinergic poisoning:
Antimuscarinic therapy
Cholinesterase Regenerator Compound: capable of regenerating active
enzyme from the organophosphorus-cholinesterase complex, is also available
to treat organophosphorus poisoning. These oxime agents include
pralidoxime (PAM), diacetylmonoxime (DAM), and Mono Iso Nitro Amide
(MINA).

By Dr. H. B. Patel & Satyajeet Singh ~ 40 ~

Class Notes- VPT 321

The oxime group (=NOH) has a very high affinity for the phosphorus atom,
and these drugs can hydrolyze the phosphorylated enzyme if the complex has
not "aged".
Pralidoxime is most effective in regenerating the cholinesterase associated
with skeletal muscle neuromuscular junctions. Pralidoxime is ineffective in
reversing the central effects of organophosphate poisoning because its positive
charge prevents entry into the central nervous system. Diacetylmonoxime, on
the other hand, crosses the blood-brain barrier and, in experimental animals,
can regenerate some of the central nervous system cholinesterase.
In excessive doses, pralidoxime can induce neuromuscular weakness and other
adverse effects. Pralidoxime is not recommended for the reversal of inhibition
of acetylcholinesterase by carbamate inhibitors.

Mushroom poisoning has traditionally been divided into rapid-onset and

delayed-onset types.
Rapid-onset type is appear within 15-30 minutes following ingestion
of the mushrooms. It is often characterized by signs of muscarinic excess:
nausea, vomiting, diarrhea, urinary urgency, vasodilation, tachycardia,
sweating, salivation, and sometimes bronchoconstriction. Although Amanita
muscaria contains muscarine, numerous other alkaloids, including
antimuscarinic agents, are found in this fungus. In fact, ingestion of A.
muscaria may produce signs of atropine poisoning, not muscarine excess.

Delayed-onset type mushroom poisoning, usually caused by

Amanita phalloides, A. virosa, Galerina autumnalis, or G marginata,
manifests its first symptoms 6-12 hours after ingestion. Although the initial
symptoms usually include nausea and vomiting, the major toxicity involves
hepatic and renal cellular injury by amatoxins that inhibit RNA polymerase.
Atropine is of no value in this form of mushroom poisoning.

By Dr. H. B. Patel & Satyajeet Singh ~ 41 ~

VPT 311

CNS PHARMACOLOGY
Brain
Central Nervous
System
Spinal Cord

Nervous System
Sympathetic
Nervous System
Autonomic
Nervous System
Peripheral Parasympathetic
Nervous System Nervous System
Somatic Nervous
System

o Sympathetic neurotransmitters are epinephrine & Norepinephrine, & in parasympathetic

acetylcholine.
o Resting stage is called as polarized stage, in this stage -70 mV (internal –ve & outer +ve). It is
maintained by sodium-pump.
o Stimulation disrupts sodium-pump & inner potential is +50 mV& called depolarization.
o After sometime bring back to normal is called repolarization.

Impulse transmission through nerve junction: 4 steps

1) Release of neurotransmitter: by Ca+2
2) Combination of neurotransmitter with post junctional receptor: whenever act on receptor,
there is 2 possibility
a) Increase permeability of Na+& Ca+2, so depolarization of muscle & positive response
(contraction)
EPSP: Excitatory Post Synaptic Potential
b) May be increase permeability of K+ &Cl- ions, so there is hyperpolarization, so
negative response or inhibitory response.
IPSP: Inhibitory Post Synaptic Potential
3) Post junctional activity: 2 types
a) Depolarization of neurotransmitter (EPSP)
b) Hyperpolarization (IPSP)
4) Destruction of neurotransmitter: neurotransmitter destructed within fraction of second.
Prolonged effect of neurotransmitter may lead to nerve fatigue or paralysis.
Ways of neurotransmitter destruction:
a) Local metabolism: by detoxification by enzyme
b) Absorbed in circulation & it is taken by liver & detoxified.
c) Diluted or dissipated in adjoining area& then taken into circulation.
Dr. H. B. Patel & Satyajeet singh
~ 45 ~
VPT 311

CNS Depressent
Lowest from to highest form of depressant is
1) Tranquilization mild
2) Sedation drowsiness
3) Hypnosis sleep
4) Narcosis deep sleep
5) Anaesthesia loss of sensation
6) Death

ANAESTHESIA
1) General anesthesia: induce amnesia (loss of memory) & analgesia (loss of pain)
2) Regional anesthesia: it is reversible loss of sensation over a large restricted area. E.g. epidural
anesthesia, paravertebral block
3) Local anesthesia: reversible loss of sensation over a very small area.
4) Basal anesthesia: it refers to very light level of anesthesia for minor surgery. E.g. removal of teeth.
5) Balanced anesthesia: combination of different drugs to get all ideal effect of anesthesia.
6) Dissociative anesthesia: patient feel dissociation from surrounding & which brought by stimulation
of brain & suppression of other parts & leads to state called as catalepsy or cataleptic stage.
Catalepsy: waxy muscular relaxation/wax like rigid muscle. Commonly used in cats.

History of anaesthesia:
In two parts, before 1846 & after 1846
o 1846: landmark of anesthesia, before 1846 surgery was not common (no aseptic condition, no
anesthesia)
o In Greek period: pressing of carotid artery, leads to unconsciousness & surgery perform.
o 1776: Priestley synthesized gaseous anesthesia nitrous oxide.
o 1776: Priestley & dewin anaesthetic property of nitrous oxide.
o 1816: Michael faraday states that diethyl ether can use as anaesthetic.
o 1821: Benzamine
o 1842: croford long: under ether removed tumor.
o 1844: Hoveswalter use nitrous oxide on his own & remove own tooth.
o 1846: William T. G. morton he was 2nd year medical student & first time demonstrated ether
anesthesia, patient was Edward Gilbert& surgeon was Dr. John Collins Warren.
o 1847: Dr. Edward mayhem used ether in veterinary practice in dog.
o 1847: James Simpson chloroform
o 1903: Barbiturate was used parental anaesthesia for first time
o 1956: Halothane as inhalant anaesthesia
o 1965: Ketamine was first dissociative anaesthesia
o 1972: Althesin was first steroid anaesthesia.
o 1990: Propafol is now used as infusion anaesthesia.

Dr. H. B. Patel & Satyajeet singh

~ 46 ~
VPT 311

Mechanism of action in general: different theories

1. Lipid theory: by mayer & overton in 1899
Action of general anaesthsia depends upon lipid solubility.
High solubility high action
Efficacy depends on lipid-water partition coefficient i.e. it is comparative solubility as compare
to water in lipid.

2. Feg n inci le: this theory states that the efficacy of anasesthesia depend upon
thermodynamic property.

3. Colloidal theory: by Claude Bernard

The anaesthesia molecule form colloid inside brain which depress consciousness of brain.

4. Surface tension theory: by Trop (adsorption theory)

Anaesthetic cause reduction in surface tension in neuron which leads to outflow & inflow of
ions are hindered.

5. Cell permeability theory:

Anaesthesia reduces cell permeability towards certain ions so reduce activity.

6. Biochemical theory: by Quantal

There is reduction in O2 utilization & uptake therefore energy production reduce.

7. Clatheratepanding theory:
Anaesthetic form miro-crystals inside neurons, which reduce conductivity.

8. Iceberg theory: by Miller

Anaesthetic form iceberg i.e. crystal of water form in neurons which prevent conductivity by
plugging the ion channels.

9. Protein theory: by Frank & Zip

Anaesthetic target certain protein which are responsible for movement or control of ions due to
ionic interference leads to anaesthesia.

10. Concentration of neurotransmitter:

GABA (inhibitory neurotransmitter), so anaesthetic which stimulate potential
Certain anaesthetic cause inhibition of glutamate (glutamate is excitatory neurotransmitter)

Different stages of anaesthesia:

They are generally observed in case of gaseous anaesthesia or inhalant anaesthesia. In parenteral
anaesthesia are stages are not observed.
Dr. H. B. Patel & Satyajeet singh
~ 47 ~
VPT 311

G del classification of anaesthesia stages:

Four stages
I. Stage- (stage of voluntary excitemrnt/stage of analgesia)
II. Stage- (stage of involuntary excitement/stage of delirium)
III. Stage- (stage of surgical Anaesthesia)
1) Plane-1
2) Plane-2
3) Plane-3
4) Plane-4
IV. Stage- V (stage of medullary paralysis/stage of toxicity/toxic stage)

Stage- & stage- combinely called as stage of induction.

All operations performed in stage- in plane-2 & 3.
Different reflexes are observed to know the which stage is going on, these reflexes are
i) Corneal reflex: by touching cornea with the help of finger, if blinking present than reflex
present otherwise not.
ii) Eyelid/palpebral reflex: medial canthus of eyelid, if eyelid blinks than reflex present.
iii) Skin reflex: tested by fine needle by touching skin, if reflex present than severing
iv) Swallowing reflex: done by gentle massage on lower jaw, if there is swallowing than reflex
present.
v) Cough reflex: put slight pressure on tracheal cartilage
vi) Pedal reflex: pinching interdigital skin, if reflex present, response takes place.
Observe color of mucous membrane, respiratory pattern, pulse rate & blood pressure.

I. Stage- (stage of voluntary excitement/stage of analgesia)

o Basically sensory cortex get depressed, but before that animal try to run away from
anaesthesia.
o There is lacrimation, salivation, urination etc.
o Blood pressure, pulse rate & respiratory rate high.
o All reflexes are present in this stage.
o At the end of this stage animal starts losing consciousness &cambing effect.

II. Stage- (stage of involuntary excitement/stage of delirium)

o Sensory cortex is totally depressed & motor cortex yet to be depress so only motor
activity/involuntary activity takes place& at the end of this stage motor activity also stop &
animal unconscious totally.
Motor activity paddling of limbs, rolloing of eyeballs, abnormal vocalization etc.
o Blood pressure, respiratory rate, pulse rate are high & reflexes are present.

Ideally speaking, anaesthetic should have rapid induction or both stage- & are very
rapid.
Dr. H. B. Patel & Satyajeet singh
~ 48 ~
VPT 311

In parenteral anaesthesia, stage- & are not observed.

III. Stage- (stage of surgical Anaesthesia)

o In this stage depression proceed from cortex to mid brain&to spinal cord.
o Entry into stage- is marked by respiratory pulse, blood pressure become normal.
This stage divided into 4 planes:
1) Plane-1
o Mid brain get depressed.
o All the reflexes except corneal & eyelid reflex lost.
Exception: pedal reflex in dog is also present.
o In this plane pulse & pressure are normal.
o Respiratory rate slow but regular.
o Pupils are normal.
2) Plane-2
o Depression starts to spinal cord.
o In this plane eyelid reflex abolish but corneal reflex persist & in dog pedal reflex also
present.
o Pulse & blood pressure normal.
o Mucous membrane starts to turning pale.
o Pupils are slightly dialated.
3) Plane-3
o All reflexes are abolished including pedal reflex in dog.
o Eyeball fixed
o Respiration starts to abdominal respiration (i.e. both thoracic & abdominal)
o Pupils get dialated
o Blood pressure start falling down
o Mucous membrane starts to turning pale blue in color.
This is stage when stop administration of anaesthesia.
4) Plane-4
o Spinal cord is completely depressed& depression starts over the medulla.
o Respiration is completely abdominal.
o Blood pressure & body temperature goes down.
o Mucous membrane is completely cyanotic.
o Pupils are dilated to maximum strength.
o Pulse is very weak & cannot feel it.

IV. Stage- V (stage of medullary paralysis/stage of toxicity/toxic stage)

o It is overdose stage.
o Medulla is completely depressed.
o Heart rate, blood pressure drastically goes down.
o Complete cyanosis
o Respiratory paralysis & death.
Dr. H. B. Patel & Satyajeet singh
~ 49 ~
VPT 311

Stage- & plane-2, muscle tone is very less or muscle is relaxed, so easily performed operations.
The recovery is exactly in opposite direction
During recovery, also there is voluntary & involuntary excitement.

General Anaesthesia
There are 2 types of general anaesthesia:

1. Inhalant anaesthesia
a) Volatile anaesthesia (e.g. ether, chloroform, halothane)
b) Gaseous anaesthesia (N2O, cyclopropane)
2. Parenteral anaesthesia

1. INHALANT ANAESTHESIA:
o This is vapor.
o They will go to lung, alveoli, blood, brain & part of this anaesthesia circulate, metabolize &
excrete, but majority of inhalant excreted in expiration.
In this two laws:
Dalton law: higher the concentration, higher the partial pressure.
Hennery law: higher the partial pressure, higher the solubility.
So higher the concentration of anaesthesia, higher the solubility in blood.

Factors affecting inhalant anaesthesia:

o Concentration of anaesthesia
o Rate of respiration
o Depth of respiration & permeability of alveolar capillary
o Blood supply to lungs
o Permeability of alveolar capillary
MAC:
o MAC is the parameter to know the potency of inhalant anaesthesia.
o It is minimum concentration of inhalant anaesthetic which should be present in alveoli for
abolition of response to standard stimuli in 50% of exposed population/animal.
Two standard stimuli:
i) Skin incision
ii) Tail clamping
o If lower concentration is required to get effect than more potency of anaesthetic.
o Methoxyfurane (MAC=0.23%) is more potent than Ether (MAC=3%).

Properties of ideal inhalant anaesthetic:

1) There should be rapid induction.
2) It should cause smooth recovery

Dr. H. B. Patel & Satyajeet singh

~ 50 ~
VPT 311

3) Should not cause any post anaesthetic complication

4) Should have high potency
5) It should cause fair amount of muscle relaxation
6) Should have pleasant odour (sweet smell).
7) Non-inflammatory
8) Non-irritant
9) Economic

Volatile liquids:
1) Ether
2) Chloroform Older
3) Halothane
4) Methoxyflurane
5) Enflurane
6) Isoflurane Newer
7) Desflurane
8) Sevoflurane

Property Ether Chloroform Halothane

1 Boiling point 35 °C 60 °C 50 °C
2 Solubility 10% in H2O 0.5% in H2O 0.5% in H2O
Most in organic Totally in organic Totally in
organic
3 Inflammable property Highly Non-inflammable Non-
inflammable
4 Irritant property Highly Moderate Very less
5 Induction Prolonged & Short & pleasant Short & pleasant
unpleasant
6 Capillary bleeding Yes No No
7 Effect on heart & B.P Not depress Depress from 2nd Depress from 2nd
stage stage
8 Myocardial No Yes Yes
sensitization
9 Muscle relaxation Fair Excellent Good
10 Potentiation of neuro Increase Slight effect Slight effect
blocking effect
11 Post anaesthetic No Delayed hepato& Lesser extent of
complication nephrotoxicity hepato&
nephrotoxicity
12 Dose Induction 10% 2-5% 2-4%
Maintenance 5% 1% 1%
13 MAC 3% 0.77% 0.87%

Dr. H. B. Patel & Satyajeet singh

~ 51 ~
VPT 311

Older drugs:

1) Ether/diethyl ether (C2H5-O-C2H5)

Advantages:
(1) Cheapest one/very economic
(2) Safest one
(3) All the stages seen, so better control over anaesthesia
(4) Preferred in small animals, not commonly used in large animals and ruminants because difficult
to restrain the animal. Also general anaesthesia is not used in large animal & ruminant because
difficult to calculate precise dose (because weight of rumen is excluded )& in large animal
surgery performed in standing position.
(5) Good relaxation of muscle.
(6) No effect on cardiac & respiratory function.
Disadvantages:
(1) Highly inflammable, cannot performed any operation which involve dithermy because it
cause spasm & they catch fire.
(2) Highly irritant
(3) Less potent
(4) Whenever it is exposed to air it converted into peroxide.
(5) Hypoglycaemia& hyperthermia

2) Chloroform (CHCl3)
o It is stored in dark colored bottle+ 1% ethyl alcohol added because in presence of sunlight &
air chloroform produce phosgene (COCl2) gas which is irritant & highly toxic, so ethyl
alcohol act as cleansing agent.
NOTE: Anesthesia containing halogen atom, cause myocardial sensitization
Advantages:

(1) Smooth induction due to pleasant smell.

(2) Non irritant
(3) Non inflammable.
(4) Good muscle relaxer.
(5) Economic

Disadvantages:

(1) Cause myocardial sensitization

(2) Direct get myocardial toxicity
(3) Direct vagal arrest
(4) Delayed hepatotoxicity
Dr. H. B. Patel & Satyajeet singh
~ 52 ~
VPT 311

3) Halothane (trifluoro-bromo-chloroethane)
Advantage:
(1) Used in small & large animals
(2) Non-inflammable
(3) Non-irritant
(4) Very potent
Disadvantage:
(1) Maximum sensitization of myocardium
(2) Hepatotoxicity
(3) Poor muscle relaxer
(4) When enter in plane-3, sudden drop blood pressure & it may be fatal. In this case adrenaline is
not given to normal the blood pressure.
o Combination of chloroform & ether in 1:2 is advisable to safety & reduce toxicity.

Newer drugs:

1) Methoxyflurane:
o Most potent inhalant anaesthetic
o MAC = 0.23%
o Non-inflammable, non-irritant, non-explosive
o Used in both small & large animals.
o It bypasses stage- & stage- , so there is no excitement.
o Good analgesic effect, also after operation.
o Good muscle relaxer
o No delayed toxicity.
Disadvantage:
Slow onset & slow recovery because it is highly soluble in blood, higher solubility slower the
induction because achieve saturation point larger duration. So longer duration for action.

2) Enflurane:
o Most potent
o MAC = 0.0212%
o Boiling point = 67°C
o Chemically derived from methoxyflurane.
o Non-inflammable, non-explosive
o Very pungent smell, so induction is not smooth.
o It is dissociative type of anaesthesia, if slight higher dose than it cause convulsion. So this is called
convulsion anaesthesia . So to prevent convulsion diazepam is given before anaesthesia.
o Causes sensitization of myocardium
o Fatal nephrotoxic effect in cat if tetracyclin is used in vicinity of this anaesthesia.
o Hypothermia

Dr. H. B. Patel & Satyajeet singh

~ 53 ~
VPT 311

3) Isoflurane:
o It is isomer of enflurane.
o MAC = 1.3-1.5%
o Boiling point = 43°C
o Non-inflammable, non-explosive
o Does not any convulsion or lesion.
o Very-very less soluble in blood so fast induction & fast recovery.
o In body metabolism: 1/10th part into enflurane, 1/100th get converted into halothane.

4) Desflurane:
o Very less potent
o MAC = 7.2%
o It is latest anaesthetic.
o Very low solubility in blood, so fast induction & recovery.
o Very good muscle relaxation.
o It causes very less myocardial sensitization.

5) Sevoflurane:
o Very latest but very low LD50 value, so it is toxic.
o Easily degradation

Gaseous anaesthesia
Two inhalant anaesthetics which are gaseous

1) N2O (nitrous oxide/laughing gas)

2) Cyclopropane

1) N2O:
o Always in blue colored bottles.
o Commonly used in veterinary practice.
o Non-inflammable
o Very low solubility in blood, so rapid induction & recovery.
o No sensitization of myocardial muscle.
o N2O is not used as sole agent, later on maintenance obtained by halothane & methoxyflurane.
o N2O never given as single gas, it given along with O2. [N2O (80%) + O2 (20%)]
At this stage it is good anaesthesia up to stage- , but not goes beyond. That is limit, if N2O
percentage increases than toxic effect occurs.
o Muscle relaxation is very poor.
o N2O is least potent.
o MAC = 105% in human
188% in dog
205% in cat

Dr. H. B. Patel & Satyajeet singh

~ 54 ~
VPT 311

2) Cyclopropane:
o Orange colored cylinder to avoid confusion.
o Mostly used in human being
o Almost insoluble in blood
o Less irritant
o No myocardial sensitization
o No renal & hepatotoxicity
o Lower potency but more than N2O
o MAC = 17.5%
o Induce capillary bleeding
o No adequate muscle relaxant
o Very costly
o Clinically cyclopropane (20%) given with O2 (80%).

MAC orders:
N2O (105%-in man, 188%-in dog, 205%-in cat) > Cyclopropane(17.5%) > Desflurane(7.2%) > Ether(3%)
> Isoflurane(1.3-1.5%) > Halothane(0.87%) > Chloroform(0.77%) > Methoxyflurnae(0.23%) >
Enflurane(0.0212%)

Disadvantages of inhalant anaesthesia:

(1) Induction is slow & sometime unpleasant, so there is lot of excitation during induction.
(2) Many inhalants are inflammable, irritant & explosive.
(3) Halogenated anaesthesia sensitizes myocardium.
(4) Poor muscle relaxer
(5) Control over anaesthesia is poor or not proper control, so not get uniform anaesthesia.
(6) Level of anaesthesia is varying person to person.

2. PARENTERAL ANAESTHESIA
I. Barbiturates
II. Chloral hydrate
i) Chloromag
ii) Chloropent
iii) Chloralose
III. Urethane
IV. Althesin
V. Imidazole derivatives
VI. Propofol

Advantages of parenteral anaesthesia:

1) Non-inflammable, non-irritant & non-explosive
2) Rapid & pleasant induction, smooth recovery
3) No capillary bleeding & no myocardial sensitization
4) Easily administered & proper control over anaesthesia

Dr. H. B. Patel & Satyajeet singh

~ 55 ~
 VPT 311

I. Barbiturates:
group of anaesthesia, very commonly used.
Chemistry: it is derivative of barbituric acid. This acid is formed by combination of two compounds
urea &malonic acid. They give compound malonyl urea.
Derivative of this barbituric acid are different barbiturates, which are commonly used.

Classification: substitution made at N1, C2, R1, R2.

Barbiturates are divided into 4 categories:
Long acting
Intermediate acting
Short acting
Ultrashort acting

N1 C2 R1 R2
Long acting Phenobarbitone H O C2H5/CH3 C6H5
(6 Hours)
Methyl barbitone
CH3 O C2H5/CH3 C6H5
Intermediate Butobarbitone H O C2H5 C4H9
acting (3-6
Hours) pentobarbitone H O C2H5 CH3(C4H7)
Short acting pentobarbitone H O C2H5 CH3(C4H7)
(1-3 Hours) Secobarbitone H O C3H5 CH3(C4H7)
Thiopentone
H S C3H5 CH3(C4H7)
Ultrashort (pentothal)
V acting (20-30 Thiamylal H S CH3(C4H7)
min.)
Methohexital CH3 O C3H5 CH3(C4H7)

Structural activity relationship (SAR) of barbiturates:

Barbituric acid does not have any anaesthetic property, to have CNS depression property, there has to
be substitution, add at R1, R2, N1, N2 or C2 either alkyl, aryl or thio group.
More the number of double bond (unsaturated) metabolize easily, so the compound is short acting.
If there is long chain substitution, so chain is easily break & metabolize & short acting.
If there is branching, they again break easily & compound is short acting.
Dr. H. B. Patel & Satyajeet singh
~ 56 ~
VPT 311

Short chain substitution, stable compound & become long acting compound.
Whenever there is substitution of sulfur at 2nd position, compound becomes ultrashort acting.
Any substitution at N1 or N3 with alkyl group the product becomes CNS stimulant.

Chemical property:
Na-salt is used as they are water soluble & given in injection but compound become alkaline&
alkali give irritant property, so most of these compounds are givenI/V.
Na-salt is water soluble, but as dissolve in water, it loses its property of anaesthesia after
dissolution, so freshly prepared water is used.
These are hygroscopic in nature so placed in dark place in water shield.
If solution keeps at room temperature for 2 days or in refrigeration for 5 days, it loses its
anaesthetic property.
While administering there should not be leakage outside the veins, because it is irritant. So in case
of small animals 2.5% solution is used, in large animals 10% solution is used.
Once start given anaesthesia, don t take out needle during anaesthesia because all veins get
collapsed & unable to raise, so after compete administration, needle will be remove.

Mechanism of action of barbiturates:

1) It reduces calcium accumulation of nerve terminals, release of neurotransmitter also reduces.
2) Most of barbiturate gets action like GABA & GABA is inhibitory neurotransmitter.
3) They reduce the sensitivity of post-synaptic receptor & this reduction is more in Ach receptor, Ach
not act properly on receptor.
4) These agents reduce oxygen uptake to brain, so this reduces brain activity in general.
5) Some of agents inhibit glutamate receptor & these glutamate receptors are excitatory receptor.

Kinetics of barbiturate in general:

1) All the barbiturates absorbed through I/V, I/M or Oral but sodium solution must be given I/V.
2) Highly soluble barbiturates absorb, distributed & excreted rapidly.
3) Due to this high solubility they have shortest duration of action i.e. ultrashort acting.
4) Thiopentone, pentobarbitone&phenobarbitone most commonly used.
5) Lipid solubility Thiopentone >Pentobarbitone>Phenobarbitone

Metabolism:
Microsomal oxidation, these are enzyme inducers.
Ultrashort acting barbiturates when given orally they are detoxified in gut, so never given orally.
Ultrashort acting barbiturates have tendency to get stored in tissues.
Glucose saline increases the permeability of barbiturate (mostly thiopentone) inside the cell, so
along with glucose they increase the depth of anaesthesia, so recovery time increases.
All these are excreted through urine.

Pharmacological property:
1) Effect on CNS: in case of nervous system, it is able to depress both motor & sensory cortex, but
motor cortex get depress at low dose & sensory cortex require higher dose to get depress, which

Dr. H. B. Patel & Satyajeet singh

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VPT 311

may mild toxic. So barbiturates are good anticonvulsant & muscle relaxant but poor in
analgesic.
2) Effect on respiratory system: particularly thiopentone causes temporary cessation of respiration
because it is highly lipid soluble. Entire drug is taken to brain; due to high concentration in brain
respiratory centre get depress so respiration stop & at this point administration of thiopentone stop.
So thiopentone get redistributed to other organs & due to redistribution concentration fall down &
respiration start again.
3) Effect on CVS: causes depression of vasomotor Centre& peripheral vasodilation, so blood pressure
fall down, so loss of heat from the body & due to heat loss shivering observe in animal. That s why
during recovery animal shivering takes place.
4) Effect on uterus & foetus: barbiturates cross the placental barrier& affect the respiratory Centre
of foetus & lead to foetus death. It causes uterine contraction so not given in pregnancy.
5) Effect on skeletal muscle: it acts on neuromuscular end plate (NMEP) & reduces the effect of
acetyl choline & this can causes muscle relaxation. In some cases post anaesthetic lameness.
6) Toxic effect: it causes phlebitis. High dose & rapid injection causes respiratory arrest & death. In
case of long acting barbiturates repeated administration cause incoordination.

Clinical uses of barbiturates:

1) Induction of anaesthesia
2) As a general anaesthesia
3) Some of agents show anticonvulsion activity, mostly long acting barbiturates are used.
4) When used for epilepsy, given for prolonged period & repeated administration.
5) Lower dose as sedative, hypnotic.
6) Ultrashort acting barbiturates are used for euthanising animals.

Doses of barbiturates:
Thiopentone:
In dog 15-17 mg/kg
In cats 9-12 mg/kg
Route I/V 2.5% solution or 5% solution
In sheep, goat & calves 5-10 mg/kg 2.5% solution I/V
These all doses are for general anaesthesia.
Duration 35-40 minutes

Pentobarbitone:
In dog & cat 24-33 mg/kg (6% solution, I/V)
In large animals 15-20 mg/kg (10% solution, I/V)
Pentobarbitone also used as sedative & hypnotic (dose: 2-4 mg/kg BW, I/V)
Duration 3 hours

Phenobarbitone:
Mainly used for an anticonvulsion or control epilepsy.
Dose: 7.5-15 mg/kg, orally
For long acting period is 6 to 7 hours.
Dr. H. B. Patel & Satyajeet singh
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 VPT 311

II. Chloral hydrate [CHCl3(OH)2]

o Always used for large animals basically horses.
o White crystalline powder having pungent odour& completely water soluble.
o It enters in body, and thenmetabolize to form product trichlorethanol & this trichlorethanol have
anaesthetic effect, sochloral hydrate is prodrug.
o Trichlorethanol gets combine with glucuronic acid to form urochloralose, this urochloralose
excreted in urine.
o It causes depression of motor cortex, so it depresses motor activity, but sensory cortex is not
depressed. So it does not produce good analgesic effect, so to get analgesic effect high dose is
given, as dose increases severely affect respiratory system & vasomotor centre& it is mildly toxic
or may be fatal. So chloral hydrate always administered at hypnotic level i.e. just below
anaesthetic level, operation is performed under local anaesthesia.
o Chloral hydrate is having activity called as physostigmine like activity&physostigmine is
cholinergic drug (Ach like) & due to this activity it causes cardiac arrest. So avoid that atropine
is given as preanaesthetic.
o Finally chloral hydrate is poor muscle relaxant.

Clinical uses of chloral hydrate:

o Chloral hydrate is given orally or I/V.
o If orally given it causes vomition & nausea hence it diluted & then given.
o When diluted form given, it only have sedative effect, never anaesthetic.
o Maximum used in horse only (in case of colic pain)
o It is used as narcotic agent, it induces sleep.
o Used as general anaesthetic (I/V)
o In cattle & buffalo, it is used as sedative, commonly used in prolapse of rectum & vagina.
o In cattle & buffalo, in case of acetonemia, nervous excitement prevented.

Doses of chloral hydrate:

o 5 gm/45kg of body weight, orally in horse & cattle
o Maximum total dose 30gm, not to be exceeding then 30gm, at this dose get dose narcotic effect.
o In sheep, goat & pig total dose 3-4gm, orally
o 6 gm/45 kg body weight, I/V, of 10% solution & this dose for general anaesthesia for horse &
cattle.

Different combinations:
i) Chloromag:[chloral hydrate (12gm) + MgSO4 (6gm), both dissolved in 100 ml of water] (Da k
formulation*)
o MgSO4 causes muscle relaxation by neuromuscular blocking activity.
o This combination increases the depth & rapid induction of anaesthesia.
o Horse 200-300 ml, I/V (30ml/ minute)
o In camel [ chloromag 12gm chloral hydrate + 12gm MgSO4] and given 6gm/100 kg BW, I/V

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ii) Chloropent (Equithesin): [Chloral hydrate (30gm) + MgSO4 (15gm) + pentobarbitone (6.6gm)
dissolve in 1000 ml of water]
o Dose: 30-70ml/45kg, I/V, in horse & cattle. It is enough for 30 minute anaesthesia.
Advantages: good muscle relxation, excitement reduce, combination increases the safety.
o It is also useful in birds, but combination is 20gm, 5gm, 10gm respectively & given 2.2ml/kg,
I/M. This formulation is known as millerbruck & walling formulation* .

iii) Chloralose: [Chloral hydrate + glucose]

o This combination gives prolonged effect but slow induction.
o Dose: 100mg/kg of 1% solution, I/V or I/P
o More commonly used as rodenticide.

III. Urethane:
o Usedfor lab animals only*.
o Chemically it is ethyl ether of carbonic acid.
o In this case, onset is slow, prolonged duration of action, there is no recovery of anaesthesia that
is terminal anaesthesia*
o It has no effect on heart rate, respiration & blood pressure etc.
o Dose: 25% solution, 6ml/kg, I/P or I/V

IV. Althesin:
o It is steroid anaesthetic.
o It is combination of 2 steroids. Steroid-1 is alphaxalone& steroid-2 is alphadalone.
o Alphaxalone (9mg/ml) + alphadalone (3mg/ml), both are dissolved in ionic detergent.
o As they dissolve in ionic detergent not used in dog, because in dog ionic detergent release
histamine, which cause anaphylactic reaction& death.
o Use in cat: 9mg/kg, I/V, give short duration anaesthetic effect (10-15 minute). If again give
anaesthesia, after 15 minute, then no cumulative effect.
o In birds: 10mg/kg, I/V
o In pigs: 2mg/kg, I/V
o In rabbit: 6-9mg/kg, I/V

V. Imidazole derivatives: mainly 2 compounds used- etomidate, metomidate

o Both are poor analgesic
o Etomidate used in dog, give rapid induction, there are no side effect like respiration & blood
pressure, so it has wide margin of safety. Dose in dog: 1.5mg/kg, I/V
o Metomidate used in birds, pigs, dogs & cats. Dose in birds: 3-4mg/kg, I/V. dose in dog, cat &
pigs: 15-20mg/kg, I/V

VI. Propofol:
o It is latest parenteral general anaesthesia.
o It is infusion anaesthesia.

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o At room temperature, it is oily solution but, it is exception that it is given I/V because
formulation in such a way that oil molecule not exposed.
o It is given as continuous, as stop recovery within 1-2 minutes.
o It potentiate on GABA
o No effect on respiration, heart rate & blood pressure.
o It does not cross the placenta, hence does not affect the foetus.
o It diluted in 5% dextrose solution.
o Dose: dog 0.5-2mg/kg, cat 5-8mg/kg, horse 4mg/kg
o Infusion rate: 0.4mg/kg/minute
o Very short half-life (4-5 minutes)

3. DISSOCIATIVE ANAESTHESIA:
o Anaesthesia in which person feels dissociative from surrounding, due to some part gets stimulated
& some part get depressed. It leads to cataleptic stage or catalepsy.
o Catalepsy is muscular rigidity like wax.
o There are mainly three compounds- 1) Phencyclidine, 2) Tiletamine, 3) Ketamine
o Out of these three phencyclidine is most potent & it is longest duration of anaesthesia, but now a
days it is banned due to abuse.
o Tiletamine is less potent, so not used
o Ketamine mainly used, each gram sold is accounted because it is abuse for amnesia (=loss of
memmory)
o Use of ketamine started from 1965 in human, but now not used in human.
o In veterinary used 1972 & still commonly used in cats.
o Ketamine causes anaesthesia, it capable of inducing stage- & stage- only. It is capable of
inducing amnesia & dissociative with catalepsy.

Mechanism of action:
o It causes inhibition of binding of GABA to its receptor, it stimulate certain parts of brain.
o It blocks the transport of 5-HT (serotonin)
o It prevents the uptake of nor-epinephrine & dopamine leads to stimulation of cardiovascular
functions.
o It causes depression of cortical centre so net effect is depression of cortical centre& stimulation of
limbic system.

Pharmacological effects:
1) Effect on nervous system: there is functional disturbance of nervous system leading to
stimulation & depression, due to this it can induce stage- & anaesthesia but not i.e. go upto
unconsciousness.
It causes muscular rigidity, so excitement not seen clinically due to rigid muscle so animal
become unconscious without showing sign of excitement.
2) Effect on cardiovascular system: due to effect on dopamine & nor-epinephrine there is increase
in B.P.

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3) Effect on respiratory system: as stage- not arrive hence respiration is normal & ventilation is
excellent.

Pharyngeal, laryngeal & swallowing reflex persist.

Ketamine induces lot of salivation but swallowing reflex present, hence swallow all saliva.
On the other hand, Pharyngeal, laryngeal reflex present, if endoscopy perform it cause
laryngospasm & it may be fatal.
Other reflexes are present & eyes are wide open.
Pedal reflex & skin reflex also not affected.
In case of ruminants, regurgitation is not affected & eructation of gas is also not affected, so it is
advantage & suitable for ruminants.
Ketamine anaesthesia is very safe & margin of safety is 5. Even if give repeated dose, there is no
cumulative effect.

Disadvantages:
1) As there is not complete anaesthesia, animal may recover in between & stand & walk.
2) Very poor muscle relaxation & muscle is tensed & contracted.

Difference between ketamine & other anaesthesia:

Ketamine Other anaesthesia
Only 2 stages All stages
Maximum reflex present No reflex
Cardiovascular & respiratory system not Affected
affected
Muscular rigidity Muscular relaxation

Clinical uses of ketamine:

Note: Always better to give atropine (0.05mg/kg, S/C) before given ketamine to reduce salivation.
1) It can give I/V or I/M
2) Normal dose @ 11 to 44mg/kg body weight.
3) As increase dose depth of anaesthesia increase.
11mg restrain animal
22mg minor operation
33-44mg major operation
4) Duration of anaesthesia 45minutes to 1 hour
5) Complete recovery 4-5 hours after given highest dose
6) Need some muscle relaxant, if want to perform operation under ketamine anaesthesia. For
muscle relaxation best drug is Xylazine.
7) Ketamine &Xylazine is best combination& recover all the side effects of both drugs & it is
suitable for all species & all operations.
Xylazine: sedative, muscle relaxant & analgesic& these properties lacking in ketamine.

Uses: restraining purpose, minor surgery, orthopedic manipulation, castration, laparotomy & caesarian.

In dog, if ketamine singly given then cause severe convulsion & jerking movement, so in dog ketamine +

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xylazine or diazepam is given

Ketamine = 11mg/kg, I/M xylazine = 0.1-0.2mg/kg
This is used in dog, cat, sheep, goat & horse

In dog: ketamine = 10mg/kg, I/V

Xylazine = 0.5mg/kg, I/M
Combination = I/M

Preanaesthetic:
Drugs which are given before administration of anaesthesia for muscle relaxation etc.
Objectives:
1) To reduce the excitement, to calm down the animal
2) To reduce dose of anaesthetic
3) For rapid induction
4) To reduce the secretions like salivation, vomition etc.
5) To have proper muscle relaxation
6) To control cardiac & respiratory side effects
7) To have proper analgesic effect
Drugs used as preanaesthetic:
1) Tranquilizers: e.g chlorpromazine = 1-2mg/kg, I/
It reduces the excitement, dose of anaesthesia, secretion & vomition.
2) Sedatives: e.g. diazepam = 1mg/kg, I/M or I/V
It induces the sleep, reduces dose, reduce excitement & muscle relaxant.
3) Anticholinergic compounds: e.g. atropine = 0.05-0.5mg/kg, S/C
It reduces all secretions
4) Analgesics: e.g. analgine&novalgine = 5-10mg/kg, I/M
To control pain
5) Muscle relaxant: e.g ketamine & inhalant anaesthesia
a) Xylazine: 0.5-1.0mg/kg
It is sedative, analgesic & muscle relaxant.
b) Diazepam
c) Gallamine: 0.25mg/kg, slow I/V or I/M
If rapid then respiratory paralysis & death

Postanaesthetics:
Given after recovery of anaesthesia & surgery.
Objective:
1) To control the pain (analgesic drug)
2) Blood & fluid replacement by fluid therapy (5% dextrose saline or blood transfusion)
3) For fast recovery vitamin A, B-complex, C, D etc
4) Antibiotic to avoid secondary infection
5) Tranquilizers because recovery stage is opposite stage, so voluntary excitement avoid.
Chlorpromazine = 1-2mg/kg, I/M
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4. LOCAL ANAESTHESIA :
Common mechanism of actions basically 3 mechanisms
1) They act as membrane stabilizing agent: they reduce the permeability of membrane. The local
anaesthetic got amino group, combine with polar group of cell membrane, it affects Na +-K+ pump
& nerve impulse is disturbed.
2) Effect on membrane Ca+2: this calcium whenever present, decreases threshold potential, so local
anaesthetic act on Ca+2 in such a manner that threshold potential gets increase.
3) Local anaesthetics bring deformities in Na+ channels: sometime Na+ channels get closed &
Na+-K+ exchange not takes place & impulse transmission not takes place.

Absorption pattern & systemic effects of local anaesthetics:

o Absorption: as far as possible, absorption must be minimum. 1st way epinephrine combines
with local anaesthesia, because epinephrine got direct effect on B.P by severe constriction
after administration. Epinephrine cause local vasoconstriction, due to this, local anaesthesia
absorb in very low amount & most of part remain at the site of injection.
1 : 10,000 or 1:20,000
Epinephrine local anaesthesia

o Addition of hyaluronidase& local anaesthesia:hyaluronidase increases the spreading of

local anaesthesia, so whenever given S/C, it cause diffusion of local anaesthesia over large
area & it is given during epidural anaesthesia.
o If it is given as such, then some part gets absorb & show systemic effect.
o After absorption of local anaesthesia, there will be CNS stimulation, due to which
excitement, convulsion.
o In cardiovascular system: vasodilatation, decreased B.P, decrease in heart rate.
o In GIT: reduction of peristalsis i.e. constipation effect

Different compounds used as local anaesthesia:

I. Cocaine: cocaine hydrochloride is used.
o Cocaine is alkaloid obtained from plant erythroxyloncocoa.
o This cocaine is 1st local anaesthesia to be used or mother of all local anaesthesia.
Characteristics:
o Does not effect on intact skin (not topically used)
o If given orally than destroyed in gastric pH.
o It is potent local anaesthetic, given S/C.

Mechanism:
It reduces/blocks the uptake of catecholamines, so epinephrine remain at the site, it itself cause the
vasoconstriction. So epinephrine is not required in addition with cocaine as vasoconstriction.
o Cocaine causes pupil dilatation, so very good anaesthesia for ophthalmic observation.
o Clinical uses: it is mainly used for observation of eyes.
o Dose: expressed in %

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o It cause of dilation of pupil & constriction of blood vessels locally, so very good for
conjunctivitis.
o It is very good anaesthetic for nasal, buccal cavity, larynx & pharynx.
o Toxic effect is same as absorbed in systemic effect.
o When given with prolonged period cause addiction.

II. Procaine:
o 1st synthetic local anaesthetic.
o To reduce the addiction property of cocaine, it was synthesized.
o It is not potent as cocaine, but less toxic.
o It has got very short half-life. Half-life is 25 minutes, so to increase its life (duration of action)
epinephrine is added & decrease absorption.
o It is metabolized to PABA, so it cannot be used along with sulfonamides.
o It cause severe vasodilatation & it is commonly used as antihypertensive drug. In this procaine is
not used but procaine amide is used.
o Procaine is contraindicated as it is require in large dose.
o Not used in shock.
o Dose: 1-2% for infiltration, 3-4% for nerve block

III. Lignocaine (lidocaine)

o Most commonly used local anaesthetic.
o Potency 2 times than procaine & not cause tissue irritation.
o Quick onset of action & duration of action is twice than procaine.
o It is quickly absorbed, hence epinephrine is added.
o Also used as surface anaesthetic/topical 5% concentration use
o Dose:0.5-1% for infiltration, 2-5% for nerve block

Lignocaine like compounds recent compounds

i) Bupivacaine
ii) Mepivacaine
iii) Prilocaine
iv) cinchocaine
o Among these bupivacaine is most potent (7 times) & 11-12 hours duration of action
o mepivacaine is 2-3 times more potent than procaine. In horse commonly used (2 hours duration of
action)
Some rarely used local Anaesthetics:
i) ethanol
ii) phenol
iii) chlorbutol
iv) menthol
v) benzyl alcohol
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Surface anaesthesia:
Ethyl chloride (spray):
o It has freezing effect locally, so it causes numbness.
o Also used as inhalant anaesthesia.
Amethocaine (tetracaine):
o Used for ophthalmic purpose, also for infiltration.
o It is 10 times potent than cocaine.
o For topical purpose 0.5-1%, For infiltration 1-2%

TRANQUILIZERS
o Tranquilization: calmness or peace of mind.
o Tranquilizers are the drugs which calm down or unaware to surrounding.
o It is also called as psychotropic/neurotropic/ataractic drugs.
o Ataractic because they produce ataraxia & ataraxia means calmness or undisturbed stage & it is
mildest form of CNS depression, quieting, reduction in excitement & control over aggressiveness.

Tranquilizers are divided into 5 categories:

I. Phenothiazine derivatives
II. Butyrophenones
III. Benzodiazepenes
IV. Thioxanthenes
V. Rauwolfia derivatives

I. Phenothiazine derivatives:
Substitution at 2nd& 10th position gives different derivatives with different efficacy.
Common derivatives:
1) Promazine, 2) chlorpromazine, 3) acepromazine, 4) triflupromazine, 5) prochlorpromazine, 6)
trimeperazine
All of these have same property & chlorpromazine is representative of all of them.
Chlorpromazine:
They are absorbed orally, I/M & I/V all three routes & get effect depending upon route of
administration.
All these agents are metabolized in liver by sulfoxidation & they are excreted through urine.
Action & effects:
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1) Sedative action: chlorpromazine causes depression in brain stem & cortex & it generally affects
motor cortex. Due to effect on brain stem there is calmness or drowsiness & due to effect on
cortex, decreased activity but all reflexes are present.
2) Inhibition of adenosine at different synapses & this action leads to antianxiety.
3) It blocks dopamine receptors: dopamine receptors are of 2 types- 1) Doe- excitatory receptor, 2)
Doi-inhibitory receptor
It blocks Doe receptor & due to blockage of this receptor there is muscular rigidity (catalepsy) &
also causes reduction in Spontaneous Motor Activity (SMA).
This block the receptor which present in CTZ, it leads to antiemetic effect (vomiting centre in
CTZ). This effect due to this drug, it only controls vomition due to motion (travelling) due to
central nervous system or brain, not due to local irritation of GIT. It is used during
transportation of animal.
4) It has antihistaminic effect: it nullifies the effect of histamine. Used as antipruritic.
5) Antiautonomic effect: 2 types of effect- antiadrenergic & anticholinergic effect
Antiadrenergic effect: it blocks the receptors & reduces the blood pressure.
Anticholinergic effect: it reduces all secretions so used as preanaesthetic.
6) Weak antispasmodic action: reduce spasm of muscle
7) It cause depletion of catecholamines in hypothalamus & due to this action it is able to control
over heat stress (heat stroke)
8) It cause release of prolactin, so it get galactagogues effect (increase milk secretion)
9) It causes release of epinephrine from adrenal medulla, leads to hyperglycaemia.
10) It has got muscle relaxation power due to paralyzing skeletal muscle.

Clinical uses:
1) Used as preanaesthetic, because they cause CNS depression, reduce dose of anaesthetic, reduce
secretion & antiemetic.
Usually given before 1 hour of anaesthesia.
2) Used as trazquilizer for restraining the animal or reduce excitement or even performing minor
surgical operations.
3) Very strong antiemetic to control vomition so used for motion (travelling) sickness.
4) In human used in vomition during pregnancy.
5) Used in dermatitis or pruritis.
6) Used in tetanus to control animal & relaxation of muscles.
7) Used as psychotropic, used in depression or epilepsy
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8) Used in spasmodic colic.

9) Used in pseudopregnancy, to control abnormalities.

Dose & route:

1) Chlorpromazine:
Dose: 0.5-1mg/kg, I/M or I/V
2-4mg/kg, orally
Not used in horse
2) Acepromazine:
Most commonly used in horse.
It is most potent phenothiazine derivative
Dose: 0.05-0.07mg/kg, I/M;
0.025-0.035mg/kg, I/V
In horse there is incidence of phymosis&paraphymosis.
In other animals almost same dose is used.
3) Trichlorpromazine: (siquil)
Commonly used in veterinary practice.
It must be use separately in single syringe.
Dose: 1-2mg/kg, I/V
2-4mg/kg, I/M
Siquil is not used in cat because it causes stimulation of simbic system (excitement)
For large animals: 0.2-0.4mg/kg, I/V or I/M
4) Prochlorprazine: (stometil commonly given in motion sickness)
Dose: 1-4mg/kg, orally
0.5-1mg/kg, I/M or I/V

Contraindications:
1) Never use epinephrine (lifesaving drug) if animal is under the influence of phenothiazine drug.
Reason: usually epinephrine given during shock, low blood pressure due to dales s reversal
phenomenon
generaly Receptors epinephrine B.P
But phenothiazine already occupy -receptors, Hence now
Epinephrine occupy -receptors B.P further

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2) Phenothiazine should not to be given if local anaesthesia is already given. If done then severe
hypotension by local anaesthesia.
3) Phenothiazine should not be used during organophosphate toxicity. During this toxicity lot of
excitement & convulsion, if phenothiazine is given then aggregation of organophosphate.
4) Contraindicated in horse, due to violent incoordinated movement.

II. Butyrophenone derivatives:

1) Droperidol, 2) haloperidol, 3) azaperone
Most of actions similar to phenothiazines.
a) Butyrophenones block the action of dopamine, epinephrine & nor-epinephrine.
b) Butyrophenones have the action like GABA, as it get the similar action of GABA it inhibit the
action of nervous system.
c) It blocks the action of glutamic acid at synapse.
d) It blocks the -receptors, so epinephrine is contraindicated.
e) Strong antiemetic drug, net effect is tranquilizer & reduce Spontaneous Motor Activity (SMA),
reduce catalepsy (muscular rigidity), strong antiemetic property & reduce stress.
f) Among all droperidol is most potent, it is 10 times more potent than haloperidol & 400 times
than azaperone.
Clinical uses:
1) It is used as immobilization of wild animals. (due to catalepsy)
2) Antiemetic effect, this effect is 1000 times more as compared to chlorpromazine.
3) Used as anti-stress agent
4) Duration of action is very short & around ½ to 4 hours.
5) Droperidol has wide margin of safety.
6) Dose: droperidol 0.01mg/kg, I/M or I/V
Haloperidol 0.1mg/kg, I/M or I/V
Azaperone 0.8mg/kg, I/M or I/V
7) Droperidol & haloperidol usually used as immobilization & antiemetic &azaperone as
tranquilizer, neuroleptanalgesia.
8) Fluanisone is latest introduced & similar to droperidol.

III. Benzodiazepines:
E.g. diazepam, chlordiazepam, midazolam

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o Action: interfere with action of catecholamines in brain

o GABA like action
o Specific receptors of benzodiazepines
o In addition to tranquilization, also have anticonvulsant & muscle relaxation property & also
anxiolytic property (reduction in excitement)
o It has no antiemetic effect.
Clinical use:
a) Commonly used as preanaesthetic
b) Used as anticonvulsant& muscle relaxation
c) In human side use as nervous depression & induce sleep.
d) Dose: diazepam 1mg/kg by any route I/M, I/V or orally
e) It also used as neuroleptanalgesic
f) Commonly combine ketamine & xylazine for complete anaesthesia.

Drawbacks:
a) Diazepam gives rise to tolerance (reduced effect on successive exposure)
b) It induces dependence (drug consumption become compulsory or habitual)
Antagonist to diazepam is flumazenil (used in suicidal case of human being)

IV. Thioxanthenes:
o E.g. chlorprothixene not used but has antihistaminic & antiemetic property.So used for
tranquilization & emesis
o Dose: 0.5-1mg/kg, I/V
o Used in dog & small animals (sheep & goat)

V. Rauwolfia derivatives:
o Reserpine it is natural alkaloid compound derived from plant Rauwolfia serpentine.
o It acts by causing depletion by nor-epinephrine
o It never used clinically, it may use for experimental purpose
o It acts as tranquilization & sedation.
o It has severe hypotensive effect.

SEDATIVES
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Definition: these are mild CNS depressant which induce drowsiness (lethergic) & it relieve the patient
from nervousness & excitement, whereas hypnotic (greek word = god of dreams) which induce sleep.
Hypnotic also called as soporofies or somnifacients.
These hypnotic act on R AS (Reticular Activating System) & depresses it.
Compounds for sedatives &hypntics:
i) Barbiturates: long acting are generally used e.g. phenobarbiturates
Dose: in dog 30-40mg/kg, orally
In cats 50-60mg total dose (12-15mg/kg)
ii) Choral hydrate: for large animals, dose 10mg/kg, orally
iii) Diazepam: (mainly sedative)
1-2mg/kg, I/M, I/V or orally
iv) Xylazine:
For small animals 1-2mg/kg, I/M
For large animals 0.1-0.2mg/kg, I/M

ANTICONVULSANTS
These are the agents which are administered to control convulsions, epilepsy, seizer, excessive CNS
stimulation & even during tetanic condition.
Convulsion or epilepsy commonly seen in dog, cat & human being.
Discuss separately because they only control convulsion without causing any depression to CNS.
There are 2 anticonvulsants , these only cause reduction in convulsion.
Mechanism of convulsions:
convulsion basically due to hyperactivity of motor cortex. In motor cortex some of neurons act as firing
point (stimulant) & these neurons even at lower threshold potential they require to fire stimulation.
Once these are stimulated, they are capable of stimulatingneighboring neurons & entire area gets
stimulated lead to convulsions.
Anticonvulsion drugs:
I. Phenytoin:
o It acts as stabilizing agent at synapse. It will allow to passes of impulses at higher threshold at
synapse. When it act on firing neuron, firing neuron not stimulate by lower threshold
stimulation.
It is due to expulsion of actively Na+ ions outside. Drug mainly acts on motor cortex without
affecting sensory cortex. So that is reason that there is no CNS excitement.
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o It inhibits GABA, will cause slight excitement (minor effect)

o Dose: 4mg/kg, orally, initially 4 times a day &repetition is decrease.
o As frequency increases, its dose has to be increase because it induces enzymes.
Epilepsy: treatment first start with phenobarbitone (4-6mg/kg, orally) then phenytoin & then
primidone (10-13mg/kg/day) & given for 1-2 month of period.
In addition to this there is combination of phenobarbitone & primidone available.
If convulsion is mild then diazepam orally 1-2 times per day is sufficient.

ANALGESICS
Analgesic: drug control the pain. It is categorized in 3 groups:
I. Neuroleptanalgesics
II. Narcotic analgesic
III. Non-narcotics or NSAIDs (Non-Steroid Antiinflammatory Drugs)

I. Neuroleptanalgesics: it is combination of neuroleptic drugs & analgesic drugs. It is recent

drug. Neuroleptics control anaesthesia & analgesics control pain.
Combinations:
i) Droperidol + fentanyl
ii) Fluanisone + fentanyl
iii) Acepromazine + etorphine

i) Droperidol + fentanyl
In this combination neuroleptics & analgesic in proportion of 50:1.
Droperidol: potent tranquilizer, potent antiemetic, but not having analgesic effect.
Fentanyl: very potent analgesic. Fentanyl is 100 times more potent then morphine & this fentanyl
causing analgesia acting on different opioid receptors & causes analgesia. After combining they
act independently not interfere in action.
Advantages:
1) It causes tranquilization
2) Strong antiemetic
3) Cough depressant
4) Good analgesic during operation & after operation.
5) Recovery s very smooth
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6) Respiration & heart rate not at all affected

7) Very good margin of safety
Disadvantages:
1) Any loud, animal get stand, because no narcosis & anaesthesia.
2) In certain species it is undesirable & unexpected CNS excitement (horse, cat, pig) so
mainly used in dog & lab animals.
Dose: combination contains 20mg droperidol& 4mg fentanyl per ml of injection.
1ml/10kg, I/M or 1ml/25kg, I/V
ii) Fluanisone + Fentanyl
Used in dog & lab animals
Dose: 0.5ml/kg, I/M
iii) Acepromazine + Etorphine
o Acepromazine is tranquilizer & strong antiemetic.
o Etorphine is thebaine derivative& 1000 times more potent than morphine. It is sedative &
analgesic. Etorphine is commonly used in immobilization of wild animals, it is very fast acting.
Dose 0.5µg/kg
o During immobilization always higher dose is given & then capturing animal brought back to
awaken, so antagonist diprenorphine, because small dose initially there is excitement & then
depression.
o This combination commonly used in horse.
Dose: acepromazine (0.1mg/kg) + etorphine (0.025mg/kg), I/V given after mixing

II. Narcotic analgesic

Pain sensation decrease due to depression of CNS & induce deep sleep. (pain unpleasant response
to mechanical, chemical or thermal stimuli)
o These are mainly opium alkaloids.
o Opium compound obtained from poppy seeds.
o Papaver somniferum plant from capsule of seed while given cut a milky white juice
comes out, which is dried & powdered, which contain many alkaloid categorized in 2
groups:
i) Phenanthrine derivatives: e.g. morphine, codine, thebaine (these are very potent analgesic)
ii) Benzyl isoqionolones: e.g. narcotine, papaverine & narceine (mainly have spasmolytic
activity)
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Out of all these morphine is important, so study in detail:

Morphine causes:
1) CNS stimulation 1st than CNS depression
2) Very good analgesic
3) Suffer severe constipation
4) Very good cough sedative
Types of pain:
1. Chronic state pain: this is due to some stimuli to nociceptor receptor, so by this
neurotransmitter bradykinin (substance-P) release causes pain. Also histamine, serotonin &
Ach released & cause pain.
2. Phantam limb pain: there are no receptors or neurotransmitters involved but still pain is
there. No drug till today to control this pain.
Contraindications of morphine:
1) Strychnine poisoning
2) Tetanus
3) Traumatic shock severe vasodilatation B.P
4) In head injury respiration depression
5) Pregnancy

Opioids all those drugs acting on opioid receptors

Opiates compound derived from morphine
Opioid receptors basically are G-protein coupled receptors. When drug act on these, they will
cause inhibition of adenyl cyclase, so the neurotransmitter movement stop & there is cure of pain.
Types of opioid receptors: 4 types
i) µ-receptor
2 subtypes µ1& µ2
µ1 responsible for analgesic effect
µ2 cause respiratory depression
ii) -receptor
For other effects of opioids
iii) -receptor
True opioid receptor, present in almost all the sites where opium is act.
All the opium definitely act on receptor
iv) -receptor
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These receptors are acted by only endogenous opioids e.g. -endorphine, enkephalins,
dynorphins.
Toxicity of morphine:
1) Initially CNS stimulation
2) Initially increases gastric motility
3) Causes habbit of consuming & tolerance
Antagonist of morphine:
Nalorphine
Naloxone
Diprenorphine
levolorphine
Mechanism of action of opium alkaloids/analgesics:
Act on opoid receptors, cause inhibition of adenyl cyclase release of substance-P (neurotransmitter)
is inhibited
Pharmacological effects:
o Initially CNS stimulation & then depression dog, human & monkey
o Only CNS stimulation rest of all species
1) Effect on CNS:
o Acts on cerebral cortex initially, euphoria, hallucinations, excitement, followed by sedation,
narcosis & analgesia.
o The analgesic effect is observed at very low dose, so at that dose other CNS functions are
not affected.
o At very low dose sensory cortex is affected & analgesia is there.
o All pains are controlled by morphine.
2) Action on spinal cord:
o Initially stimulation than depression
o Morphine is contraindicated during poisoning & tetanus
o In brain different centers are also get affected.
o Vagal, occulomotor & vomiting centre they are 1st stimulated & then depressed.

3) Effect on GIT:
Initially diarrhoea, salivation, vomition then followed by severe constipation & dryness of
mouth.
4) Effect on respiratory system:
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Only depression reduced & shallow respiration

Cough centre depressed so these agents used as excellent cough sedatives.
5) Effect on eyes:
Initially constriction of pupil & find pin-point pupil in humans, dogs & monkeys & later on
the size comes back to normal, but in rest of species there is dilatation of pupil.
Exception: in birds no effect of morphine on size of pupil because the muscles of pupil are
unresponsive to morphine.
6) Effect on vasculation:
Severe vasodilatation which cause fall in B.P.
In addition morphine cause increase in temperature (hyperthermia) in cattle, sheep, goat, horse
where in dogs, monkeys & human there is hypothermia.
Straub test: performed on rat & mice. There is stiffening of muscle of base of tail, so the tail
is raised when administration of morphine is done.
7) It induces habituation & it causes tolerance so subsequent higher dose is required.

Clinical uses of morphine:

Used in dogs at very low dose 0.1-0.2mg/kg, I/M
Used as preanaesthetic, analgesic, intestinal sedative & diarrhoea control by orally
Used as cough sedatives
Vasomotor, cough & respiratory centre orally depressed.

Morphine derivatives:
These are compounds derived from morphine or semisynthetic compound.
I. Codeine phosphate:- it is nothing but methyl morphine. Due to methylation there are some
changes, codeine is excellent expectorant & suppress the cough. On other hand analgesic property
completely reduced. Side effect of constipation is persists. Dose: 1.1-1.2mg/kg, orally.
II. Hydromorphine:- 5 times more potent in analgesic property than morphine. In this case
stimulation drastically reduced. Dose: 1.1-1.2mg/kg, S/C & used as analgesic drug.
III. Oxymorphine:- 10 times more potent in analgesic property. Also have sedative & narcotic
property. It is used neuroleptanalgesic drug & combined with triflupromazine.
IV. Diacetylmorphine:- it is heroin. It is very-very potent analgesic drug but highly addictive.
Morphine substitutes:
It is completely synthetic compound. In this case addiction property is not seen. They are generally
used as analgesic, narcotic, spasmolytic & sedative.
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I. Meperidine (Pethidine):- it has all above properties. It does not cause any stimulation, so no
vomition. It is clinically used in spasmodic colic & preanaesthesia. Used in labour pain in human.
Dose: 5-10mg/kg, I/M
II. Methadone:- this is potent analgesic, cough sedative & spasmolytic. Used in cough &
preanaesthetic. Dose: 1.1mg/kg, S/C & very small dose as preanaesthetic (0.1mg/kg)
III. Dextromethorphan:- purely cough sedative. Dose: 1.2mg/kg, orally
IV. Pentazocine:- 100% non-addictive, very-very good analgesic but sedation is very less. So it is
mostly used as post anaesthetic.
Dose: dog 2.5-3mg/kg, I/M
Horse total exceed 400mg (i.e. 1mg/kg, I/V)
V. Butorphenol:- it is analgesic, cough sedative & it is narcotic antagonist causes reversal of
narcosis. Dose: horse & dog 0.1-0.4mg/kg, I/V
VI. Thiorphenol:- it is enkephalins inhibitor which destruct enkephalinase & terminate activity of
enkephalin.

III. Non-narcotic Analgesic/ NSAIDs (Non-Steroidal Anti-inflammatory

Drugs)
These cause analgesia without affecting brain activity.
They have 3 main properties:
1) Analgesic, 2) antipyretic, 3) anti-inflammatory

Classification: classified in 10 groups

1. Salicylic acid: - aspirin, diflunisal, benorylate

2. Aniline derivatives: - paracetamol, phenacetin

3. Pyrazolone derivatives: - (largest t1/2 of 50-100 hour) phenylbutazone, oxyphenbutazone,

azapropazone

4. Indole acetic acid derivatives: - (most potent inhibitor of COX-2) indomethacin, sulindac

5. Anthranilic acid derivatives/Fenmetes: - meclofenamic acid & mefenamic acid

6. Aryl acetic acid derivative: - diclofenac

7. Propionic acid derivative: - ibuprofen (drug of choice for inflammatory joint), naproxane,

flurbiprofen, ketoprofen & fenbufen (prodrug)

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8. Oxicams: - piroxicam, tenoxicam, meloxicam

9. Selective COX-2 inhibitors: celecoxib, rofecoxib, valdecoxib, parecoxib

10. Sulfonanilides: - nimesulide

11. Miscellaneous: - flumixin, melaquinine

Common mechanisms of action:

1) Anti-inflammatory treatment mechanism:- whenever any injury to cell, membrane
phospholipase is liberated (Phospholipase A2). It acts on lipid & formation of acid called
arachidonic acid which acted upon by 2 enzymes 1) Cyclooxygenase (COX), 2)
lipooxygenase.
o Whenever acted by cyclo-oxygenase it leads to synthesis of prostaglandins & by
lipooxygenase formation of leukotrienes.
o These all NSAIDs inhibit COX, so inhibit production of prostaglandins.
o Some prostaglandins are beneficial & some are harmful.
o Different prostaglandins:-
PG1 causes inflammation, pyrexia & pain.
PGE1 & PGE2 responsible for vasodilatation
PGI2 causes severe fall in B.P
TXA2 Thromboxane causes platelet aggregation
PGD2 it is anti-aggregation factor for platelet.
o All these PGs sensitize nerves & induce pain.
2) Antipyretic mechanism:- any infection causes release of endotoxins. These endotoxins act
as pyrogen (raise temperature). These endogenous toxins cause release of PGE. This PGE
act on hypothalamus, it raises set point temperature.
o NSAIDs cause inhibition of PGE by inhibiting COX enzyme.
o This will also in addition to inhibition of PG, they also reduce heat production or loss
of heat from the body.
3) Analgesic mechanism:- NSAIDs block the action of substance-P (bradykinin) & cause
analgesia.

1. Salicylate:
This inhibits PG & SRSA (leucotrienes) & bradykinins.
This inhibit hyaluronic acid, cause heat loss because of vasodilatation, so sweating is set at
normal.
It inhibits platelets aggregation (TXA2) so it causes gastric bleeding if therapy is prolonged.
Aspirin causes less gastric bleeding than sodium salicylate.
It prevents thrombus formation in heart attack patients by inhibiting TXA2 & used in heart
patient.
Salicylates earliest drug introduced, sodium salicylate introduced in 1875 by Buss &
aspirin in 1899 by Bayer.

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Toxicity:
a) Gastric bleeding
b) In cats, it is contraindicated because it make glucuronic conjugation (it absent in cat)
Dose:
In dog 10mg/kg, orally
Aspirin
In large animals 30mg/kg, orally

In dog 10mg/kg, orally

Sodium salicylate
In large animas 50mg/kg, orally
Now-a-days buffered aspirin (disprin) does not cause gastric bleeding too much.

2. Aniline derivatives: (Para amino phenol derivates)

It is potent analgesic, antipyretic but not anti-inflammatory.
It is also called as paracetamol or acetaminophene.
Paracetamol is more toxic (hepatotoxic) & phenacetin is hepato & neurotoxic & these are
even more toxic than salicylates.
In metabolism paracetamol is converted into N-acetyl benzoquinone imine, which is
hepatotoxic.
Dose: 10mg/kg
Now-a-days combination ibuprofen + paracetamol is used.

3. Pyrazolone derivatives:
It is analgesic, anti-inflammatory but less antipyretic.
It induces microsomal enzymes & has high protein binding (phenylbutazone = 98%) &
half life in human is 72 hours.
It is c0mmonly used in doppiing in race horse.
Clinically used for laminitis & myositis.
Dose: in horse 10mg/kg, I/M
In dog 40-45mg/kg, I/M or orally
Metamizole more analgesic & less anti-inflammatory.

4. Indole derivatives:
Highly toxic (indomethacin) so not used clinically. E.g sulindac
It inhibits enzyme aldose reductase which is responsible for conversion of glucose to
sorbitol.
This prevents cataract.

5. Anthranillic acid derivatives:

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Commonly used as antirhuematic in horse.

Dose: 2.2mg/kg/day

6. Aryl acetic acid derivative:

Eg diclofenac
Selective COX inhibitor
Commonly used in veterinary but now banned.
In dog, it causes gastric bleeding.

7. Propionic acid derivatives:

e.g. ibuprofen, brufen, naproxen etc.
Anti-inflammatory & analgesic but poor antipyretic.
Dose: 10/mg/kg, orally or I/M
Neproxane it is commonly used in horses because it is used in laminitis & myositis.
When given orally 50% is absorbed only, so it is given I/V 10mg/kg
Protein binding is 99% & that is why the half life is around 96 hours.
In dog orally causes gastritis.
Now-a-days in dog & large animals ketoprofen is used 5mg/kg, orally or I/V.

8. Oxicams:
E.g. meloxicam (vet.) & piroxicam (human)
It is selective COX2 inhibitor.
[COX1 gives beneficial PG while COX2 give harmful PG]
So it inhibit the production of harmful PGs by inhibiting COX2
It has no any side effect when orally given (it does not cause acidity & gastric bleeding)
A very low dose is sufficient highly potent
Dose: 0.3-1mg/kg, orally or I/M
Half life is very long so single dose is sufficient for a week.

9. Selective COX-2 inhibitors:

E.g. celecoxib, rofecoxib, valdecoxib, parecoxib
Directly targets the COX-2 without affecting the COX-1. COX-1 is involved in the
synthesis of PGs & Thromboxane but COX-2 is only involved in the synthesis of PGs.
Therefore inhibition of COX-2 inhibits only PGs synthesis without affecting
thromboxanes & thus has no effect on platelet aggregation or blood clotting.
COX-2 is an enzyme responsible for inflammation & pain. Selectivity for COX-2 reduces
the risk of peptic ulceration.

10.Sulfonanilides:
E.g. nimesulide
Selective COX2 inhibitor but less anti-inflammatory action.
It also inhibit superoxide formation.

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It also inhibit the release of histamine, so can be used in shock or anaphylactic reaction.
Dose: 2mg/kg mostly available as oral preparation

11.Miscellaneous group:
E.g. flumixin, meglumine
Flumixin all 3 actions are very potent
Dose: @ 1mg/kg, I/V or I/M
Meglumine 2.2mg/kg, I/V in large animals.

One drug not fits in any category

I.e. xylazine
potent sedative & analgesic drug & muscle relaxant
It has got analgesic property similar to morphine not has any CNS stimulant activity.
Potent sedative drug
Very good muscle relaxant.
Mechanism of action:
o It acts on 2 adrenergic receptor present in brain only. So it is 2 adrenergic receptor agonist.
o It inhibits neuronal transmission hence it is good muscle relaxant.
o It causes stimulation of vomiting centre in brain & invariably causes vomition.
Side effects of xylazine in dogs & cats:
o It causes bradycardia & hypotension (low B.P & low heart rate)
It also causes aerophagia (taking air inside) in ruminants & causes bloat in rumen.
The margin of safety is very good in xylazine.
Ruminants are very sensitive to xylazine so they require 1/10th of the dose of dog & cats.
Pigs are insensitive to xylazine, so not a drug of choice in pigs.
I/M get effect in 10-15 minutes.
I/V get effect in 3-5 minutes.
Sedative effect last for 1-2 hours & complete recovery in 5-6 hours.
Dose:
Small animals 1-2mg/kg, I/M 0.5-1mg/kg, I/V
In ruminants 0.1-0.2mg/kg, I/M
Clinical uses:
1) Preanaesthetic
2) Minor surgical operations
3) Normal restraining of animal
4) Used in major operation like caesarean operation, in this xylazine is given & then operation is
performed by giving local anaesthesia.
5) Xylazine + ketamine combination is used in cats for major operation.
11-44mg/kg ketamine muscular rigidity
1-2mg/kg, I/M xylazine muscle relaxant & sedative.
6) In horse xylazine + ketamine + diazepam combination is used.
In xylazine toxicity, antidote yohimbine (0.1mg/kg, I/V)

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 VPT 311

CNS STIMULANTS
Those drugs stimulate nervous system.
Classified in 3 categories:
I. Predominately cortical stimulator
II. Predominately medullary stimulator Direct CNS stimulator
III. Predominately spinal stimulator
Nicotine, ammonia & lobeline Indirect or Reflexly CNS stimulator (clinically not used)

I. Cortical stimulator

A. Xanthine derivatives: these are alkaloid obtained from tea & coffee. Basically 3 alkaloids
a) Caffeine: 1,3,7-trimethylxanthine, obtained from coffee seed (Coffee arabica)
It affects dieresis, CNS & cardiovascular system
Mechanism: 4 mechanisms
1) It releases Ca+2 from the sarcoplasmic reticulum (skeletal & cardiac muscle) & also blocks the
adenosine receptors.
2) Phosphodiestrase inhibition & release of Ca+2 & probably exerted at concentrations much
higher than the therapeutic plasma concentration, while adenosine receptors blockade.
3) cAMP is metabolized by enzyme phosphodiestrase, it causes inhibition of phosphodiestrase
enzyme & more cAMP is available. So there is more steroid synthesis & release of hormones.
4) This caffeine causes im la i n f -adrenergic receptors so it causes cardiac stimulation.
Caffeine acts on adenosine receptors & block them & due to this blockage there is inhibition
of depression of cardiac pacemaker.
Clinical uses:
Given orally or I/M, when given I/M sodium-benzoate is added in caffeine which
increases solubility of it.
It is generally used in severe case of narcotic depression or sedation.
Dose: horse & cattle total dose 4mg
Sheep & goat total dose 1-1.5mg
Cat & dog total dose 100-500mg
In general there is wide margin of safety but in heavy dose lead to convulsion.
b) Theobromine: 3,7-dimethylxanthine, obtained from cocoa seeds (Theobroma cacao)
Mild effect on CNS, mainly affect cardiovascular system & dieresis.
c) Theophylline: 1,3-dimethylxanthine, obtained from tea leaves (Thea sinensis )
(Aminophylline semisynthetic)
Commonly available
o Having less CNS stimulant activity but more bronchodialator activity.
o Increases cardiac activity
o It got diuretic effect.
o It is more commonly used in respiratory depression like asthma etc.

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o It is used in congestive heart failure.

o It is commonly used in condition in horses called as Broken wind
o Dose: dog total dose = 50mg
Horse/other 1-2mg/kg, orally or I/M or I/V
o In human it is used as spray.
o Asthalin spray aminophylline/salbutamol
Out of above 3, theobromine clinically not used.

B. Sympathomimetics:
o Commonly used amphetamine & ephedrine
o They are power pressure drugs increase B.P & cardiac output
o Amphetamine dextrorotatory (CNS stimulation) & leavorotatory (cardiovascular drug)
form.
o Dextrorotatory form causes temporary stimulation of nervous system which increases mental
& physical activity. So it is drug abuse for dopping (in horses)
o It has got effect anorexigenic effect which causes anorexia (loss of appetite), so it is used as
anti-obesity effect.
o Dose: 3-4mg/kg, S/C or I/M
o Ephedrine similar to amphetamine, given orally, 3-4mg/kg

II. Medullary stimulator

These are mainly respiratory stimulant & also called analeptics.
Clinical uses:
1) Used in post anaesthetic depression
2) Used in asphyxia
3) Used in neonate asphyxia
4) Used in drwning
5) Used in barbiturate poisoning
6) Used in heat & electric shock
7) Used in chronic hypoventilation with CO2 retention.
Compounds:
i) Doxapram:
It stimulates medullary respiratory centre & it acts on chemo-receptors present in carotid
arteries & aortic arch & stimulates the respiration & also increase the B.P.
Most superior respiratory stimulant, it has got very short duration of action.
It is used as an antidote of thiopentone toxicity.
Dose: dog 1-2mg/kg, I/V
Cattle & buffalo 0.5mg/kg, I/V
ii) Leptazol, metrazol:
Stimulation of medullary respiratory centre.
Stimulation of vasomotor centre so increase blood supply.
Inhibition of GABA leads to stimulation
Acts very rapidly but is has very low margin of safety.

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Dose: dogs & cats total dose 50-100mg, I/M

Horse & cattle total dose 0.5-1mg, I/M
Given in case of extensive barbiturate depression.
iii) Nikethamide: (Coramine)
Derivative of the nicotinic acid, action similar to doxapram
It initially causes stimulation & lately depression.
Commonly used in barbiturate & morphine depression.
Available orally mainly given in small animals
Dose: dog & cat 22mg/kg, orally or I/V or I/M or S/C
Available as drops
iv) Picrotoxin: (cocculin)
Natural compound obtained by seeds of plant Anamirta cocculus.
Get effect on medulla as well as spinal cord.
It is non-competitive antagonist of GABA.
Margin of safety is less.
As it stimulates spinal cord, it causes convulsion, so no use.
v) Bemigride: (antagonist of barbiturate)
Clinically used in barbiturate poisoning.
Dose: 20mg/kg, I/V
vi) CO2: (physiological analeptic)
When CO2 concentration increase in blood it stimulate respiratory centre.
CO2 can be given eternally & causes respiratory stimulation.
It causes severe acidosis when given externally.

III. Spinal stimulants

i) Strychnine
Alkaloid derived from seed of plant Strychnos nux-vomica.
Commonly available as nux vomica powder .
Basically acts on spinal cord.
In brain reinshow cell present & it does not allow impulse to pass continuously (motor
impulse) & this strychnine blocks these reinshow cells & give exgraded response &
motor impulse passes out.
GABA act on brain
Inhibitory neurotransmitter
Glycine act on spinal cord
So this strychnine causes inhibition of these GABA & Glycine, will cause exgrated
response & lead to condition hyperaesthesia
It causes severe convulsion & muscular spasm.
Clinically used very limited used as nervine tonic.
Powder form dose:
Horse & cattle 15-16mg
Sheep & goat 10-15mg
Pig 5-8mg always orally

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VPT 311

Dogs 0.5-1mg
Cats 0.1-0.5mg
The powder is dissolved & form solution & then given orally.

MUSCLE RELAXANTS
All these agents cause muscle paralysis, so used in convulsion & extreme contration.
They either cause flaccid or spastic paralysis.
These terminology more used for neuromuscular blockage.
These are divided into 2 groups:
I. Centrally acting:
Act on brain, but not cause anaesthesia. They expected to control muscle contraction.
E.g
i) Diazepam:
It is not specific for muscle relaxation.
ii) Mephenesin:
Specific centrally acting muscle relaxant & least effect on CNS.
Not used clinically, due to various adverse reactions (it causes thrombosis & haemolysis)
It acts on both skeletal & smooth muscle all centrally acting muscle relaxant.
iii) Guaifenesin:
Commonly used muscle relaxant.
Common irritant added in cough syrup.
It causes flaccid type of paralysis.
It acts as glycine agonist
It acts on monosynaptic & polysynaptic motor nerve.
It has got wide margin of safety.
Used as cough syrup.
Controlling convulsion, due to strychnine poisoning & tetanus convulsion.
But not used against GABA induced convulsions.
If given I/V haemolysis, so given orally mostly.
iv) Baclofen:
It has GABA like activity, so it can be used in reduce spasticity in neurological disorders.
v) Methocarbamol:
Mechanism not clear
Used in dog, cat & horse as muscle relaxant.
In dog & cat 40mg/kg, orally
Horse 5-20mg/kg, I/V
vi) Dantrolene:
Directly acting skeletal muscle relaxant.
It inhibits release of Ca+2 from sarcoplasmic reticulum.
It has also some effect on brain.

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It is only specific & effective treatment for malignant hyperthermia, a life-threatening disorder
triggered by general anaesthesia.
Dose: dog 2.5mg/kg, I/V
Horse & pig 1-3mg/kg, I/V

II. Peripherally Acting/Skeletal Muscle Relaxant/Neuromuscular Blockers

Act on neuromuscular end plate & called as neuromuscular blockade.
COMPETITIVE BLOCKER NON-COMPETITIVE BLOCKER
Non-depolarizing Depolarizing
Reversible blocker Irreversible blocker
Flaccid paralysis Spastic paralysis
I. Natural compounds E.g.
d-tubocurarine (obtained from plant Succinylcholine (suxamethonium)
Candrodendrum tomentosum or pot Decamethonium
curare) -toxin present in venom of poisonous snake
E.g.
II. Synthetic compounds like cobra
Gallamine
Pancuronium
Alcuronium

Both of these groups have antagonistic effect, if given together so combination has no effect at all.

Pharmacological effects of neuromuscular blockers:

Effect on Cardiovascular system:- severer vasodilatation fall in B.P
Most of these agents when given rapid I/V injection, release histamine which causes anaphylactic
reaction, severe bronchoconstriction leads to shock & death. So given in diluted form very slowly.

Clinical uses:
1) As preanaesthesia
2) In convulsion disorder
3) Capturing the wild animals
Dose:
1) d tubocurarine:
Cat, dog, pig 0.4-0.5mg/kg
Small ruminants 0.06mg/kg
2) Gallamine:
Dog & cat 0.1mg/kg
Rest animals 0.5mg/kg
3) Succinylcholine:
Dog & cat 0.5-1mg/kg
Cattle, buffalo & horse 0.04-0.05mg/kg

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MOOD ELEVATORS
Used in human in case of depression. Also called as thymoleptics/antidepressant.

Types of antidepressents:
1) Selective serotonin reuptake inhibitors (SSRIs)
E.g. citalopram, fluoxetine, fluvoxamine etc.

2) Selective serotonin reuptake enhancers (SSREs)

E.g. tianeptine

3) Serotonin-norepinephrine reuptake inhibitors (SNRIs)

E.g. duloxetine, milnacipram, venlafexine

4) Tricyclic antidepressant (TCAs)

E.g. imipramine, desimipramine, trimipramine, amitriptyline, clomipramine

5) Monoamine Oxidase inhibitors (MAO-inhibitors)/MAOIs

E.g. selegiline, iproniazid, isocarboxazid, moclobemide, mitheum chloride
Moclobemide reversible inhibitor of monoamine Oxidase A (RIMA)

Neurotransmitters in nervous system:

1) Neurotransmitters: chemicals released from nerve terminal & acts on specific receptor
2) Neuromodulators: these are chemicals which are released from cells other than neurons &
away from syneptic site but got effect on nervous system.
3) Neuroregulators: these are released from neurons but does not enter in circulation but affect
the functioning of other neurons.

Neuro-peptide

Neurotransmitter

Non-peptide
Neuro-peptide Non-peptide
Mol.Wt.> 300 Small molecule, Mol. Wt. < 200
Slow onset of action but for prolonged period Act very rapidly & short period of action
Released by Gut Two subgroups:
CCK (Cholecystokinin) 1) Amine:
Dr. H. B. Patel & Satyajeet singh
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VPT 311

Substance-P (bradykinin) Acetylcholine

Endogenous opioids Dopamine
ACTH Norepinephrine
Angiotensin 5-HT
Histamine
2) Amino acid:
L-glutamate
L-aspartate
GABA
Glycine

Amine:
1) Acetylcholine:- it acts on nicotinic & muscarinic cholinergic receptors, stimulating in action
2) Dopamine:- act on D1 & D2 receptors, depression in action. Whenever excess of dopamine
causes schizophrenia & deficiency causes parkinson s disease.
3) Theses act on & receptors:
a) Norepinephrine:- stimulator/inhibitor
b) 5-HT/serotonin:- act on serotonin receptor. These are of 7 types 5HT1 to 5HT7. Basically
inhibitory in function & induces sleep.
c) Histamine:- act on H1, H2 & H3 receptors, action is inhibitory

Amino acid:
1) L-glutamate:- stimulation mammary function
2) L-aspartate:- stimulatory
3) GABA:- inhibitory
4) Glycine:- inhibitory

Antagonist:-
drug that interact with receptor or other component of effector mechanism & inhibits action of agonist.
1) Pharmacological antagonist:- receptor same
a) Competitive:- e.g. atropine, propranolol
b) Non-competitive:- e.g. organophosphate pesticide
2) Physiological antagonist:- opposing effect by other receptor
3) Chemical antagonist:- 2nd drug for changing structure of 1st drug
4) Physical antagonist:-e.g. adsorbent, charcoal, kaolin

Dose ratio:-effect of antagonism measured in term of dose ratio.

Dose ratio = ED50 after antagonism

ED50 before antagonism

Double reciprocal plot of Lineweaver & Burk method to analyse drug antagonism

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Therapeutic index more more selectivity of drug

Second messengers:-
The cytoplasmic components which carry forward the stimulus from the receptor are known as 2 nd
messenger. E.g. cAMP, cGMP, Ca+2, G-protein, IP3, DAG
1st messenger is being the receptor itself.
1) cAMP:- as 2nd messenger by Sutherland. In energy metabolism, cell division & differentiation,
ion transport, smooth muscle contraction
2) cGMP:- cardiac cells, bronchial smooth muscles.
3) IP3:- release Ca+2 from intracellular store
4) DAG:- activate protein kinase C & control phosphorylation of amino acids.
IP3 & DAG:- by michell. Both are degradation products of membrane phospholipid.
5) Ca+2:- bind to protein calmodulin. Release arachidonic acid by activating phospholipase &
initiate synthesis of PGs & leukotrienes.
6) G-proteins:- it is only 2nd messenger present on cell membrane, other all are intracellular. It is
consist of , & .

Basket cells hippocampus, cerebellar cortex

Granule cells olfactory bulb
Purkinje cells cerebellar cortex
D-cells spinal cord
Pyramidal cells/giant cells cerebrum

Important points:
-globulin fraction is separated from serum by dialysis.
Riboflavin stains the urine
A drug that reverses plasma-protein binding is termed as protein hydrolysate
Methotrexate never used with aspirin.
Antidote of heparin overdose is protamine sulfate.
AlCl3 is mainly used as antiperspirant.
Salicylic acid is primarily used as keratolytic agent.
All tetracycline antibiotics are destroyed by alkali hydroxides.
Moxan (moxalactam) is most closely related to cephalosporins
Drug of choice for leprosy sulfone therapy
Drug used in treating 2nd & 3rd degree burn is mafenide (trade name = sulfamylon)

Parts of prescription:
1) Date:-
2) Identity of owner & detail of patient:-
3) Superscription:-
Rx means you take & symbol of roman god Jupiter

Dr. H. B. Patel & Satyajeet singh

~ 89 ~
VPT 311

4) Inscription:-
It is heart of prescription in which drug dose, route & ingradients are written
Curative/basis
Adjuvant enhance action of curative drug
Corrective prevent untoward reaction of curative/adjuvant
Vehicle suitable medium
5) Subscription:-
Directions for pharmacist to compound & diagnose the medicine.
6) Transcription:-
Directions given to owner to administer drug
7) Prescriber signature:-

Instruments:
1) Plethismograph:- used for screening of anti-inflammatory activity of drug.
2) Hg-manometer:- for recording blood pressure of animal.
3) Metabolic cages:- for effect of diuretic & antidiuretic drug.
4) Convulsiometer:- study of effect of anticonvulsing effect of drug.
5) C k le climbing a a a :- for screening effect of drug on CNS
6) Analgesiometer:- for studying analgesic property of drug.
7) Magnus apparatus/heart perfusion assembly:- study the effect of various drugs on heart.
8) Actophotometer:- for measuring Spontaneous Motor Activity (SMA)

Dr. H. B. Patel & Satyajeet singh

~ 90 ~
Class Notes- VPT 321

E.g. zafirlukast, montelukast

7) Anti-inflammatory agents:
E.g Beclomethasone,
Budesonide
Flunisolide
Fluticasone used as Inhalor
Mometasone
Triamcinolone
Prednisolone used in horse for relief from COPD

5. Analeptics:
Drugs which stimulate the respiration & they are used to relieve the respiratory depression
especially due to overdose of anaesthesia or due to toxicity of other CNS depressant drugs.

E.g

a) Doxapram
Dose: Horse: 0.5-1.0 mg/kg, I/V
Dog & cat: 1.0-5.0 mg/kg, I/V
Foal: 0.02-0.04 mg/kg, I/V
b) Nikhetamide
Dose: 2-4 mg/kg, P/O or I/M or I/V
c) Methyl xanthine:
Stimulate the medullary respiratory centre.
E.g caffeine

AUTOCOIDS
Auto = self, coids = remedy

Also called “local hormone” (because they synthesized locally & act locally & degraded
quickly)

While hormone synthesized by specific gland, poured into blood stream & carried to target
cell.

Autocoids have 3 classes:

1) Amines

By Dr. H. B. Patel & Satyajeet Singh ~ 84 ~

Class Notes- VPT 321

E.g histamine, 5-HT

2) Lipids
E.g. PAF, Eicosanoids

3) Peptides
E.g. Angiotensin, rennin, bradykinin

Histamine
Source:

Animals, plants, bacteria, venom.

Found in all tissue, higher in lungs, skin, GIT, mast cells, histaminergic neurons in brain.

Synthesis:

l –histidine

Histidine decarboxylase

Histamine

N-methyl histidine

N-methyl histamine imidazoleacetic acid (IAA)

N-methyl imidazoleacetic acid urine

Physiological functions of histamine:

1) contraction of intestinal smooth muscle

2) sensation of pain & itching in CNS
3) tissue growth & repair
4) body temperature regulation
5) stimulation of gastric secretion (H2)
6) cardiac stimulation (H2)
7) vasodilation (H1)
8) increased vascular permeability (H1)
9) contraction of most smooth muscle, except blood vessels (H1)

Pathological functions of histamine:

By Dr. H. B. Patel & Satyajeet Singh ~ 85 ~

 Class Notes- VPT 321

1) peptic ulcer
2) itching/pain
3) vasodilation/decreased B.P
4) type I hypersensitivity reaction

o Histamine produces effects by acting on H1, H2 or H3 (and possibly H4) receptors on

target cells.
o All receptors are excitatory except vascular smooth muscles.

I. H1 receptors:

Location
o Smooth muscles of intestine
o Smooth muscles of bronchi
o Smooth muscles of blood vessels
o Uterus
o Brain
Functions:
o Contraction of intestinal smooth muscle
o Constriction of bronchi
o Relaxation of vascular smooth muscles
o Vomition induction
o CNS stimulation
o Afferent nerve stimulation
H1 agonist:
Histaprodifen
H1 blockers:
Mepyramine, phenaramine

II. H2 receptors:

Location:
o Gastric parietal cells
o Heart
o Brain
o Mast cells
Functions:
o stimulation of gastric secretion
o increase heart rate
o CNS excitation

H2 agosnists:
Amthamine

By Dr. H. B. Patel & Satyajeet Singh ~ 86 ~

 Class Notes- VPT 321

H2 blockers:
Ranitidine, cimetidine, roxatidine

III. H3 receptors:

Location:
Brain

Function:
Excitation in brain

H3 agonist:
α-Methylhistamine, imetit, immepip

H3 blockers:
Thioperamide

Pharmacological effects of histamine:

1) Vascular smooth muscles:
Cause intense vasodilation producing hypotensive crisis.

2) Heart:
Increase force of Contraction (Positive Inotropic effect)
Increase heart rate (Positive Chronotropic effect)
Increase coronary blood flow

3) Triple response:
Intradermal injection of histamine causes flush, flare & weal formation known as
triple response.
Flush reddening at the point of injection (local vasodilation)
Flare surrounding redness (in sensory nerves releasing a peptide mediator)
Weal escape of fluid from capillary (direct action on blood vessels)
Sting of bee, scorpion contain histamine.

4) Extravascular smooth muscles:

o Bronchiole muscle
Constriction in man
Relaxation in cat, sheep, rat

o GIT
Increase motility & tone
Increase secretion of gastric acid

5) S/C injection:
Causes pain & itching

By Dr. H. B. Patel & Satyajeet Singh ~ 87 ~

Class Notes- VPT 321

ANTIHISTAMINES :

Mechanism of action:
1) Release inhibitors: reduce the degranulation of mast cells that results from
antigen-IgE interaction, so no membrane lysis of mast cells & no histamine
release.
E.g. Corticosteroids, cromolyn, nedocromil

2) Physiologic antagonist: it causes vasoconstriction so no effect of histamine

release action.
E.g. epinephrine
Injection of epinephrine can be lifesaving in systemic anaphylaxis in which
massive release of histamine.

3) Histamine receptor antagonists

Classification of H1 blockers:
1) Ethanolamine derivatives
E.g. diphenhydramine, carbinoxamine

2) Ethylenediamine
E.g. pyrilamine, antazoline

3) Alkyl amine (selective H1 blocker)

E.g. pheniramine, chlorpheniramine, bromopheniramine

4) Piperazine
E.g. hydroxyzine, cyclizine, meclizine

5) Phenothiozine
E.g. promethazine, trimeprazine

6) Miscellaneous
E.g. cyproheptadine

Other classification:
1) Highly sedative
E.g. promethazine, diphenhydramine

2) Moderately sedative
E.g. cyproheptadine, pheniramine

3) Mild sedatives
E.g. chlorpheniramine (Avil), cyclizine
By Dr. H. B. Patel & Satyajeet Singh ~ 88 ~
Class Notes- VPT 321

4) Non-sedative
E.g. cetrizine, astemizole, fexofenadine

Pharmacological effects antihistamine:

1) Antihistaminic effect
2) Antimuscarinic effect
3) Antiemetic effect (E.g. cyclizine, promethazine)
4) CNS sedation (but not by cetrizine)
5) Local anaesthetics (E.g. promethazine, diphenhydramine)

Clinical uses of antihistamines:

1) Allergic disorders
2) Anaphylactic syndrome
3) Motion sickness
4) Eczema
5) Sedation
6) Preanaesthetic

Serotonin/5-HT/5-Hdroxytryptamine
Serotonin was the name given to an unknown vasoconstrictor substance found in the serum
after blood had clotted. It was identified chemically as 5-hydroxytryptamine in 1948 and
originate from platelets. It was subsequently found in the gastrointestinal tract and central
nervous system (CNS), and function both as a neurotransmitter and as a local hormone in the
peripheral vascular system.

Distribution, biosynthesis & degradation:

5-Hydroxytryptamine occurs in the highest concentrations in three organs.

1) In the wall of the intestine. Over 90% of the total amount in the body is
present in the enterochromaffin cells in the gut.
2) In blood. 5-HT is present in high concentrations in platelets, which accumulate
it from the plasma by an active transport system and release it when they
aggregate at sites of tissue damage.
3) In the CNS. 5-HT is a neurotransmitter in the CNS.

5-HT arises from a biosynthetic pathway similar to that of noradrenaline, except that
the precursor amino acid is tryptophan instead of tyrosine. Tryptophan is converted
to 5-hydroxytryptophan (in chromaffin cells and neurons, but not in platelets) by
the action of tryptophan hydroxylase. The 5-hydroxytryptophan is then
decarboxylated to 5-HT by amino acid decarboxylase. Platelets possess a high-

By Dr. H. B. Patel & Satyajeet Singh ~ 89 ~

Class Notes- VPT 321

affinity 5-HT uptake mechanism, and platelets become loaded with 5-HT as they
pass through the intestinal circulation.
The mechanisms of synthesis, storage, release and reuptake of 5-HT are very similar
to those of noradrenaline. Many drugs affect both processes randomly, but selective
serotonin reuptake inhibitors (SSRI) have been developed and are important
therapeutically as antidepressants.
5-HT is often stored in neurons and chromaffin cells as a cotransmitter together
with various peptide hormones, such as somatostatin, substance P or vasoactive
intestinal polypeptide.

Degradation occurs mainly by monoamine oxidase, forming 5-hydroxyindoleacetic

acid (5-HIAA), which is excreted in urine

Pharmacological effects of 5-HT:

1) GIT
By 5-HT1 increases secretion & peristalsis
By 5-HT3 slow the motility of intestine
2) Smooth muscles of uterus & bronchiole: causes contraction
3) Platelets: platelet aggregation by 5-HT2 receptor
4) CNS: 5-HT excites some neurons and inhibits others
5) Nerve endings: 5-HT stimulates nociceptive (pain-mediating) sensory nerve
endings by 5-HT3 receptor. If injected into the skin, 5-HT causes pain.

Classification of 5-HT receptor:

Currently there are 15 known receptor subtypes. These are divided into 7 classes (5-HT1-
7), with further subtypes of 5-HT1 (A-F) and 5-HT2 (A-C). All are G-protein-coupled
receptors, except 5-HT3, which is a ligand-gated cation channel.

Main 5-HT receptor subtypes

Receptor Location Main effects Agonists Antagonists

Neuronal inhibition
Spiperone
Behavioural effects: sleep, Buspirone
1A CNS Methiothepin
feeding, thermoregulation, 5-CT
Ergotamine (PA)
anxiety
CNS
Presynaptic inhibition
Vascular
1B Behavioural effects Ergotamine (PA) Methiothepin
smooth
Pulmonary vasoconstriction 5-CT
muscle
CNS Cerebral vasoconstriction
Sumatriptan Methiothepin
1D Blood Behavioural effects:
5-CT Ergotamine (PA)
vessels locomotion
CNS Neuronal excitation Ketanserin
2A LSD
PNS Behavioural effects Cyproheptadine

By Dr. H. B. Patel & Satyajeet Singh ~ 90 ~

Class Notes- VPT 321

Smooth Smooth muscle contraction Methysergide

muscle (gut, bronchi, etc.)
Platelets Platelet aggregation
2B Stomach Contraction α-Me-5-HT -
CNS
α-Me-5-HT
2C Choroid Cerebrospinal fluid secretion Methysergide
LSD
plexus
Neuronal excitation
(autonomic, nociceptive Ondansetron
PNS
3 neurons) Chlorophenyl- Tropisetron
CNS
Emesis biguanide Granisetron
Behavioural effects: anxiety
5-Methoxy-
PNS (GI Various experimental
Neuronal excitation tryptamine
4 tract) compounds (e.g. GR113808,
increased GI motility Metoclopramide
CNS SB207266)
Tegaserod
5 CNS Not known Not known Not known
6 CNS Not known Not known Not known
CNS
GI tract 5-CT Various 5-HT2 antagonists
7 Not known
Blood LSD No selective antagonists
vessels

2-Me-5-HT = 2-methyl-5-hydroxytrypamine
5-CT = 5-carboxamidotryptamine
LSD = lysergic acid diethylamide
PA = partial agonist
α-Me-5-HT = α-methyl 5-hydroxytrypamine

Actions and functions of 5-hydroxytryptamine:

Important actions are:

o increased gastrointestinal motility (direct excitation of smooth muscle and

indirect action via enteric neurons)

o contraction of other smooth muscle (bronchi, uterus)

o mixture of vascular constriction (direct and via sympathetic innervation) and

dilatation (endothelium-dependent)

o platelet aggregation

o stimulation of peripheral nociceptive (pain sensitive) nerve endings

o Excitation/inhibition of central nervous system neurons.

Physiological and pathophysiological roles include:

o In periphery: peristalsis, vomiting, platelet aggregation and haemostasis,

inflammatory mediator, sensitisation of nociceptors and microvascular control

o In CNS: many postulated functions, including control of appetite, sleep,

mood, hallucinations, stereotyped behaviour, pain perception and vomiting.

By Dr. H. B. Patel & Satyajeet Singh ~ 91 ~

Class Notes- VPT 321

Clinical conditions associated with disturbed 5-hydroxytryptamine function include

migraine, carcinoid syndrome, mood disorders and anxiety.

Eicosanoids
In mammals, the main eicosanoid precursor is arachidonic acid.
The initial and rate-limiting step in eicosanoid synthesis is the liberation of arachidonic
acid, from phospholipids by the enzyme phospholipase A2 (PLA2).

The free arachidonic acid is metabolised by several pathways, including the following:

o Cyclo-oxygenase (COX). Two main isoform forms, COX-1 and COX-2,

transform arachidonic acid to prostaglandins and thromboxanes.

o Lipoxygenases. Several subtypes synthesise leukotrienes, lipoxins.

Platelet Activating Factor/PAF

PAF is released from activated inflammatory cells by phospholipase A2 and acts on
specific receptors in target cells.

Pharmacological actions include vasodilatation, increased vascular permeability,

chemotaxis and activation of leucocytes (especially eosinophils), activation and
aggregation of platelets, and smooth muscle contraction.

PAF is implicated in bronchial hyperresponsiveness and in the delayed phase of

asthma

Bradykinin

BK is a peptide 'clipped' from α-globulin, kininogen, by kallikrein.

It is converted by kininase I to an octapeptide, BK1-8, and inactivated by kininase II
(angiotensin-converting enzyme) in the lung.

Pharmacological actions:
o vasodilatation
o increased vascular permeability
o stimulation of pain nerve endings
o stimulation of epithelial ion transport and fluid secretion in airways and
gastrointestinal tract
o Contraction of intestinal and uterine smooth muscle.
There are two main subtypes of BK receptors: B2, which is constitutively present, and
B1, which is induced in inflammation.

By Dr. H. B. Patel & Satyajeet Singh ~ 92 ~

Autonomic Nervous System
Dr R D Singh
 Anatomical divisions / Organization of the
Nervous System
• The nervous system is divided into central
nervous system and peripheral nervous
system (CNS & PNS).
• ANS - involuntary, innervates smooth muscle,
cardiac muscle, glands, etc., at neuro-effector
junctions.
• SMS (Somatic Nervous System) -voluntary,
innervates skeletal muscle at neuromuscular
junctions.
Sensory = Afferent
Motor = Efferent
 CNS ANS
One of two main divisions of the One of the Part of PNS. Other is
nervous system somatic nervous system.
The part of nervous system consisting Composed of sympathetic,
brain and spinal cord parasympathetic and enteric
nervous systems
Occurs in the dorsal body cavity Occurs in the periphery of the body

Main function is to receive sensory It controls and co-ordinates

output from the peripheral nervous involuntary functions of the body
system (PNS), process and send like functions of heart, digestion,
necessary information to the various respiration, pupilary response,
parts of the body through the PNS. urination etc.

In simpler terms, CNS act as CPU of the computer, and

ANS connects brain with organs
Somatic nervous system Autonomic nervous system
Involves both afferent and efferent Involves only the efferent pathway
pathways
Perform voluntary activities Control involuntary activities
including locomotion.
Effectors are skeletal muscles Effectors are cardiac muscles,
smooth muscles, fat cells, glands,
viscera etc.
Efferent signals originate at the Unconscious signals originate in
cerebral cortex as a conscious hypothalamus, brain stem, and
decision and activate neurons in the spinal cord and activate target
brainstem or spinal cord neurons that lie in the peripheral
nervous system
No synapse : One neuron (efferent ) Synapse within ganlion .
system with mylelinated axons (fast Presynaptic axons: myelinated
conduction) Postsynaptic axons: non-myelinated
 Autonomic Nervous System (ANS)
• It is also known as the visceral, vegetative or involuntary
nervous system widely distributed throughout the body
controlling the so called autonomic or vegetative functions.
• The ANS mediates the body's response to emergency
situations.
• ANS conserves energy and maintains homeostasis.
• The ANS regulates activity of structures like the smooth
muscles, cardiac muscle and secretory glands other than
endocrine glands.
• The ANS is responsible for maintaining respiration, blood
pressure, heart rate, eye function, gastrointestinal activity,
urinary output and virtually all visceral functions within
well defined, physiologic limits.
Components: Afferent, Central and Efferent
Afferent and Efferent Neurons
 AFFERENT FIBRES

– It is the first link in the reflex arcs of the ANS.

– Arise from visceral structures
– Generally non-myelinated
– Cell bodies are in the dorsal root ganglia of spinal
nerves and sensory ganglia of cranial nerves
– Convey information to the brain and then to the
system to be acted upon by efferent fibres.
 Central connections (CNS)
• Within CNS afferent information is processed,
integrated and responses initiated. The structures
involved are:
– Spinal cord – It directly connect afferents and efferents,
mediates reflex changes in blood pressure, sweating and
micturation
– Medulla oblongata – It controls blood pressure and
respiration
– Hypothalamus - It is the principal locus of integration,
control body temperature, water balance, carbohydrate
metabolism, sexual reflexes and autonomic emotional
responses
– Cerebral cortex - It controls volitional changes and
conditioned autonomic responses.
 EFFERENT FIBRES
• In efferent fibres, two neurons (Preganglionic and
Post ganglionic fibres) with effector cells / target
organs are generally involved.
• Preganglionic fibres
– Exit the spinal cord and terminate in ganglia
– Acetylcholine (ACh) is the neurotransmitter released by
the preganglionic nerves in autonomic ganglia. This
connection is known as nicotinic cholinergic synapse.
• Postganglionic fibres
– Exit from ganglia and innervate the effector cells /organs
– Neurotansmitters released at the neuroeffector
junctions depending on the innervations
• ACh mediates muscarinic cholinergic transmission
• Norepinephrine mediates adrenergic transmission
Thank You
Divisions of Autonomic Nervous System:
Sympathetic and Parasympathetic
Nervous Systems
Dr R D Singh
• ANS comprises of Parasympathetic and Sympathetic divisions
• Major Activities of Parasympathetic and Sympathetic divisions
Organ/system SYMPATHETIC PARASYMPATHETIC
Activated in Emergency situations, Stressful Resting state
conditions Body at Rest
response to: 3 (F) – Fight, Flight & Fright R & D – Rest & Digest

Eyes Dilated eye pupil – Mydriasis Constricted pupil - Miosis

Heart H.R. and force of contraction H.R. and force decreased

both increased; B.P. increased. (Beats more slowly)
(Beats faster & stronger)

Lungs Relaxes airways to allow breathe Constricts airways

more deeply (Broncho-constriction )
(Broncho-dilation)
Digestion Inhibits digestion Stimulates digestion
(Motility & blood flow (Motility, blood flow &
decreased) peristalsis increased)
Scanty and viscous saliva Watery saliva
Skeletal Muscles Increases blood flow Reduce blood flow
Vasodilation of blood vessels in
skeletal muscles, Glycogenolysis
 Effect of sympathetic and parasympathetic
activations on different body organs
Structure Sympathetic Activation Parasympathetic Activation
Iris (Radial Muscle) Pupil dilated ---
Iris (Sphincter --- Pupils constricted
Muscle)
Glands --- Increased secretion
Lacrimal Increased lacrimation Increased lacrimation
Salivary secretion Scanty viscous and thick secretion Generalized secretion - copious
Sweat in the palms watery secretion
Heart Rate Increased Decreased
Force (Ventricles) Increased Decreased
Blood Vessels Constiction (generally) Slight effect; Dilation in some
Dilation (large blood vessels)
Bronchi Dilated Constricted
Intestine Tone & motility decreased Tone & motility increased
Adrenal Medulla Secretion of epinephrine and ---
norepinephrine
Sex Organs Vasoconstriction, Contraction of Vasodilatation & erection
vas deferens, Seminal vesicle and
Prostatic musculature (ejaculation)
 Sympathetic Nervous System
• Thoracolumbar outflow - preganglionic fibres
originate in the intermediolateral columns of
spinal cord from the 1st thoracic to the 3rd
lumbar vertebrae
• Adrenal medulla is embryologically and
functionally a sympathetic ganglion; innervated
by typical sympathetic preganglionic neurons.
• Adrenal medulla is an exception where ganglionic
transmission causes release of epinephrine
(adrenaline) into the blood.
• Pre-ganglionic fibres are short and usually synapse
well before the target organ in either:
– Vertebral (Para-vertebral) ganglia which include the
cervical ganglia, consisting of 22 pairs on either side of
vertebral column
– Pre-vertebral ganglia in abdomen (celiac, cranial and
caudal mesenteric)
– Innervations are diffuse, with pre-ganglionic to post-
ganglionic ratio upto 1: 20
– Postganglionic fibres are long and innervate target organs
– Fibres from vertebral ganglia innervate blood vessels, the
eyes, salivary glands, heart, bronchi, sweat glands and hair
follicles.
– Fibres from pre-vertebral ganglia innervate the stomach,
intestine, bladder, urinary and rectal sphincters and genital
organs.
 Parasympathetic Nervous Systems
• Craniosacral outflow
• Pre-ganglionic fibres are long
• Cranial nerve no. 3, 7, 9 & 10 are under parasympathetic
nervous system

SN Origin Cranial nerve Synapse formation

1 Midbrain III - Oculomtor Ciliary ganglion
2 Medulla VII - Facial Submandibular ganglia
3 oblongata IX - glosso- otic ganglion
pharyngeal
4 X - Vagus terminal ganglia in the
heart, lungs, liver,
spleen, GI tract, kidney
• Innervation is discrete, with pre-ganglionic to
post-ganglionic ratio of 1:1
• Post-ganglionic fibres are short and innervate
target organs:
– Cranial division innervates the eye, salivary glands,
heart, bronchi, gastrointestinal tract
– Sacral division innervates bladder, colon, urinary
and rectal sphincters and genital organ
 Diff. b/w Sympathetic NS and Parasymp. NS
Sympathetic Nervous Parasympathetic Nervous
Criteria
System System
Outflow from CNS Thoracolumbar Craniosacral
Ganglia Paravertebral; prevertebral Intramural ganglia-close to
close to CNS; a few intra- effector organ
mural ganglia close to organ
Ratio of Preganglionic neurons Preganglionic neurons
preganglionic : synapse with many synapse with few
postganglionic postganglionic neurons. postganglionic neurons.
Diffuse (1:20) Discrete (1:1)
Function “Fight or flight” / energy is Conservation of energy /
spent “Live and let live” / "Rest
and digest"
Effectors Smooth and cardiac muscle, Generally the same as
glands Sympathetic
Transmitters ACh (ganglia), NE ACh (both at ganglia and at
(Neuroeffector junction) neuroeffector junction)
 Single or dual innervations
• In organs receiving both sympathetic and
parasympathetic innervations the effects of the two
divisions are usually opposed or antagonistic.
– Example: Heart, bladder, bronchi, GI tract (even in these
organs one division is usually predominant).
• In organs receiving dual innervations with the
influences of the two divisions in the same direction
and effects are complementary.
– Example: salivary glands ( salivary secretion is viscous and
scanty with sympathetic tone and profuse and watery with
parasympathetic tone)
• In organs receiving only single innervations from one or
the other division of ANS, the neuronal control level of
function is by increasing or decreasing activity.
 Single innervations
Sympathetic Parasympathetic
Adrenal medulla Eye – cilliary muscles
Most blood vessels Gastric galnds
Spleen Pancreatic glands
Hair follicles
Sweat glands

Predominance of type of tone in various structures

Sites /organ where Sites /organ where
Sympathetic (Adrenergic) tone Parasympathetic (Cholinergic)
is predominant tone is predominant
Arterioles Heart: Atrium & SA node
Veins Eye: Iris & Ciliary Muscle
Heart: Ventricle G.I. Tract
Sweat Glands (Sympathetic Urinary Bladder
innervations but NT is Ach) Salivary Gland
 Distribution of cholinergic and
adrenergic neurons
• Adrenergic
– Most postganglionic sympathetic nerves
– Innervations to cardiovascular system
• Cholinergic
– All motor nerves to skeletal muscle
– All postganglionic parasympathetic nerves
– All preganglionic autonomic nerves (including those
to adrenal medulla)
 Adrenergic and cholinergic receptors
Features Adrenergic receptors Cholinergic receptors
Definition Adrenergic receptors are Cholinergic receptors
autonomic receptors are autonomic
that bind to receptors that bind to
Noradrenaline and acetylcholine
adrenaline
Responsible Sympathetic nervous Parasympathetic
nervous system nervous system
system
Responding Noradrenaline and Acetylcholine
neuro- adrenaline
transmitters
Major types Alpha and beta receptors Muscarinic and nicotinic
(α & β) receptors (M & N)
Thank You
 Unit-2
(Drugs acting on ANS)
Neurohumoral transmission
Dr R D Singh
 Neurohumoral transmission
• Neuro : neurons
• Humoral (fluid) : chemical agents:
Neurotransmitters
• Transmission : Propagation/ passage/ transfer
• Transmission of impulses (information) from a
pre-synaptic neuron to a post-synaptic neuron
by means of a humoral agent.
• Neurons in afferent nerve fibres: generally non-myelinated
• Synapse: In ANS, most synapse form within ganglion
Synapse

• Junction between axon terminal

of first neuron and dendrites
(cell body) of second neuron.
• Gap/cleft is known as synaptic
cleft
• Synaptic cleft: 200 to 400 Å
• Junction/ gap between neuron and organ (effector) is
known as neuro-effector junction.
• Conduction
– Passage of nerve impulse along a nerve axon : axonal conduction is
referred as “first step in NHT”.
• Neurohumoral transmission(NHT):
– aka chemical neurotransmission (other is electrical – less common)
– Passage of nerve impulse across the synaptic cleft or neuro-effector
junction
– Through chemicals : NEUROTRANSMITTERS (NTs)
• Neurotransmitters
– Chemicals that is released in the synapse and help in propagation
of nerve impulse and thus in communication between neurons
– Neurotransmitters are synthesized in and released from nerve
endings into the synaptic cleft.
– They bind to receptor proteins present in the post synaptic
membrane of the next neuron or tissue. The post-synaptic
neuron or effector organ/tissue gets excited or inhibited, as per
nature of receptor.
• Excitatory neurotransmitters
– Acetylcholine (ACh) – except in heart
– Norepinephrine (NE): also known as noradrenaline
– Epinephrine: also known as adrenaline
– Glutamate
– Histamine
• Inhibitory neurotransmitters
– gamma-Aminobutyric acid (GABA)
– Serotonin (5-HT)
• Both excitatory and Inhibitory neurotransmitters
– Dopamine
• Neuromodulator
– Synapse-associated chemical substances which does not directly
participate in neurotransmission but may modulate or alter the
release or functions of NTs.
– Generally not synthesised or release at function sites
– Longer action than NTs
– e.g. prostaglandins, neuropeptides, etc.
• Neuromediator
– Function is similar to neuromodulators.
– Enhance the postsynaptic response of specific NTs
– Secondary messengers (cAMP, cGMP, DAG, IP3)
• Co-transmitters
– When a effect is achieved by more than one NTs.
– Presence of two or more NTs within single synaptic terminal
 Principal neurotransmitters in ANS
Nerve endings Sympathetic System Parasympathetic System
Pre-ganglionic (released Acetylcholine (ACh) Acetylcholine (ACh)
in ganglia)
Post-ganglionic Noradrenaline (NA) or Acetylcholine (ACh)
Norepinephrine (NE)

Nerves that release the Acetylcholine

(Ach) as a neurotransmitter are called
as Cholinergic Nerves.

Nerves that release the Nor-adrenaline

or Adrenaline are called as Adrenergic
Nerves.
Steps involved in Neurotransmission
1. AXONAL CONDUCTION
2. NEUROTRANSMITTER RELEASE

3. RECEPTOR EVENTS: Excitatory or Inhibitory

4. INITIATION OF POSTSYNAPTIC ACTIVITY

5. DESTRUCTION OR DISSIPATION OF NTs

6. NON-ELECTROGENIC FUNCTION
 1. AXONAL CONDUCTION
• Impulse generation and propagation is in the form of
action potential (electrical signal), if stimulus is above a
threshold value
• At rest or steady state, nerve cells are at RMP (resting
membrane potential): negatively charged inside cell i.e.
-70 to -85 mV.
• When a stimulus above threshold (-55 V) arrives: Na+ ion
channels opens and due to entry of Na+ ions inside axon
from extracellular space leads to DEPOLARIZATION
 Eq Na+: + 58 mV • DEPOLARIZATION
– Voltage gated Na+
Overshoot
channel
– Occur when -70 mV goes
to -55 mV
Na + in K + out – Entry of Na+ occurs
– These channels
inactivated when action
potential overshoots (0
Na+ - K+ ATPase: to +58 mV)
3 Na+ out, 2+ K in
• REPOLARIZATION
Hyperpolarization
Eq K+ : -93 mV – Due to movement of
voltage gated K+ ions
• RESTING MEMBRANE POTENTIAL
– At rest, the Na+ concentration is high
at extracellular space and low in
intracellular fluid
– Na+/K+ ATPase Exchange Pump
maintains the RMP
– Na+/K+ ATPase : use the energy from
the ATP hydrolysis to move 3 Na+ ions
from the cytoplasm to the exterior of
the cell while simultaneously moving
2 K+ ions from the exterior of the cell
into the cytoplasm
 Resting Membrane Potential -70 to -85 mV

EVENTS IN AXONAL CONDUCTION

stimulus -------------------threshold -55 to -50 mV
Generation of Impulse DEPOLARIZATION
(Action Potential)
0 mV
Overshoot
+ 20 to + 40 mV (Eq for Na+ ion: +58 mV)

REPOLARIZATION
- 70 to -85 mV
HYPERPOLARIZATION (inhibits AP)
- 90 to -120 mV (Eq for K+ ion: -93 mV)
Na+ - K+ ATPase
Resting Membrane Potential -70 to -85 mV
 Toxins interfering with axonal conduction
Name of toxin Source Mechanism Result
Tetradotoxin Puffer fish poison Blocks Voltage Inhibit generation
gated (sensitive) of Action Potential
Na+ channels, so (impulse) even if
blocks entry of Na+ stimulus is above
normal threshold
Batrachotoxin An alkaloid toxin from it causes increase Persistence
south American frog Na+ entry into the depolarization
nerve due to failure
of closure of Na+
ion channels
 2. NEUROTRANSMITTER RELEASE
• NTs are synthesized by nerve cells using enzymes and stored in
Granules or Vesicles inside the cells/neurons in inactive or bound
forms. This process is Ultrafast/Supersensitive.
• At rest, neurotransmitter-containing vesicles are stored at the
terminal of the neuron along the pre-synaptic membrane in
"active zones" and surrounding areas.
• The influx of calcium ions triggers a series of events, which
ultimately results in the release of the neurotransmitter from a
storage vesicle into the synaptic cleft.
• The storage vesicles are held in place by Ca2+-sensitive vesicle
membrane proteins (VAMPs)
 Action Potential arrives at nerve terminals through axonal conduction

Depolarization of nerve membrane at terminals (axonal endings)

RELEASE OF NTs

Activation of voltage-dependent calcium (Ca2+) channels

embedded in the pre-synaptic membrane

Ca2+ ions enter into cell from ECF

Ca2+ ions causes fusion of vesicles to axoplasmic membrane

Release of NTs from vesicles into synaptic cleft by process of exocytosis

 3. RECEPTOR EVENTS: Excitatory or Inhibitory
• Once NT released, it diffuse across the Synaptic Cleft/ junctional
tissues and combines with receptors located on post-synaptic
membrane.
• This interaction of NT and Receptor may initiates two types of
effects:
– Excitatory [Excitatory Post Synaptic Potential (E PS P)]
OR
– Inhibitory [Inhibitory Post Synaptic Potential (I PS P)]
• EPSP is generated due to a general increase in permeability
of PS membrane for all ions and events occurring in a
similar fashion to events in axonal conduction.

• IPSP is generated when NTs initiate an inhibitory response.

In this case, there is selective increase in permeability of
small ions (K+ and Cl-) due to which hyperpolarisation of PS
membrane occurs and thus, threshold to stimuli increases.
 4. INITIATION OF POSTSYNAPTIC ACTIVITY
• Depending upon type of NT released and type of receptor located
at PS membrane there will be NT- Receptor interaction and
accordingly it will produce excitatory (EPSP) or inhibitory (IPSP)
effects on cells/effector organs.
• If EPSP--reaches Post Synaptic Membrane in neurons or skeletal
muscle or cardiac muscle (Effector organ) there is increased
muscle contraction, increased muscle tone, increased secretion
of glands in periphery.
• If IPSP-- no initiation of Action Potential, so no excitation in
effector organs and inhibitory effect is observed
 5. DESTRUCTION OR DISSIPATION OF NTs
• For rapid action of NT, its action must be terminated.
• Three ways to terminate the action of NT:
– Metabolic Degradation: Some specific enzymes inactivate the NTs. These
enzymes are produced by Pre synaptic membranes or by synaptic tissues.
For e.g.
– Ach hydrolysed by Acetylcholinesterase (AchE).
– Nor-adrenaline hydrolysed by COMT & MAO.
• COMT= Catecholamine o-methyl transferase (causes extraneural
hydrolysis)
• MAO= Monoamine Oxidase (causes intraneural hydrolysis)
• End product of Nor-adrenaline oxidation by MAO is VMA (Vanillylmandelic Acid)
2. Reuptake: Certain NTs after their release are taken back into Pre
Synaptic Membrane by specific carrier. E.g. Nor-adrenaline
reuptake by nerve cells terminates its action at synapse.

3. Diffusion: Small amount of NTs are diffused by surrounding tissues

& metabolised locally. E.g. Peptide NTs & Peptidase enzyme.
 6. NON-ELECTROGENIC FUNCTION
• During resting stage small quantity of NTs is released
continuously but not sufficient to initiate the EPSP & IPSP
but require maintaining the physiological responsiveness
of cell/stimuli.
Thank You
 Unit-2
(Drugs acting on ANS)
Pharmacology of Neurotransmitters
Part – 1 Adrenergic transmission
Dr R D Singh
 Pharmacology of Neurotransmitters
• Neurotransmitters in ANS
– Adrenergic transmission
• Noradrenaline (NA/NE)
• Dopamine CATECHOLAMINES
• Adrenaline (Substances having 3,4-di-
– Cholinergic transmission hydroxybenzene and an
amine containing side chain)
• Acetylcholine
 Adrenergic transmission
– Transmission mediated by Nor-adrenaline (or Nor-
epinephrine) at Sympathetic Postganglionic Nerve fibres is
known as Adrenergic Transmission
– Exception: Sweat glands – ACh is the NT.
• Biosynthesis of NE and other catecholamines
• Storage & Release
• Fate (disposition)
• Adrenergic receptors
 Biosynthesis of NE and other catecholamines

• Precursor: Phenylalanine/ l-Tyrosine

(An essential aminoacid)
L-phenylalanine l-Tyrosine
(diet) (liver)
• Site of synthesis:
– Cytoplasm of sympathetic neurons
– adrenomedullary cells
– other chromaffin cells
– specific nuclei in the brain
 In neuron cytosol [Stereospecific enzyme; Rate Limiting Step]

In neuron cytosol (axoplasm)

CATECHOLAMINES

In synaptic vesicles/ storage vesicles

In chromaffin cells of adrenal medulla

This enzyme is ABSENT in adrenergic neurons
Storage and Release :
• Dopamine is transported into vesicles with the help of VMAT
(Vesicuar MonoAmine Transporter)
• In nerve cells, nor-epinephrine is stored in synaptic vesicles along
with ATP (in Adrenal medulla Chromaffin Cells).
• Release of NE is calcium dependent process.
• When action potential arrives, Ca2+ inflow is enhanced, so granules
release nor-epinephrine in synaptic cleft by exocytosis.
• Proteins helpful for release of catecholamines from the vesicles:
– VAMPs : Vesicle associated membrane proteins
– SNAPs : Synaptosomal nerve associated proteins
Feedback/ Auto-regulation:
• There is a self regulatory/Feed Back mechanism in Nor-epinephrine
release.
NE released in Synapse  combines with Presynaptic α2 Receptor
 no formation of cAMP  closing of Ca2+ gated channels &
resultant failure of exocytosis
Destruction/Disposition of Nor-adrenaline:
Enzymes: In mitochondria Liver & Intestinal epithelium
• MAO: Monoamine oxidases (intracellular) Axoplasmic degradation  in
Adrenergic Nerve Terminal
• COMT : catechol-O-methyltransferase (extracellular)  neuronal and
Non-neuronal tissues (circulatory degradation)
• Important metabolites:
– Adrenaline and Nor-adrenaline: VMA or Vanillyl mandelic acid or
3-methoxy-4-hydroxy mandelic acid
– Dopamine: homovanillic acid
• Termination of action of NE is mainly by reuptake of NE into
presynaptic Vesicles.
– 60-70 % reuptake of NE into vesicles (as such)
– 10-20% reuptake into Extraneuronal tissues & enzymatic breakdown by COMT
– 5% bind with receptors
– 15% metabolised by MAO
Reuptake mechanisms for NE:
• Uptake 1: Major part : Active process (energy dependent) : back into nerve
terminal with the help of NETs (NE transporters)– reused
• Uptake 2: in extraneuronal tissues (blood vessels and tissues with wider
junctional gap)
• Uptake 1 has high affinity for noradrenaline than adrenaline.
Site of action of drugs on adrenergic transmission
DRUG ACTION
Reserpine Block the transportation of
dopamine into the storage
vesicles
α-methyl Act as ‘false neurotransmitter’
dopamine in place of dopamine
Bretylium Inhibit exocytosis and release
Guanethidine of noradrenline
Cocaine Inhibit reuptake (uptake-1) of
Imipramine noradrenline
Pargyline MAO - inhibitors
Selegiline
Pyrogallol COMT - inhibitors
Tolcapone
 Adrenergic receptors
• Present in postganglionic sympathetic nervous system
(except: sweat gland and renal blood vessels) supply to all
important viscera
• Also present in Central Nervous system
• Belongs to GPCR super family – membrane bound receptors
• Based on response to adrenergic agonists, classified into two
families: alpha (α) and beta (β).
• Adrenergic agonists: Noradrenaline (aka norepinephrine),
adreneline (epinephrine), and isoprenaline (isoproterenol
i.e. isopropylamine analogue of adrenaline).
 Broad classification & subtypes

Adrenergic Receptor Receptors

Action on secondary
messengers
α1 Activate PLC , IP3 &
α β DAG
α2 Inhibit adenylate
α1 α2 β1 β2 β3 cyclase,
cAMP
All β Stimulate adenylate
All α-Receptors are : Excitatory (except in GIT) cyclase,
All β-Receptors are : Inhibitory (except in Heart) cAMP
 Affinity of adrenergic receptors to agonists
Receptor Order of Affinity Nature
Alpha (α) A ≥ NA >>> Iso (very weak) Excitatory (except in GIT)
α1 A ≥ NA e.g. Vasoconstriction
α2 A = NA Salivary secretions

Beta (β) Iso > A > NA Inhibitory (except in heart)

β1 A = NA (equal response) e.g. Bronchodilation,
β2 A >> NA Positive ionotropic & chronotropic
β3 NA > A effect in heart
(Iso is non-selective β-adrenoceptor agonist
having same affinity for β1 and β2).

A = Adrenaline
NA = Noradrenaline (or NE)
Iso = isoprenaline
The main effects of adrenergic receptors activation are as follows:
α1-receptors: vasoconstriction, relaxation of gastrointestinal smooth
muscle, salivary secretion and hepatic glycogenolysis
α2-receptors: control /inhibition of NT release (including noradrenaline
and acetylcholine release from autonomic nerves), platelet
aggregation, contraction of vascular smooth muscle, inhibition of
insulin release
β1-receptors: increased cardiac rate and force of contraction
β2-receptors: bronchodilatation, vasodilatation (b.v. of skeletal muscle/
liver), relaxation of visceral smooth muscle, uterine relaxation, hepatic
glycogenolysis.
β3-receptors: lipolysis (mainly present in adipose tissues)
Selective agonists and antagonists of adrenergic receptors
Receptors Agonists Antagonists

α1 Phenylephrine Prazosin
Methoxamine
α2 Xylazine Yohimbine
Clonidine
Detomidine
β1 Dobutamine Metoprolol
Atenolol
β2 Salbutamol Butoxamine
Terbutaline
Clenbutarol
β3 --- ---
Thank You
 Unit-2
(Drugs acting on ANS)
Pharmacology of Neurotransmitters
Part – 2: Cholinergic transmission
Dr R D Singh
 Pharmacology of Neurotransmitters
• Neurotransmitters in ANS
– Adrenergic transmission
• CATECHOLAMINES like Noradrenaline (NA/NE)
– Cholinergic transmission
• ACETYLCHOLINE
 Cholinergic transmission
– Transmission mediated by acetylcholine at
parasympathetic and pre-ganglionic sympathetic Nerve
fibres is known as cholinergic transmission
– Also in brain stem and forebrain (CNS), and sweat glands
– Adrenal medulla, Somatic nerves in skeletal muscles
• Biosynthesis of Acetylcholine
• Storage & Release
• Action (Receptor events) & Fate
• Cholinergic receptors
 Biosynthesis of Acetylcholine
• Acetylcholine (Ach) synthesis occurs in axon (cholinergic terminal)
• Acetyl CoA is synthesized in Neurons
• Choline is supplied from Vitamin-B complex as extraneural source

Acetic acid + ATP Acetyl AMP

Acetyl AMP + CoA Acetyl CoA

Choline Acetyltransferase (ChAT)

Acetyl CoA + Choline Acetylcholine + CoA

(Rate limiting process in biosynthesis of ACh is the choline transport)
 Storage & release of Acetylcholine
• After synthesis, ACh is stored into storage vesicles within terminal
• 1 - 50 thousand ACh/Vesicle and > 3 Lakhs vesicles in each nerve terminal
Action Potential/Nerve Impulse arrives at the nerve terminals

Ca2+ channels open

Increased influx of Ca2+ ions

Increased Ca2+ conc. causes fusion of vesicles with cell membrane

Exocytosis of vesicles occurs

Release of Ach into synapse (~ 3 millions ACh on each nerve impulse)

Acetylcholine as neurotransmitter
 Action (Receptor events) & Fate
• Released Ach diffuse across synapse and combines with receptors
located on post-synaptic membranes
• Some Ach receptors are also present at pre-synaptic membrane.
• Interaction with receptors initiates the biological events
depending upon the nature of receptors.
• Action of Ach with receptor lasts only for 2 miliseconds (ms)
• After their action with receptors, Ach dissociated or hydrolysed
into choline & acetyl CoA by enzyme Acetylcholinesterase (AChE).
AChE
Acetylcholine (Ach) 150 microseconds Acetyl CoA + Choline
(Reuptake of choline occurs along with co-transport of sodium ion)
 Acetylcholinesterase (AChE)
• Also known as true or specific cholinesterase
• Present in very high conc. in vicinity of cholinergic synapse
• Also present in RBC and grey matter
• Causes very fast hydrolysis of ACh
• 1 X 105 ACh molecule per AChE per minute
• Other cholinesterase in body is Butyryl or pseudo or plasma or
non-specific cholinestrase (BChE) which is present in plasma, liver,
intestine and white matter, but hydrolysis by this enzyme is slow.
• AChE is more sensitive to physostigmine (reversible inhibitor)
whereas BChE is more sensitive to organophosphates (irreversible).
Action of AChE Enzyme
Site of action of drugs on DRUG ACTION
cholinergic transmission Hemicholinium Competes and
inhibits choline
transport/ uptake
Vesamicol Inhibit uptake (&
packaging) of Ach
into vesicle
Botulinum toxin Block exocytosis
Bungarotoxin process and thus
(snake venom) release of ACh
Black widow Initially increase
spider toxin release of Ach but
(Latrotoxin) later decrease
release of Ach
 Site of action of drugs on cholinergic transmission in
Somatic Nervous System (Skeletal muscles)
DRUG ACTION
Agents Interfere with Hemicholinium & Triethylcholine competes and inhibits
synthesis & storage choline transport/uptake
Interfere with release Local anaesthetic (Procaine) : Inhibits Na+ channels and
axonal conduction
Tetrodotoxin & Saxitoxin: Block axonal action potential
Botulinum toxin blocks exocytosis and release of ACh
Mg 2+ ions competes with Ca2+ (entry into nerve)
Interfere with action d-tubocuranine and suxamethonium block nicotinic receptors
and act as neuromuscular blocking agents
Dantrolene sodium (direct acting muscle relaxant) interfere
with Ca2+ release from the sarcoplasmic reticulum
Interfere with metabolism Physostigmine and Organophosphates inhibits AChE.
 Cholinergic Receptor

Muscarinic (M) Nicotinic (N)

M1 M2 M3 M4 M5 Muscle Type (Nm) Neuronal Type (Nn)

(Skeletal Muscle) (Neuronal tissues)

MUSCARINIC RECEPTOR NICOTINIC RECEPTOR

GPCR (G-protein coupled receptor) Ligand gated cation (e.g. Na+/Ca2+) channel
Selectively activated by muscarine, derived Selectively activated by nicotine, derived from
from toxic mushroom Amanita muscaria tobacco plant (Nicotiana tabacum)
These are present mainly in autonomic These receptors are present in autonomic
effector cells in heart, smooth muscles, ganglion (both sympathetic & parasympathetic),
exocrine glands and some parts of CNS adrenal medulla and some parts of CNS
 Subtypes of muscarinic (M or mAChR) receptors

M1 = Neural
M2 = Cardiac
M3 = Glandular

M4 & M5 are
present in CNS

• M1, M3 & M5 are stimulatory in nature whereas M2 & M4 are inhibitory receptors.
• M1, M3 & M5 receptors promote the release of the intracellular Ca2+.
• M2 and M4 receptors have an inhibitory function and negatively modulate adenylyl cyclase.
(AC) which results in decreased cytoplasmic concentrations of cAMP.
 Important Subtypes of Muscarinic receptors
Nature of
Location Effect
Receptor
Increased adrenaline & HCl secretion
Excitatory Autonomic ganglion,
M1 Mediate gastric secretions on vegal
(Gq) Gastric glands, CNS
stimulation
Inhibitory Decreases heart rate & force of
M2 Heart, GIT, CNS
(Gi) contraction, decreases NE release
o Glands (exocrine) o Stimulate salivary, bronchial, lacrimal
o Smooth muscles of & sweat gland
Excitatory
M3 viscera (Bronchi, GIT, o Contraction of bronchiole & GIT but
(Gq)
Urinary tract & Blood exception in blood vessels where
vessels) relaxation i.e. dilatation occurs
 Nicotinic (N or nAChR) receptors
• Generally, nicotinic Receptors do not respond to low dose of ACh.
ACh binds wth nicotinic receptors (Ligand gated Ion Channels)

Ach binding induces conformational changes in Receptor proteins

Pore is created & Na+ enters via pores

leading to depolarization and Ca2+ influx

Contraction of skeletal muscle

Stimulation of Postganglionic Nerve Effects
Secretion of Adrenaline from adrenal medulla
Selective agonists and antagonists of cholinergic receptors
Receptors Selective Agonists Selective Antagonists

Oxotremorine Pirenzepine, Telenzepine

M1 (Used to treat peptic ulcers)
Methacholine Methoctramine
M2 Tripitramine
Bethanechol (used in urinary Hexahydrosiladifenidol
M3 retention) Darifenacin
PTMA (Phenyltrimethyl d-tubocurarine (a plant* alkaloid)
NM (muscle) ammonium) α-bungarotoxin (in elapidae snake
like Cobra, Krait)
DMPP (Dimethylphenyl Hexamethonium
NN (Neuronal) piperazinium), Epibatidine Trimetaphan

*Chondrodendron tomentosum
Thank You