Pharmacology

For
Veterinary Medicine
Students

Part I
By

Prof.Dr.Elgendy

2021-2022

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 Contents
Item Page

 General pharmacology…………………………………………..........4

 Autonomic nervous system………………………………………........38

 Central nervous system…………………………………………..........78

 Cardiovascular system……………………………………..…...........104

 Respiratory system……………………………………………….......123

 Digestive system……………………………………..…......................130

 Urinary system…………………………………………….…….........141

 Reproductive system……………………………………………........149

 Endocrine system……………………………………….……............159

 .Pharmacology of skin …………………………………….................176

 Pharmacology of eye…………………………………….....................185

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 General
pharmacology

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 General pharmacology
Pharmacology (Pharmakon : drug & Logos or ology : Science) can be defined as
the science that deals with studying drugs .
A drug is any substance or mixture of substances or any chemical used in the treatment,
prevention or diagnosis of diseases either man or animals.
Drug-nomenclature:
1-Chemical name: States the chemical composition and molecular structure.
2-Generic name :Usually it is suggested by the united states of adopted name council.
3-Official name :As listed in the U.S. Pharmacopeia.
4-Brand or trade name :The trade or proprietary name

For example:
• Chemical name: 7-Chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-
one
• Generic name: diazepam
• Official name: diazepam, USP
• Trade name: Valium®
Pharmacology and its subdivisions:Pharmacology includes the following branches:-
1-Pharmacokinetic (ADME):
It is the action of body on the drug (including drug absorption, distribution,
biotransformation and excretion.
2-Pharmacodynamic:
Is the study of the actions of drugs on body. It is particularly concerned with the
mechanisms by which drugs produce their physiologic effects and with the dose-
response relationship. Or Pharmacodynamics is the study of biochemical and
physiological effects of drugs and their mechanism of action on the functions of the
tissues.
3-Toxicology:
Is that science of poisons and toxicity. It focuses on the harmful effects of drugs
and other chemicals as well as on the mechanisms by which toxic agents produce
pathologic changes, disease or even death.
4-Clinical veterinary pharmacology:
Is that science deals with application of the drugs to treat diseased animal
5-Pharmacovigilance: It is science and activities relating to the detection, assessment,
understanding and prevention of adverse effects of drugs or any other
medicine/vaccine related problem.
6-Pharmacogenetics and pharmacogenomics: They involve the studying the role of
inheritance of individual variations in drug response, that varies from potentially life-
threatening adverse drug reactions to equally serious lack of therapeutic efficacy.
a-Pharmacogenetics :science has evolved significantly with a huge number of
studies exploring the effect of with studies of single genes, which had major
effects on the action of particular drugs(effect genetic variants on
interindividual variability of drug response)

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b-Pharmacogenomics :The study the role of the genetic makeup of an
individual on their response to drugs.
Posology: that science deals with study of medicinal dosage.
A dose: is the safe quantity of medication when administered to adult animal produce
desired effect.
Metrology: is a science studying weight and measures as applied to preparation and
administration of drugs.
Pharmacy: is a separate and complementary health care profession concerned with
collection, preparation, standardization and dispensing of drugs.
Materia medica: is a book concerned with pharmacy, posology, pharmacogonsy and
indications for therapeutic use of drugs. This subject is descriptive in nature and
replaced in the modern veterinary medical curriculum by the science of comparative
pharmacology.

Drugs Development & Regulation

A- Preclinical testing
B- Clinical testing: Phase 1 Phase 2 Phase 3 Phase 4

Fig:(1) Drugs Development & Regulation

Pharmacopoeias and official books of drugs

Pharmacopeia (Pharmakon & Poiein.Poiein means make)

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A pharmacopeia or formulary is the book that containing a list of drugs with
descriptions and formulas which is published by authorized committee
• There was no reference book published detaling all officially accepted drugs
until middle of 19th century.
• Pharmacopoeia :
• It is book published by an authority constituted by law.
• It contains most common drugs, their formulas, description and directions for
their preparations and dose.
• It is published every 5-10 years and interm, supplements are published
including new preparations.
• Abbreviations of Pharmacopoeia are added after the name of the drug or
preparation.
• These books are worldwide accepted.
* Most countries produce their own Pharmacopoeias
1-United States Pharmacopoeia (U.S.P.)
 1820
 Published every 10 years
 Revised by Pharmacopoeial committee
2-British Pharmacopoeia (B.P.)
 1864
 Published every 5 years
 Revised by general medical council
3-National Formulary (N.F.)
 1888
 Published by American pharmaceutical Association
 An analogue to B.P.C. contain details about preparations and formulation of
accepted useful drugs.
4-British Pharmaceutical Codex (B.P.C.)
 1907
 Published every 5 years
 Revised by pharmaceutical Society
 Details and monographs on action, uses, toxicity and antidotes
5-Egyptian Pharmacopoeia (E.P.)
 1953
 Revised by Egyptian pharmaceutical Society
6-International Pharmacopoeia (I.P.)
 Published every 5 years
 Revised by committee of experts
7-United States Dispensatory (U.S.D.)
 Huge volume book contains information about all officially recognized drugs
in U.S.P. ,I.P. and N.F. as well as new non-officially recognized drugs.
 Contain comments on therapeutic theories and methods
 Also contain section on veterinary applications.
8-New and non-official Remedies (N.N.R.)
 Published annually
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  Revised by American medical Association
 Description of marketed drugs which satisfy the standards
9-British Veterinary Codex (B.V.C.)
 Published by pharmaceutical Society
 Includes details of veterinary drugs and preparations with action, uses, toxicity
and antidotes.
10-British Veterinary Pharmacopoeia (B. V.P.)
 1977
 Published by British Medical committee and modeled on British
Pharmacopoeia.
11-Materia medica:
Concerned with pharmacy, posology, pharmacogonsy and therapeutic use of drugs.

Pharmacokinetics
Definition: pharmacokinetics is the actions of the tissues of the animal body on the
drugs.It includes absorption, distribution, metabolism and excretion

Absorption
Definition: It is the transfer of the drug from its site of administration to the blood
stream.
1-The rate and efficiency of absorption depends on the route of administration.
2-For i.v. administration no absorption as the total drug dose is directly and
completely injected into blood.
3-Drug delivery by other routes may result in only partial absorption and thus lower
the bioavailability.
4-Oral route requires that a drug is liberated from the pharmaceutical form (tablet,
capsule ...ect) then dissolved in the gastrointestinal fluid and penetrate the epithelial
cells of the intestinal mucosa, disease states or presence of food may to be absorbed.
The latent period:
It the time elapsed between drug administration and the onset of its action
Factors affecting latent period:

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a-Route of drug administration.
b-Rate of drug absorption.
c-Rate of penetration of the drug to its site of action.
A-Transport of drug from GI tract:
Drug may be absorbed from GIT either by passive diffusion or active transport
depending on the chemical properties of the drug.
1-Passive diffusion:
a-The driving force for passive absorption of a drug is the concentration gradient
across a membrane separating two body compartments, that is. The drug moves from
region of high concentration to one of lower concentration (along with concentration
gradient).
b-Passive diffusion does not involve a carrier or expending energy.
c-The vast majority of drugs gain access to the body by this mechanism.
d-Lipid-soluble drugs readily move across most biological membranes, whereas
water-soluble drugs penetrate the cell membrane through aqueous channels as shown
in(Fig. 5).

Fig (5): Schematic representation of drugs crossing cell membrane of epithelial cell of gastrointestinal tract

In ruminant animals:
a-The drug passage across the highly specialized ruminal epithelium are still not well
established.
b-Drugs given orally are initially diluted by the contents of the fore-stomachs.
c-Drugs are known to be absorbed by the passive diffusion of unionized, lipid-soluble
molecules through the ruminal epithelium and the process is pH dependent .e.g.
thiabendazole, sulphonamides, amphetamine and pentobarbitone, salicylate,
antipyrine and quinine. However, the rate of transfer is slow compared with other
portions of the gut with the result that for many drugs only small amounts will be
absorbed before the contents have been passed on into the abomasum and small
intestine. So many drugs, oral administration to ruminants is impractical.
2-Active transport:
a-This route of drug entry involves specific carrier proteins that span the membrane.
A few drugs that closely resemble the structure of naturally occurring metabolites are
actively transported across cell membranes using these specific carrier proteins.
b-Active transport is energy-dependent and is driven by the hydrolysis of adenosine
triphosphate (Fig. 5).

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c-It is capable of moving drugs against a concentration gradient, which is from a
region of low drug concentration to one of higher drug concentration.
3-Pinocytosis: it is a phenomenon, that the cell has an ability to engulf materials (drugs)
by invagination of the cell membrane.
Factors influencing the rate of drug absorption:
a-Factors related to the drug:-
1-Physico-chemical properties of the drug e.g. Lipid solubility, water solubility,
degree of ionization, molecular weight, valency and chemical structure.
2-Pharmaceutical form of the drug. Solution is rapidly absorbed than suspension
followed by solids according to particle size.
b-Factors related to the animal:-
1-Route of drug administration.
a-Faster Absorption Parenterally (injection)
- Inhaled (through lungs) > Intraperitoneal (IP)>Intramuscular (IM)> Subcutaneous
(SC)
b-Slow Absorption through Mucus Membranes
- Oral Mucosa (e.g. sublingual)
- Nasal Mucosa (e.g. insufflated
- Topical/Transdermal (through skin)
-Rectally (suppository)
2-Effect of pH on drug absorption:
Most of drugs are either weak acids or weak bases.
*Acidic drugs (HA) release H+ causing formation of a charged anion (A-):
HA  H+ + A-
*Weak bases (BH ) can also release a H+, however the protonated form of basic
+

drugs is usually charged and loss of a proton produce the uncharged base (B):
BH+  B + H+
a-Passage of an uncharged drug through membrane:
Thus for a weak acid, the uncharged HA can permeate through membranes and A-
cannot. For a weak base, the uncharged form, B penetrate through the cell membrane,
but BH+ does not. Thus, the effective concentration of the permeable form of each drug
at its absorption site is determined by the relative concentrations of the charged and
uncharged forms. The ratio between the two forms is in turn determined by the pH at
the site of absorption and by the strength of the weak acid or base which is represented
by the pKa.
pKa: It is pH at which 50% of the drug is in ionized form and 50% unionized. It is a
measure of the strength of the interaction of a compound with a proton. The lower the
pKa, the stronger the acid conversely, the higher the pKa, the stronger the base.
Distribution equilibrium is achieved when the permeable form of the drug achieves an
equal concentration in all body water spaces. Highly lipid-soluble drugs rapidly cross
membranes and often enter tissues at a rate determined by blood flow.
b-Determination of how much drug will be found on either side of a membrane:
The relationship of pKa and the ratio of acid-base concentration to pH is expressed
by the Henderson-Hasaselbalch equation:
- log protonated species = pKa- pH
Unprotonated species

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  For acids: pKa - pH = -log (HA)
(A-)
 For bases: pKa - pH =- log (BH+)
(B)

This equation is useful in determining how much drug will be found on either side
of a membrane that separate two compartments that differ in pH.
e.g. stomach (pH 1.0-1.5) and blood plasma (pH 7.4)
N.B.: The lipid solubility of the non-ionized drug directly determines its rate of
equilibration.
3-Blood flow to the absorption site:
Absorption from the intestine is more than from the stomach due to much greater
blood flow to the intestine more than to the stomach
N.B. Shock severely reduces blood flow to cutaneous tissues, leads to decrease
absorption from s/c administration.
4-total surface area available for absorption:
The intestine has surface rich in microvilli so it has a surface area 1,000 times of
the stomach that leads to more efficient absorption of the drug across the intestine.
5-Contact time at the absorption surface:
a-Diarrhea decreases absorption from the GIT and vice versa to constipation.
b-Conversely ,anything that delays the transport of the drug from the stomach to the
intestine delays the rate of absorption of the drug.
c-Presence of food in the stomach dilute the drug and slow gastric emptying so the drug
taken with meals is generally absorbed more slowly.
6-Effect of GIT disease on drug absorption:
a-The GIT is susceptible to a wide variety of infections and infestations. Many
conditions cause diarrhea, which can give rise to drug and nutrient mal-absorption.
Among these are shigellosis (bacillary dysentery), salmonella gastro-enteritis,
staphylococcal food poisoning and infestation by worms or protozoa.
b-The absorption of ampicillin and nalidixic acid is reduced by diarrhea.
c-The wide variety of diseases that can affect the GIT and indirect direct interactions
between orally administered drug products and other drugs and substances give rise to
vast number of circumstances that can alter the absorption of orally administered
compounds. d-
Pancreatitis, paralytic ileus, intestinal obstruction, gut ischemia and intestinal cancer
can have profound effects on drug absorption.
e-In the horse, GIT appears to function similarly to simple stomach animals. Acidic
drugs such as meclofenamic acid and phenylbuazone are well and rapidly absorbed
from the horse stomach (pH 1.1-6.8) and weakly basic drugs are absorbed from the
small intestine. Nevertheless, the caecum may play a role in slowing the kinetics of
insoluble drugs since in the horse like the ruminants and unlike other simple stomached
animals, benzimidazole anthelmintics are effective oral doses.
Bioavailability
Bioavailability is the fraction of administered drug that reach the systemic
circulation chemically unchanged. e.g. if 100 mg of a drug is administered orally and
70 mg of this drug is absorbed unchanged. The bioavailability is70 %.

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Factors that influence bioavailability:

1-first pass hepatic metabolism:

Drugs that are absorbed from the gut reach the liver via the hepatic portal vein
before entering the systemic circulation (Fig: 6). Many drugs, such as felodipine
(antihypertensive agent), propranolol and lidocaine are extensively converted to
inactive metabolites during their first pass through the gut wall and liver, and have low
bioavailability after oral administration. This phenomenon is called the first-pass effect.
To overcome this, Drugs administered by the sublingual or rectal route undergo less
first-pass metabolism and have a higher degree of bioavailability than do drugs
administered by the oral route.

Figure :( 6) First-pass drug biotransformation. Drugs that are absorbed from the
gut can be biotransformed by enzymes in the gut wall and liver before reaching
the systemic circulation. This process lowers their degree of bioavailability.

2-Solubility of the drug:

Very hydrophilic and extremely hydrophilic drugs are poorly absorbed because
they are totally insoluble in the aqueous body fluids and therefore, can,t gain access to
the cell surface.
3-Chemical instability:
For example penicillin G is unstable in the pH of the gastric contents. Also insulin
may be destroyed in GIT by degradative enzyme.
4-Nature of the drug formulation:
Drug absorption may be altered by factors unrelated to the chemistry of the drug
such as particle size, salt form, crystal polymorphism and presence of excipients.
Bioequivalence
Two drugs forms containing the same active principle are termed bioequivalent if
they showed comparable bioavailability and same peak blood concentrations when
administered via same route of administration.

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 Drug distribution
1-Drugs are distributed to organs and tissues via the circulation from which may diffuse
into various body compartments as free in blood plasma, free in extracellular fluid, free
in intracellular, bound to plasma protein, bound to tissue protein and stored in fat depots.
2-Most drugs are not uniformly distributed throughout the total body water and some
drugs are restricted to the extracellular fluid or plasma compartment.
3-Drugs with sufficient lipid solubility can diffuse into cells and some drugs are
concentrated in the cells by the phenomenon of ion trapping.
4-Drugs may also be actively transported into cells (e.g. some drugs transported into
hepatic cells, where they may undergo enzymatic biotransformation). In the intestine,
carrier-mediated drug transport in the blood-to-lumen direction leads to a net secretion
of anticancer drugs into the intestinal tract.
5-The process of passive diffusion is the method by which the great majority of the
drugs distribute in animal body. There are a few exceptions where drugs are transported
against a concentration gradient by active transport mechanism.
6-Active transport of drug molecules requires energy and is mediated by carrier
substances which complex with drugs and transport it through the membrane. The two
sites where active transport mechanisms are of most importance are in the renal tubular
epithelium and in the carotid plexus.
7-Active transport, are important for penicillin and account both for their low
concentration in CNS and their rapid excretion. Other drugs for which active transport
mechanism have been demonstrated are some sulphonamides and phenylbutazone.

Blood barriers:
Capillaries of certain organs, are selectively permeable to some drugs and not to
others. These barriers includes:
1-Blood brain barrier:
Blood brain barrier, which is the barrier between the plasma and CSF. This
barrier lack water channels (only endothelium and glial cells) possess a special
selectivity mechanism for the passage of drugs, ions and organic metabolites that the
brain needs. Lipid soluble drugs .e.g. volatile anesthesia and bromides penetrates CNS
rapidly and water soluble drugs penetrate it with difficulty or not at all.
a. Lipid soluble drugs and small molecular size, poorly bound to protein, and
non-ionized at the pH of cerebrospinal fluid (CSF) will cross BBB most readily.
b. BBB tends to increase in permeability in the presence of inflammation or at
the site of tumors.
c. BBB is poorly developed in neonates; hence, chemicals can easily gain access to
the neonatal brain.
2-Placental barrier:
a-Water soluble drugs as insulin, tubocurarine do not pass the placenta.
b-Lipid soluble drugs as Hypnotics, anesthetics, cardiac glycosides, hypotensives,
sulphonamides and most antibiotics, pass the placental barrier.
c-Thalidomide (tranquilizer) is toxic to fetus in the first stage of pregnancy.
d-Morphine, anticoagulant and antithyroid are toxic to fetus in last stage of pregnancy.
N.B. Other barriers including milk, intestinal and serous barriers

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Storage depots: The drugs may be stored in:
1-Plasma protein…such as albumin, protein bound form is inactive, not metabolized,
not excreted .e.g. phenylbutazone and suramin, it may cause difference in drug
absorption, distribution, biotransformation and excretion.
Def. of plasma protein binding:-It is special affinity of certain drugs for reversible
bind to plasma proteins.
a- Albumen binds many acidic drugs
b- α1 acid glycoprotein binds many basic drugs
c-To lesser extent β globulin
Characters of plasma protein bounding drug: The protein bound drug is inactive
because it cannot pass biological membranes reaching to the site of action, not
metabolized and not excreted
2-Extracellular tissues: e.g. C.T. and mucopolysaccharides bound to ionic drug. Hair,
bone and teeth act as reservoir to heavy metals and tetracyclines.
3-Tissue protein: e.g. digitalis in cardiac muscles, quinine in liver, iodine in thyroid
gland.
4-Fat: Lipid soluble drugs as DDT and thiopental.

Effects of protein binding on drug kinetics:

1-Enhance absorption by lowering concentration of free drug.
2-Act as a carrier for drugs insoluble in plasma so it help distribution.
3-Slowing drug metabolism and excretion prolonging the drug action.
4-Increasing the initial dose to reach the therapeutic dose of the free drug.
5-Needing to decrease of the dose in case of hyperproteinemia.
6-Drug interaction on binding sites may cause toxicity .e.g Asprin ,phenylbutazone,
clofibrate, sulphonamides displace other drugs from plasma binding sites e.g .Oral
anticoagulant(dicumarol),Oral hypoglycemic(Tolbutamide),Bilirubin in neonates,
increasing the free drug concentration Inducing Bleeding, Hypoglycemia ,and Jaundice
respectively
Volume of distribution
The apparent volume of distribution (Vd) is the volume of fluid in which a drug would
need to be distribute in order to have the same concentration as that in the plasma.
A-Water compartments in the body:
1-Drug distributes in Plasma compartment:
If a drug has a very large molecular weight or binds extensively to plasma
proteins, it is too large does not move out through endothelial sits junctions of the
capillaries and thus is effectively trapped within the plasma (vascular compartment). As
a consequence, the drug distributes in volume of plasma which is about 6 % of the
body weight (e.g. Aminoglycoside antibiotics)
2-Drug distributes in Extracellular fluid:
If a drug has a low molecular weight but is hydrophilic, it can move through the
endothelial slit junctions of capillaries into the interstitial fluid, however, hydrophilic
drugs as cannot move across the membranes of the cells to inter the water phase inside
the cell. Therefore, these drugs distribute into a volume that is the sum of the plasma,
extracellular fluid and the interstitial fluid. This is about 20 % of the body weight.
3-Drug distributes in Total body water:

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 If a drug has a low molecular weight but is lipophilic, it can not only move into
the interstitial fluid but also can move through the cell membranes into the plasma,
extracellular fluid, interstitial fluid and intracellular fluid. Therefore the drug distributes
into a volume of about 60 % of the body weight.
4-Other sites:
In pregnancy, the fetus may take up drugs such as thiopental.
Factors affecting distribution:
1-Organ blood flow:
a-Drugs are rapidly distributed to highly perfused tissues e.g. brain, heart and kidney.
b-Drugs are distributed slowly to less highly perfused tissues such as skeletal muscles.
c-Drugs are distributed even more slowly to those with the lowest blood flow, such as
skin and adipose tissue.
2-Plasma protein binding:
Almost all drugs are reversibly bound to plasma protein, primarily albumin. The
extent of binding depends on the affinity of a particular drug for protein-binding sites
and ranges from less than 10 % to as high as 99 % of the plasma concentration. The
increase free drug concentration will accelerate drug biotransformation and excretion.
3-Molecular size: Large molecular size such as heparin is largely confined to the plasma
although it undergoes some biotransformation in the liver.
4-Lipid solubility: lipid solubility is a major factor affecting the extent of the drug
distribution, particularly to the brain, where the blood-brain barrier restricts the
penetration of polar (ionized) molecules.
Drug biotransformation (drug metabolism)
Drug metabolism is defined as chemical alteration of drugs to a polar more water
soluble metabolites that are readily excreted.
Site: Most drugs metabolized in liver but there are drug-metabolizing enzymes in many
other tissues including the gut, kidneys, brain, lungs and skin.
Drug biotransformation and excretion are the two processes responsible for the
decline of drug plasma concentration over time during terminal elimination phase (β).
Reactions of drug metabolism:
The kidney cannot efficiently eliminate lipophilic drugs that readily cross cell
membranes and are reabsorbed in the distal tubules. Therefore, lipid-soluble agents
must first be metabolized in the liver using two general sets of reactions, called phase I
and phase II (Fig. 6).

Fig. (6): The biotransformation of drugs

1-Phase I:(Oxidation,reduction or hydrolysis)

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 Phase I reactions function to convert lipophilic molecules into more polar
molecules by introducing or unmasking a polar functional group, such as –OH or –NH2.
Phase I metabolism may increase, decrease or leave unaltered the pharmacologic
activity of drug.
a-Phase I reactions most frequently involved in drug metabolism are catalyzed by
the cytochrome P-450 system (also called Microsomal mixed function oxidase).
Drug + O2 + NADPH + H+  Drug modified + H2O + NADP+
The oxidation proceeds by the drug binding to the oxidized form of cytochrome
P-450 and then O2 is introduced through a reductive step coupled to NADPH-
cytochrome P-450 oxidoreductase.
b-Phase I reactions not involving the P-450 system:
These include amine oxidation (for example, Non Microsomal oxidation of
catecholamines or histamine), alcohol dehydrogenation (for example, of procainamide)
(Fig. 7).

Figure :(7) Phase I drug biotransformation. Many drugs are biotransformed by

oxidative, hydrolytic, or reductive reactions and then undergo conjugation with
endogenous substances. A few drugs bypass phase I reactions and directly enter
phase II biotransformation.

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 1-Oxidative reaction:
A few drugs are metabolized by cytoplasmic enzymes for example, ethanol is oxidized
by alcohol dehydrogenase, and caffeine and thyopylline are biotransformed by xanthine
oxidase.
2-Hydrolytic reactions:
Esters and amides are hydrolyzed by a variety of enzymes. These include the
cholinesterases and other plasma esterases that inactivate cholinesters, local
anaesthetics and drugs such as esmolol (β adrenergic receptors blockers).
3-Reductive reactions:
Reductive reactions are less common than are oxidative and hydrolytic reactions. e.g.
Chloramphenicol and few other drugs are partly metabolized by a hepatic nitroreductase.
2-Phase II (Synthetic reaction):
Drug molecules undergo conjugation with an endogenous substance such as
acetate, glucuronate, sulfate or glycine (Fig. 8).
Conjugating enzymes are present in liver and other tissues .They serve to
conjugate various drugs with the endogenous substance to form water soluble
metabolites that are more easily excreted. These enzymes are located in the cytoplasm
except microsomal glucuronosyl transferases. Most conjugated drug metabolites are
pharmacologically inactive.
Types of conjugation reactions:
a-Acetylation:
Acetylation is accomplished by N-acetyl-transferase enzymes that utilize acetyl
coenzyme A(acetyl CoA) as a source of the acetate.
b-Glucuronide formation:
It the most common conjugation reactions and utilized glucuronosyl transferases
to conjugate a glucuronate with a drug molecule.
c-Sulfation:
Sulftransferase catalyzes the conjugation of several drugs, including minoxidil
and triametrene with their sulfate metabolites are pharmacologically active.

Figure :(8) Phase II drug biotransformation. UDP = uridine diphosphate.

3-Reversal of order of the phases: Not all drugs undergo phase I and II reactions in
that order e.g. isoniazid is first acetylated (as phase II reaction) and then hydrolyzed to
isonicotinic acid (as phase I reaction)

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 Effect of diseased condition on drug metabolism:
1-The impaired liver function occur in both acute and chronic liver diseases, will
reduce drug clearance. Plasma and tissue drug concentration will be markedly higher
at given dose regimens in patients with hepatic diseases compared to individuals with
normal hepatic function e.g. propranolol, lidocaine and some narcotic analgesics.
2-Some barbiturates (hypnotic drugs are destroyed by the liver and if the liver
function is impaired the duration of sleep is abnormally prolonged)
3-Hepatic diseases can produce no change (e.g…warfarin), decrease (e.g…diazepam)
and even an increase (e.g…tolbutamide) in clearance of drugs. Furthermore, volume
and half-life some time change (e.g…..ampicillin). Drug half-life is significantly
prolonged in patients with hepatic diseases.
Drug-induced changes in the rate of drug metabolism:
1-Certain lipophilic drugs and environmental chemical substances (pesticides and
carcinogens) cause reduction in the hepatic blood flow. Decreased binding of
extensively bound drugs can increase their availability fort metabolism
2-Some drugs act as Hepatic microsomal enzyme inducers that stimulate the hepatic
microsomal enzyme system (Phenobarbital, phenytoin, phenylbutazone ) means increase
enzyme synthesis and is called enzyme induction
3-Hepatic microsomal enzyme inhibitors are drugs that inhibit microsomal enzyme
activity include quinidine, chloramphenicol, organophosphorus insecticides and carbon
tetrachloride
4-Chloramphenicol increase duration of pentobarbital anesthesia in dogs and decrease
body clearance of both phenobarbital and phenytoin which used as anticonvulsant
drugs. So the ability of some drugs that stimulate or depress the microsomal drug
metabolizing system requires that this possibility to keep in mind when considering
multiple drug therapy.
5-The rate of drug metabolism can be depressed by inhibition of plasma pseudo-
cholinesterase and MAO irreversible inhibition of plasma pseudo-cholinesterase by
compounds (organophosphorus compounds).
The influence of species variation on drug metabolism
Young animals lacking drug metabolizing enzyme in all species.
1-Ruminants:They are rich mainly in oxidative enzymes.So shorter duration of
barbiturates action.
2-Horses:They are rich in several enzymes especially oxidative enzymes (short
duration of action pentobarbitone), reducing enzymes that change chloral hydrate to its
active form, trichloroethanol however many drugs excreted unchanged as procaine HCl
in urine.
3-Dogs: Sulphonamides are toxic for dogs due to lacking of acetylase enzymes.
4-Cats:Cats lack conjugation and oxidative enzymes. So drugs metabolized by
conjugation and oxidation are cumulative and toxic for cats e.g .barbiturates.
5-Birds:
a-Birds have lowered conjugating enzymes than mammals.
b-Among birds there are species variations for examples:
i-Demethylase enzyme activity is lower in liver of ducks than chickens
ii-Conjugating enzymes rich in sulphate but deficient in glucuronide
iii-Conjugation in birds is clear in young than adult birds, on contrast to mammals.

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6-Fish: The conjugating enzymes are lacking in fish, so they susceptible to poisoning
by wide range of chemicals.
Drug excretion
Clearance
Clearance of a drug is the rate of elimination relative to the concentration of drug
in any biologic fluids.
Clearance = Cl = rate of elimination. Clearance can expressed as a volume per unit of
time
Half-life of the drug
Half-life of the drug is the time takes for the plasma concentration to be reduced
by 50 %. The time course of the drug in the body will depend on both the clearance and
volume of distribution. t½ = 0.693 V/C
Drug elimination
Removal of a drug from the body may occur via a number of routes, the most
important being through the kidney into urine. Other routes include the bile, intestine,
lung or milk.
1-Renal drug excretion:
Most drugs are excreted in the urine, either as the parent compounds or as drug
metabolites. Drugs are handled by kidneys in the same manner as physiologic
substances undergo the processes of glomerular filtration, active tubular secretion and
passive tubular re-absorption. The amount of drug excreted is the sum of the amounts
filtered and secreted minus the amount reabsorbed; The drug excretion and renal
clearance is shown in figure (9).

Figure :(9)Nephron and renal excretion process

a-Glomerular filtration: It is the first step in renal drug excretion, in this process the
free drug enters the renal tubules as a dissolved solute in the plasma filtrate. If the drug
has a large fraction or bound to plasma proteins, it will have a low rate of glomerular
filtration.
b-Active tubular secretion:
Some drugs, particularly weak acids and bases, undergo active tubular secretion by
transport system located primarily in proximal tubular cells.

18
* This process is competitively inhibited by other drugs of the same chemical class.
Example: The secretion of penicillins and other weak acids is inhibited by probenicid.
* Active tubular secretion is not affected by plasma protein binding. This is because
when the free drug is actively transported across the renal tubule, this fraction of drug
is replaced by a fraction that dissociates from plasma proteins in order to maintain the
equilibrium of free drug bound drug.
c-Passive tubular re-absorption:
The extent to which a drug undergoes passive reabsorption a cross renal tubular
cells and into the circulation depends on the lipid solubility of the drug. Drug
biotransformation facilitate drug elimination by forming polar drug metabolites that are
not as readily reabsorbed as the less polar parent molecules.
Most non-electrolytes including ethanol are passively reabsorbed a cross tubular
cells. Ionized weak acids and bases are not reabsorbed a cross renal tubular cells and
they are more rapidly excreted in the urine than are non-ionized drugs that undergo
passive re-absorption.

The GIT
Some drugs excreted from stomach as morphine and some others are excreted
from colon as anthracene purgatives.
2-Biliary excretion and enterohepatic cycling:
Many drugs are excreted in the bile as the parent compound or a drug metabolite.
Biliary excretion favors compounds with molecular weight that higher than 300 Dalton.
Numerous conjugated drug metabolites including the glucoronate and sulfate
derivatives of steroids are excreted in bile. After the bile empties into the intestine, a
fraction of the drug may be reabsorbed into the circulation and eventually return to the
liver. This phenomenon is called enterohepatic cycling (Fig. 10).

Fig:(10) Enterohepatic cycling.

Conjugated drugs may be hydrolyzed to the free drug by intestinal bacteria and this
facilitates the drug's reabsorption, since conjugated metabolites are more polar and less
lipid soluble than are the parent compounds. Antibiotics that kill the intestinal bacteria

19
 may reduce the enterohepatic circulation of estrogens and thereby cause a reduction in
their plasma concentration and therapeutic effect.
3-The lungs:
Volatile anesthesia can be excreted via expired air (as ether, chloroform and ACE
mixture)
4-Exocrine glands:
 Iodides are excreted from salivary gland and bronchial glands
 Volatile oils are excreted from the sweat
 Many drugs are excreted in milk through mammary gland as oxtetracycline
5-Eggs:
Antibiotics and coccidiostates given to laying hens are hazardous to human
consumers as excreted through eggs
Prolongation of duration of drug action
This can be achieved by one of the following:
I-Delaying drug absorption:
1-Reducing of vascularity of absorbing surface (adrenaline + procaine).
2-Decreasing the solubility of the drug as procaine penicillin.
3-Giving the drug in oily solution as adrenaline or hormones in oil.
4-Adding demulcent to the drug as gelatin in depot heparin.
5-Drug implantation as zearonal as a growth promoter
II-Increasing plasma protein binding tendency: Increasing plasma protein binding
tendency of drug leads to delaying metabolism and consequently delay drug excretion
e.g. long acting sulphonamides.
III-Delaying the metabolism of drug in the liver by depressing liver microsomal
enzyme: e.g. quinidine and chloamphenicol.
IV-Delaying renal excretion e.g. probenicid block penicillin active tubular excretion.

Pharmacodynamics
Pharmacodynamics: It is the study of drugs actions on body.It is particularly
concerned with action, mechanisms of action by which drugs produce their
physiologic effects and also with the dose-response relationship which is the
relationship between drug concentration (dose) and magnitude of drug effect.
Cellular response to drugs: Drugs not induce a new function in the living cells, they
only increase or decrease its function.
1-Stimulation means increasing of the tissue function.
2-Inhibition or depression means decreasing of the tissue function.
3-Irritation means an inflammatory reactions in the tissues.
4-Exhaustion is decrease or absence of the cell function resulted from excessive or
prolonged stimulation
5-Relaxation absence of the cell functions resulted from prolonged inhibition.
Pharmacodynamic action:-
Pharmacodynamic action of the drugs include pharmacotherapeutic effects, side
effects and toxic effects.
a-Pharmacotherapeutic effect:
It is the desired therapeutic effect of the drug which is either. It includes:-

20
i-Local or topical effect: means the drug induce its action before entering the circulation
e.g. action of drugs on the skin and m.m by application of lotions, ointment, powders,
etc.
ii-Systemic action: means the action of the drug after absorption to systemic circulation
iii-Reflex or indirect action: that drugs induce action from local action on sensory
nerves of skin or m.m of nose, mouth, stomach or intestine (e.g. ammonia inhalation).
b-Side effect:
Means the undesirable effect of the drug which accompany its therapeutic
action. e.g. drowsiness, vomiting and diarrhea.
c-Toxic effect:
These are untoward bad effects of the drug as allergic response, exaggerated
response, secondary effects to the drug action, production of disease by drugs,
teratogenic effects, drug-drug interaction and intolerance.
Mechanism of drug action
1-Replacement:e.g hormones and iron
2-Physically includes:-
a-Adsorption e.g. Kaolin and activated charcoal that absorb toxins and gases
b- Osmosis e.g. osmotic purgative (MgSo4) and osmotic Diuretics (Pot.citrate).
c- Colloidal or surface forces e.g. dioctyl sulphosuccinate
3-Chemically
a- Chelation: is the loose binding of a substance by a drug e.g. EDTA chelates calcium
and lead
b- Neutralization e.g. antacids (sodium bicarbonate in hyperacidity)
4-Alter permeability: Changing Cell Membrane Permeability e.g.
 Polymaxin -------- dissolve phospholipids
 Lidocaine----------------Blocks sodium channels
 Verapamil, nefedipine-------Block calcium channels
 Bretylium----------------Blocks potassium channels
 Adenosine---------------------Opens potassium channels
5-Interference of enzyme activity e.g.
 Anticholinestrases----- inhibit Cholinestrase
 Xanthines----------inhibit phosphodiestrase
6-Biological antagonism
Drugs may act as antimetabolites and change the cell function when mistaken into a
metabolism scheme of cell. e.g.
 Sulphonamides inhibits the multiplication of bacteria by Competing with
PABA and results in inhibiting folic acid synthesis in the bacteria.
 Anticancer drugs rapidly inhibit proliferating cancer cells by substituting
for vital substances in cellular metabolic schemes that are responsible for
DNA synthesis (Cytotoxic effect)
7-Drugs may influence bound forms of physiologically active substances.
a-They may displace a hormone from plasma protein binding increase free
hormone.
b-They may displace a hormone from tissue sites and make the hormone more
active, e.g. ephedrine causes the release of norepinephrine from storage and go to
active sites

21
8-Drugs may act upon the nervous system by either:
a-Being a neurotransmitter.
b-Mimicking a neurotransmitter.
c-Influencing the action of neurotransmitters.
d-May inhibit or accelerate the biosynthesis of a neurotransmitter.
e-Block the action of neurotransmitter
9-Drug may acts on specific receptors
A drug may compete with another drug or an endogenous substance for an active site
on a receptor. e.g. A.ch. versus curare or atropine.
Atropine or curare blocks A.ch. receptors and prevent the action of A.ch
Receptor: is macromolecule (protein) which is chemically reactive area on the cell
on which drug acts producing biological response.
*No drugs produces a single action in the animal's body
Protein targets for drug binding:
Four kinds of regulatory proteins are commonly involved as primary drug targets
1-Enzymes
2-Carrier molecules
3-Ion channels
4-Loose receptors
N.B. Receptor means any target molecule with a drug molecule has to combine in order
to elicit its specific effect, which can include any of the four types listed.
Nature of drug receptors:
Macromolecule (protein) which is chemically reactive area on / in the cell on which
drug acts producing biological response.
Structural activity relationship:
a-The molecular structure and spatial configuration of a drug will determine its ability
to fit or interact with a corresponding active site of receptor in or on certain cells
b-Receptors is an area on or adjacent to cell membrane have a geometric, 3 dimensional
form are most likely protein in nature, are enzyme or enzyme like..........ect.
c-Drugs may have two parts or segments having 3 dimensions. These two parts of the
drug molecule result in the following drug-receptor interactions:
1-The1st part that attaches the drug to the receptor area (affinity).
2-The2ndpart of the molecule that has exact fit and result in molecular changes
(efficacy).

22
Types of ligands:
• Agonist is a drug possesses both affinity(ability to bind receptors ) and efficacy
(elicit a response) and will give action when it reaches a specific receptor
• Antagonist is a drug possesses affinity but no efficacy (reacts with and fills
receptor site but does not elicit action) is called a competitive antagonist and thus
is a receptor blocker.
• Partial agonist is an agonist with efficacy less than maximal efficacy(only
produce sub-maximal response )
• Inverse agonists (negative agonists) as agonist but produce the reverse effect of
agonist because it has negative efficiency e.g. Benzodiazepine receptors
Benzodiazepines are agonists produce hypnosis and anticonvulsant effect while
β- carbolines are inverse agonist produce insomnia and convulsions.
Drug-receptor binding-bond types
1-Van der Waals (weak bond).
2-Hyrogen bonds-with O2 and N2 through H O H.
3-Ionic bonds
Types 1, 2,3 are reversible at body temperature.
4-Covalent bonds-are very strong, difficult to reverse.
Drug-Receptor interactions
Cellular response occurs when drug binds to its specific receptor and includes two stages:-
1-Drug affinity:
It is the tendency of a drug to combine with its receptor and is a measure of the
strength of the drug receptor bounding. According to the law of mass action, the number
of receptor (R) occupied by a drug (D) depends on the drug concentration and the drug-
receptor association and dissociation rate constants (K1 and K2)
K1
(D) + (R) ---------- (D-R) ---------- Effect
K2
The ratio of K2 to K1 is known as the KD and represents the drug concentration
required to saturate 50 % of the receptors. The lower the KD the greater is the drug's
affinity for the receptors.
Drug receptor interaction theories
1- Receptor occupation theory:
The strength of the drug action depends on number of receptor occupied. When
maximum effect is reached and still some receptors remain free unoccupied they are
termed spare receptors.
2- Rate Theory: Agonist activity is proportional to the rate of drug-receptor
combination rather than the number of occupied receptors
Agonist has a rapid association and dissociation of the drug and the receptor for
further of fresh agonist with free receptors.
An antagonist has a high association rate but a slow rate of dissociation few receptor
available for further combination.

Tachyphylaxis
23
Acute acquired tolerance where the drug protects against its own action e.g.
Ephedrine, amphetamine, serotonin have slow dissociation rate, few receptor available
for further combination.

Fig(2): Tachyphylaxis
3-Macromolecular perturbation theory
Drug binding converts (macromolecule) inactive receptors to active one
1. (Agonist) produces favorable conformational changes.
2. (Antagonist) produces unfavorable conformational changes.
N.B. Reality is most likely a mixture or blend of all these theories
Potency of drug is absolute amount of drug required to produce an effect. More
potent drug is the one that requires lower dose to cause same effect
2-Signal transduction:
Signal transduction is the process by which receptor binding initiates a cascade of
biochemical events that ultimately leads to a physiologic response or effect. Membrane
receptors are often coupled with a G protein ion channel or an enzyme (Table 1)

Family , type of receptors Mechanism of signal transduction drug

ligand

G protein coupled receptor

α1adrenergic receptor Activation of phospholipase Phenylephrine(ag)
α2 adrenergic receptor Inhibition of adenyl cyclase clonidine (ag )
β adrenergic receptor Stimulation of adenyl cyclase Isoproternol(ag)
Muscarinic receptors Activation of phospholipase Atropine ( ant)
Ligand gated ion channel
GABA receptor Chloride influx Benzodiazepines(ag)-

Nicotinic ACh receptors Sodium influx Carbachol (ag)

Membrane bound enzyme
Atrial naturiuretic factor receptor Activation of guanylyl cyclase Nitroglycerine
Insulin receptor Activation of tyrosine kinase insulin
Nuclear receptors
Steroid Activation of gene transcription Steroids
receptors Thyroid hormone receptors Activation of gene transcription
Thyroxin

Table(1): Examples of drug receptors and signal transduction mechanisms.

24
Receptor regulation and drug tolerance:
1-Down regulation: Repeated exposure of receptor to agonist drug a can reduce the
number of receptors.
Receptor down regulation leads to a process in which the receptor-binding sites move
into the cell and no longer exposed to the drug on the cell surface, so induce
pharmacodynamic tolerance. The rapid pharmacodynamic tolerance is called
tachyphylaxis. Pharmacokinetic tolerance is caused by accelerated drug elimination.
2-Up regulation: repeated exposure to antagonists can increase the number of
receptors.

N.B. Disease state may alter the function of receptors e.g. Myasthenia gravis is an
autoimmune disorder which antibodies destroy some of the nicotinic receptors in the
skeletal muscles leading to impaired neurotransmission and muscle weakness or even
paralysis. This condition is treated by administration of nicotinic receptor agonist.
Types of Dose-response relationships (Curves):
In pharmacodynamics studies different doses of drug can be tested on isolated
organs or cells or tissues. The relationship between drug concentration at the receptor
site and the strength of response is called dose-response relationship. This relation may
be called graded response or quantal (all or-non) response.
1-Graded dose-response relationship:
Relates dose of drug to intensity of response elicited within single biological unit.
It is described as percentage of the maximal response and is plotted against the log dose
of the drug (Fig. 2). Graded dose-response curves illustrate the relationship between
drug-dose, receptor-occupancy and the magnitude of the resulting physiologic effect.
For given drug the maximal response is produced when all of the functional receptors
are occupied and the half-maximal response is produced when 50% of the functional
receptors are occupied. In some cases, only small percentage of the total number of
the receptors must be occupied in order to produce maximal response. Because the
only some of receptors are considered functional while the rest are considered "spare
receptors"

Fig. (2): Graded dose-response relationship.

25
*Potency: is the dose required to produce a defined magnitude of drug effect.
*Median effective dose (ED50): is that dose of the drug produces 50 % of the maximal
response.
*Efficacy: is the ability of drug to produce a response.
2-Quantal-dose-response relationship:
In quantal dose-response relationships, the response elicited with each dose of a
drug is described in terms of the cumulative percentage of subjects exhibiting a defined
all or none effect and is plotted against the log dose of the drug .It relates dose to
frequency of response (Fig. 3) e.g. All or none effect is sleep when a sedative is given.
With the quantal dose-response relationship, the median effective dose (ED50) is that
dose that produces the defined effect in 50 % of the subjects.

Fig(3):Quantal-dose-response relationship. Fig(4)Therapeutic index(TI),Certain safety factor (CSF).

Therapeutic index(TI):
It defined as the ratio between the median lethal dose (LD50) and the median
effective dose (ED50). It provides a general indications of the safety margin of a drug.
Fig(4)
Certain safety factor (CSF):
Is defined as the ratio between the dose that is lethal in 1 % of subjects (LD1) and
the dose that produces a therapeutic effect in 99 % of subjects (ED99) .e.g. Phenobarbital
tested in animals it was found to have a TI of 10 and CSF of 2 since the dose that will
kill 1 % of animals is twice the dose that is required to produce the therapeutic effect in
99 % of animals, the drug has a good margin of safety.
Adverse effects of drugs
Pharmacovigilance: is the study of adverse drug reactions (ADRs).
Grading of severity of adverse drug:
a-Minor: No therapy, antidote or prolongation of hospitalization is required.
b-Moderate: Requires change in drug therapy, specific treatment or prolongs
hospital stay.
26
c-Sever: Potentially life-threatening, causes permanent damage or requires intensive
medical treatment.
d-Lethal: Directly or indirectly contributes to death.

Classification of adverse drug effects (Toxicity of drugs)

I-Predictable adverse effects :Type- A (Predictable)
- An extension of drug pharmacology, based on pharmacological properties, dose
related, and accounts for most adverse reactions (e.g. β-adrenoreceptor antagonist-
induced bradycardia or AV block).
Properties
1-Expected and undesirable 2- Related to actions of the drug 3-More common
4-Dose related 5-Mostly preventable and reversible
They includes the following:-
1-Side effects:
1-Predictable undesirable secondary actions produced by therapeutic dose of the drug
and through the same mechanism of action of therapeutic action.
2-Side effects may vary for each individual depending on the person's disease state,
age, weight, gender, ethnicity and general health e.g. dry mouth induced by atropine,
sedation with the first generation antihistamines
2-Overdose:
1-It is the ingestion or application of a drug substance in quantities greater than are
recommended.
2-An overdose may result in exaggerated normal response, toxic state or death.
3-Teratogenicity: The ability of the drug to induce congenital fetal malformation
when given to pregnant mothers e.g. Aspirin induces cardiac septal
defect,Methimazol induces over active and enlarged thyroid
4-Carcinogenicity: e.g. Smoking may induce bronchogenic carcinoma.
5-Cytotoxicity: refers to a substance or process which results in cell damage or cell
death .e.g. hepatotoxicity by halothane and nephrotoxicity by gentamicin.
6-Iatrogenic disease: Drug induced diseases e.g. bone marrow depression cause
cyclophosphamide and chlorpromazine cause Parkinsonism.
7-Drug Interactions: Displacement from plasma protein binding sites e.g.
Phenylbutazone displaces oral hypoglycemic induce sever hypoglycemia, Aspirin
displaces warfarin resulting in Hemorrhage and Sulfonamide displaces bilirubin resulting
in Kernicterus.
8-Drug dependence: It is related to tolerance and may be either habituation or
addiction mainly in human.
a- Habituation e.g. smoking, coffee, and tea.
1- Psychic dependence 2-Sudden stop induce Psychic craving
b-Addiction e.g .morphine , barbiturates , alcohol
1- Psychic and physical dependence
2- Sudden stop induce withdrawal symptoms (Abstinence syndrome)
II-Unpredictable adverse effects
Type- B (Non-predictable)
-Based on Immunological response and genetic make-up of animal, not dose related, rare
but severe (e.g. chloramphenicol induced aplastic anemia).

27
 Properties
1-Unexpected and undesirable 2-Related to the patient 3-Less common
4-Non dose related 5-More serious and require drug withdrawal.
They includes the following:-
1-Allergy (Hypersensitivity):
a-is an immune-mediated abnormal response due to antigen antibody reaction.
b-does not occur on 1st exposure to drug.
c-Symptoms range from mild to severe and may include fever, urticaria, skin rash
,bronchial asthma, anaphylaxis, and serum sickness.
d-Treatment is drug discontinuation, supportive treatment e.g. antihistamines ,
corticosteroids and sometimes desensitization.
2-Idiosyncrasy:
a-It refers to an individual’s susceptibility to a drug ADR based on genetic abnormality.
b-Abnormal response occur on 1st exposure to drug e.g. sulphonamides use in genetic
deficiency of glucose phosphate dehydrogenase (G -6-PD) induce hemolytic anemia.
3-Super-sensitivity (Intolerance): increased sensitivity to the drug inducing
exaggerated normal response on using the usual therapeutic dose of e.g. Adrenaline in
patient with thyrotoxicosis.
4-Tolerance:
a-Is the unusual reduced response to the ordinary dose of a drug i.e. Large
dose is needed to give the usual effect.
b-Types: 1- Congenital or inborn 2- Acquired occur after repeated use of drug.
III- Other types of drug reaction (much rarer):
– type C reaction – continuous reactions due to long term use: analgesic
nephropathy;
– type D reaction – delayed reactions of carcinogenesis or teratogenesis;
– type E reaction – drug withdrawal reactions (e.g. benzodiazepines).
Drug-induced Organ toxicity
The adverse effects and therapeutic effects of a drug are caused by different
mechanisms e.g. in (Table 2):Table (2): Drug-induced organ toxicities
Organ toxicity Examples of adverse Examples of inducers
effects
Cardiotoxicity Cardiomyopathy. Daunorubicin, doxorubicin and idarubicin
Inflammatory fibrosis Methylsergide
Hematopoietic Agranulocytosis* Captopril, chloropromazine, chloropropamide & pylthiouracil
toxicity Aplastic anemia* Chloramphenicol and phenylbutazone
Hemolytic anemia* Captopril, levodopa and methyldopa
Thrombocytopenia* Quinidine, rifampin and sulfonamide

Hepatotoxicity Cholestatic jaundice* Erythromycin estolate and phenothiazines

Hepatitis Amiodarone, captopril, isoniazide, phenytoin & sulfonamides
Nephrotoicity Acute tubular necrosios Aminoglycosides, amphotericin B, vancomycin
Interstitial; nephritis* NSAIDs, penicillins (especially penicillins)
Ototoxicity Vestibular and cochlear Aminoglycosides, furosemide, vancomycin
disorder
Pulmonary Inbflammatory fibrosis Methylsergide
toxicity Pulmonary fibrosis Amiodarone, bleomycin, busulfan, nitrofurantoin
Skin toxiocity All forms of skin rash* Antibiotics, diuretics, phenytoin, sulfonamides, sulfonylurase

28
 Drug interaction
It is modifications of pharmacologic action of one drug by the prior or
concomitant use of another drug or food.
Types of drug interactions:
1-Pharmaceutial interactions:
Pharmaceutical interactions or incompatibilities, are usually due to a chemical
reaction between drugs prior to their administration
e.g.When penicillin solution and an aminoglycoside solution are mixed, they will form
an insoluble precipitate because penicillins are negatively charged and aminoglycosides
are positively charged.Many other drugs are incompatible and should not be combined
before they are administered.
2-Pharmacodynamic interactions:
Pharmacodynamic interactions, refers to when two or more drugs have additive,
synergestic or antagonistic effects on a tissue, organs system microbes or tumor cells.
a-Additive effect: 1 + 1= 2
is that effect which equal to the sum of the individual drug effects.
b-Synergestic effect: 1 +1 > 2
is that effect which is greater than the sum of the individual drug effect.
*Synergism: Two or more drugs, given at same times, result in enhancement of a
pharmacologic response.
*Clinical synergism: drug actions are not at the same site, not even the same response,
but one drug enhances the therapeutic effect of another drug e.g. when adrenaline and
procaine are mixed and injected for local anesthesia the adrenaline slow the absorption
of the procaine from the site and hence prolong its duration of action locally.
c-Potentiation effect :( 1 + 0 =2)
Means enhancement of action of one drug by another one of dissimilar properties
(that response of the two drugs is greater than just the sum of the actions of each drug)
d-Antagonism: (1+(-1 )= 0)
Means the drug action oppose the action of another drug when given together and
can be divided into:-
i-physiological antagonism:
e.g. Histamine and adrenaline do not act on the same receptor.Histamine is
bronchoconstrictor and adrenaline is bronchodilator.
ii-chemical antagonism:
Drug reacts chemically with another drug to form inactive complex e.g. protamine
with heparin.
iii-pharmacological antagonism
Where both drugs act on the same receptor e.g. tubocurarine with Ach. at nicotinic
receptors in the neuromuscular junctions inducing relaxation (competitive antagonism).
When one drug antagonizes the action of another without competition for the same
receptors as succinylcholine at the cholinergic receptors in the neuromuscular junction
(non competitive antagonism).
3-Pharmacokinetic interactions:
A drug can alters the absorption, distribution, biotransformation and excretion of
anther co-administered drug.
a-Altered drug absorption this process occurs by several mechanisms:

29
  Binding to another drug in gut and preventing its absorption e.g. cholestyramine
binds to digoxin and prevents its absorption.
 Altering gastric or intestinal motility affecting absorption of another drug(tab,3).
b-Altered dug distribution
When antibiotics are taken concurrently with oral contraceptives containing
estrogen, they may reduce the plasma concentration of estrogen and cause contraceptive
failure.
c-Altered drug biotransformation: biotransformation is affected by drugs that alter
hepatic blood flow. It is affected by drug interactions that either induce or inhibit drug-
metabolizing enzymes…..e.g.
1-Inducers of cytochrome P-450 enzymes includes barbiturates and rifampin. Enzyme
induction increases the clearance and reduces the half-life of drugs biotransformed by
the enzyme. When the inducing drug disappeared the synthesis of P-450 enzymes
gradually returns to the pretreatment level.
2-Inhibitors of cytochrome P-450 enzymes include cimetidine and erythromycin.
Significant interactions occur when these drugs reduce the clearance and increase the
plasma concentration of other drugs e.g. Iitraconazole inhibits the biotransformation of
cisapride
d-Altered drug excretion: Many drugs can alter the renal or biliary excretion.
 Drugs as carbonic anhydrase inhibitors alter the renal pH can alter the ionized
form to non-ionized form of other drug and affect its renal excretion.
 Probenicid competes with other organic acids such as penicillin, for the active
transport system in the renal tubules decreasing its excretion.
 Quinidine and verapamil decrease the biliary clearance of digoxin so increase
serum digoxin levels.
Table (3): Management of clinically significant pharmacokinetic drug interactions

Examples of inducers or Examples of affected drugs Management

inhibitors
Inhibitors of drug absorption
Aluminum, Tetracycline Give tetracycline 1 hour before or 2 hours
calcium after giving the other agent
and iron
Cholestyramine Digoxin and Give Digoxin or warfarin 1 hour before or
Warfarin 2 hours after giving Cholestyramine
Interaction with drug distribution
Asprin Displace(from plasma binding Increase free
,phenylbutazone,clofibrate, sites) Bleeding
sulphonamides Oral anticoagulant(dicumarol) Hypoglycemia
Ora lhypoglycemics(Tolbutamide) Jaundice
Bilirubin in neonates
Inhibitors of drug biotransformation
Cimetidine Benzodiazepine, Instead of giving cimetidine, substitute a
Lidocaine, phenytoin, histamine blocker that does not inhibit drug
theophylline & warfarin metabolism
Disulfiram Ethanol Make sure the patient understand that
disulfiram is used therapeutically to
promote abstinence from alcohol (ethanol)
Erythromycin Carbamazepine and Lower the dose of the affected drug during
Theophylline erythromycin therapy
Erythromycin, Astemizole, cisapride Avoid concurrent therapy and therby avoid
itraconazole And terfenadine potential QT interval prolongation and fatal
& ketoconazole cardiac arrhythmias

30
 Monamine oxidase Levodopa and Avoid concurrent therapy if possible;
Inhibitors sympathomimetic otherwise, give a subnormal dose of the
drugs affected drug
Inhibitors of drug clearance
Diltiazem, Digoxin Give a subnormal dose of digoxin and
qunidine monitor the plasma drug concentration
and verapamil
Preobenecid Cephalosporins Advise the patient that the combination of
and penicillin drugs is intended to increase the plasma
concentration of the antibiotic
Thiazide diuretics Lithium Give a subnormal dose of lithium and
monitor the plasma drug concentration

Clinical significance of drug interactions

1-Avoiding the concurrent administration of some drug to prevent toxicity.
2-Toxicity can be avoided by proper dosage adjustment.
3-Use of drug interactions as antidotal treatment in case of toxicity.
4-To obtain potentiated therapeutic response.
Principles Of Ruminants Pharmacology
A-Reticulo-rumen (RR) dynamics:-
1-Reticulum and rumen contain large volume of water, considered a great dilution
factor.
2-Large volume of saliva constantly secreted into the RR. (10-12 L per day).This is 2.5
times as the extracellular volume per day.
3- RR is a place of environment which favors growth of microbial activity.
4-It contains large volume of feedstuffs.
5-Motility, proper contractions of the RR are vital for proper bacterial digestion and end
product absorption.
6-The aqueous phase moves to the abomasum and small intestine in 4-8 hours.
B-Drugs entry into the RR occurs through:-
1-Oral administration.
2-Saliva.
3-Diffusion from plasma.
C-Absorption of drugs from RR:
1-Occurs by passive diffusion depending on.
a-Lipid solubility enhances.
b-Must be non-ionized in the rumen fluid.
c-Moves down a concentration gradient.
2-Factors that influence absorption:
a -Proper blood flow.
b-Motility: Increased motility increases absorption because contact with ruminal
papillae is increased. Rumen stasis decreases absorption.
c-Increased RR motility also increases rate of passage into abomasum and intestine ,thus
increases total rate of absorption.
d-The greater the dilution the more prolonged the absorption.
e-Binding to feedstuff slows absorption.
3-Drugs absorbed from the rumen: including sulphonamides, salicylates, levamisol and
atropine.
D-Microbial action upon drugs in the rumen:-

31
1-Biodegradation: This ends by inactivating the drug. The following are examples of
drugs that are degraded in the rumen:-
-Chloramphenicol, Ivermectin, Trimethoprim, Soluble oxalate and Gossypol
2-Biotransformation(Bioactivation):This end by activating the drug. The following are
examples of active substances produced from inactive substances:-
-Cyanogenic glycosides
-Amygdalin  HCN (toxic)
-Nitrate  Nitrite (toxic)
-Tryptophan  3-methylindole (toxic)
-Chlorophyll  phylloeythrin
E-Distribution (entrance) of drugs to the reticulo-rumen from the plasma:-
1-Occurs by passive diffusion from plasma into rumen fluid:
a-Lipid solubility enhances.
b-Must be non-ionized in the rumen fluid.
c-Moves down a concentration gradient.
2-Ion trapping: Rumen fluid (pH 5 to 7) tends to trap bases in the RR.
3-Dilution is a large factor in the rumen:
a-Reduces concentration in the RR which favors drug movement into the RR.
b-Withdraw drugs from plasma into the rumen fluid.
4-Serve as a reservoir of sequestered drug in RR may lead to a longer body elimination
time.
5-May create a dosage problem. As it is variable. Some drugs do and some drugs do not
move into the RR in significant amounts.
6-Distribution of drugs into the RR:
a-Drugs that pass to rumen:Sulphamethazine, salicylates, levamisol, lincomycin and
tylosin.
b-Drugs that not pass to rumen: Tetracycline, oxytetracycline and penicillins.
7-When antimicrobial drugs reach RR:
a-Induce inhibition of certain species of the microflora.
b-May enhances or depress microbial digestion, depends upon which microorganism,
and which drugs in concentration dependent manner.
c-Oral route is dose dependent while parenteral is depend on back diffusion, and
saliva content.
Factors that modifying drug response and dosage regimen
There are many factors affecting drug response and dosage regimen including the
following:-
I-Route of administration:
a-The dose and magnitude of response relationship may vary greatly with different
routes of administration: e.g. isoproterenol as cardiac stimulant.
The dose I/V. inhaled and oral routes is 1, 20, 1,000 mg.
b-Drug action may be altered by route of administration:
1-Mg. Sulphate, hot packs will reduce swelling.
2- '' '' orally produce a laxative and purgative actions.
3- '' '' I/V produce CNS depressant action plus muscle relaxation and large
doses will stop the heart.
c-Onset and duration of action depends upon route of administration
32
 I/V----quicker onset but shorter duration. Oral----slower onset but longer duration.
d-Large volumes of a drug given I/M or S/C at one injection site may create an
inflammatory response, get walled off and be very poorly absorbed.
II-Timing of administration:
a-Time of day: hypnotics are more potent at night, stimulants are more potent during
the day.
b-Relation to season: involves the interaction of the drug with animal's (biological
clock). Hormone levels and enzymes have been shown to have rhythmic variations
during a 24 hour period.
c-Relation to environment: ambient temperature, humidity, O2 supply, handling of the
animals has a response of animals to anesthesia.
d-Oral administration of drugs relative to time of feeding in simple stomached animals
affecting binding drugs with food.
III-Species variation:
a-Cell and organ response difference:
1-Morphine produces CNS depression in dog but produce stimulation and even mania
in the cat.
2-Diethylcholesterol can induce abortion in cattle but will not induce abortion in man.
3-Horses appears to be very sensitive to the phenothiazine derivatives tranquilizers and
in some cases they may even produce CNS excitation.
4-There are great differences in the sensitivity among animals to digitalis glycosides
e.g. LD50 of digitoxin in the rat is 670 times the LD50 for the cat.
5-The response of drugs to induce emesis is extremely variable. No drug is able to
induce vomiting in mice, rats, rabbits, horses or ruminants because these animals are
either unable to vomit or vomit with extreme difficulty.
Dogs and cats can be easily induced vomit.
b-Plasma level and active site level of the free drug :
1-Differences in biotransformation and/or excretion rates.
Plasma half-life of salicylates varies greatly among the species because of a
marked difference in the rate of biotransformation. Plasma t½ in cat 38 hours, in the
dog 8 hours, while in man t½ of salicylates is about 5 hours.
N.B:-This means that the dosage and dosage interval must be based upon the kinetics
of the drug in each species and recommendations for one species may not be proper for
another.
e.g. goats biotransformation and inactivate pentobarbital much faster than dogs. Goats
and dogs given I/V 25 mg /kg pentobarbital Na will be anaesthetized. Both will awaken
when the plasma concentration reaches the same level about 12 mg/ml. The difference
is that is takes the goat 1.5 hour to reach this level and awaken and it takes the dog 12
hours to reach this level and awaken due to slower inactivation.
2-Differences in binding in plasma and tissue:
Plasma and tissue proteins vary from species to species: e.g. Antibiotic cloxacillin
is 93 % plasma protein bound in man but only 30 % plasma protein bound in horses.
There will be a great deal more free antibiotic to be active in the plasma in the horse.
c-Differences in the digestive tract:
In Vet. Med. We must treat simple stomached omnivores, simple stomached
herbivores and ruminants.

33
IV-Individual variation:
a-Body weight: It is usually the primary determining factor of dosage and is stated as mg/kg
or mg/lb., has many limitations and variables: fat vs lean animals, status of full of GIT, a
severely dehydrated animals, old animals or newborn.
b-Age: Very young and very old animals usually require smaller and less frequent doses
because they metabolize and excrete drugs at a slower rate.
c-Sex: There is considerable evidence for response differences between male and
female animals. Drug use must take into account the status of the reproductive tract.
Also whether the animal is lactating or not.
d-Temperament of each individual animal need to be considered:
e.g. drugs affecting CNS (tranquilizer).
e-Genetic factors:
Pharmacokinetics is the study of these factors related to drug responses.
Quantitative (degree of) and qualitative (nature of) response differences are due to
inherited characteristics. Cellular make up differences between animals are governed
by the genetic make-up of the animals.
f-Biochemical variability(abnormal reactions to the drug) may be involved in the
following:
Drug intolerance
Drug intolerance means the sensitivity of the body to the action of therapeutic
doses for certain drugs. It includes:-
1-Hypersensitivity: animals shows symptoms of drug toxicity when given therapeutic
or small dose e.g…vomiting, drowsiness. When happen occasionally with single dose
of sodium salicylate or streptomycin
2-Idiosyncrasy: it is a type of sensitivity to drugs where abnormal reactions to the drug
are observed due to genetic absence or reduced enzymes in animals
e.g…sulphonamides may produce hemolysis in RBCs due to lack of glucose-6-
phosphate dehydrogenase enzyme.
3-Anaphylactic: means the symptoms and signs of the sensitivity occurs after drug
administration directly caused by release of histamine which leads to death from
circulatory collapse.
4-Allergy: the sensitivity occurs slowly not after given the drug directly. The time of
allergy hours to several days e.g…penicillin, sulphonamides, liver extracts and
nitrofuran.
2-Tolerance (drug resistance):
Is the unusual quantitative decrease in response to the ordinary dose of a drug.
Needing an increased dose to give the usual effect.Tolerance develops after continuous
exposure of the animal to a drug except congenital tolerance.
Types:- congenital tolerance and acquired tolerance
a-Congenital tolerance (natural):
The animal is born by the natural tolerance without exposure to any drug. Occur
by certain species of animals e.g. Rabbits tolerate large doses of atropine and ruminants
tolerate large doses of barbiturates. This effect occurs by metabolizing enzymes present
in these animal species.
b-Acquired tolerance: It is a type of tolerance induced by repeated drug use.
*Special types of acquired tolerance are:

34
i-Cross tolerance: when animal becomes tolerant to one drug may also be tolerant to
another drug of the same chemical or the same activity group e.g. Barbiturates.
ii-Tachyphylaxis: It is rapid development of tolerance and considered acute acquired
tolerance. It is occurred by repeated administration at short intervals as ephedrine,
amphetamine and serotonin.
iii-Drug resistance: The bacterial resistance to antibiotics or the resistance of parasites
to anthelmintics. This type of tolerance induced by enzymatic activation in the bacteria
or parasites.
Mechanism of tolerance:
i-Cells may increase biotransformation of drug and hence is inactivated faster and less
drug is available to bring about its action.
ii-Cells may adapt or become acclimatized, some cell may incorporate the drug into
their metabolic schemes.May help to explain drug dependence and withdrawal
symptoms.
iii-Increased excretion of the drug or decreased its absorption.
e.g. ephedrine: cause the release of nor adrenalin as neurotransmitter from the nerve
ending. Repeated ephedrine dosing depletes nor-adrenaline stores from the nerve
ending so depleted stores of nor adrenaline are less able to give action because there is
less of the neurotransmitter released to act on target cell.
V-Pathological conditions:
Altered absorption, biotransformation and excretion due to disease may alter the
plasma levels and hence the drug response. Diarrhea decrease the drug absorption in the
GIT whereas constipation increase drug absorption.
*Hepatitis-decrease biotransformation of the drug e.g. barbiturate act longer.
*Kidney disease-decreased drug excretion.
*Inflammation of CNS (meningitis, encephalitis) enhances entry of certain drugs into
CNS.
VI-Drug augmentation:
Cumulative effect: The sum of two or more doses brings about a gradual increase in
the plasma level of the drug because the dose is repeated before prior administered
drug is totally biotransformed and /or excreted e.g a drug at half-life of 4 hours and
when t½ is doubled drugs administered at the same interval. It is important to
recognize that with a change in the t½ to 8 hours, that if one administers drug B at the
same frequency as recommended for drug A which the half-life 4 hours. Toxic
reactions could appear after 8 hours and death after 24 hours
VII-Drug interaction:
There is more than one drug acting in the animal's body at the same time. One
drug influences the action or metabolism of the other drugs.
1-may be desirable and have therapeutic value.Therapy involving drug combinations
may have tremendous value
2-may be desirable and bring about therapy failures and adverse drug reactions
VIII-Side effects: Usually a predictable additional response. May be tolerated in order
to achieve the desired effect
IX-Contraindication: A drug should not be given for a predictable reason. Oxytocin
should not be given to a pregnant brood mare. Penicillin should not be given to a known
hypertensive animal.

35
 Drug residues
Drug residue is an amount of a drug that is temporary stored in certain tissue. The
concentration overtime of drug in meat, milk and eggs and fish.
Sources of compounds that enter the animal body may lead to tissue residues:
1-Purchased with prior medication 2-Medication
3-Feed and/or water 4-Environmental pollution …via skin or lung
Tolerance level of the drug is that concentration in fat, kidney, liver, muscles, skin,
milk or eggs that is permitted by law…e.g…..0.1 ppm for tissues or 0.01 ppm for milk.
These levels is not harmful to man and are set by FDA for drugs and by the EPA for
pesticides.
Carcinogens have a zero tolerance based upon a lifetime risk of 1 in a million over 70
years. Zero tolerance also applies to any drug without an established tolerance
Violative residue…a drug is found in tissues at a concentration that is greater than its
tolerance
Safe level…applies to drugs that do not have an established tolerance
Picogram = 1 ppm = 10-12 gm
The existence of drug residues in the milk or edible tissues of food producing
animals is opf concern as a public health matter. Residues can occur not only because
of the physicochemical properties of the substance itself but also because of the success
of those pharmaceutical and bioengineering devices which seek to extend the plasma
half-life of the drug in question.

*The problem appeared by the long persistence of organochlorine pesticide residues in

the body fat and their damaging effect on species high in the food-chain e.g…birds or
prey. The organochlorine as DDT have very high oil water partition coefficient and so
significant amount enter body fat rapidly and enjoy chemical stability in a protected
location which they leave very slowly. Penicillin contaminated milk can induce
sensitization in man. Residues of pesticides in dairy products and antibiotics and growth
promoters in meat were soon detected.
ADI (acceptable daily intake) = NEL x 70  B.wt./kg
100  safety factor
Where NEL is the non effective level (mg/kg) defined from long term
administration of substance of lab. Rodents by mouth.
Withdrawal or withhold period, which must elapse between the last dose of the
drug and the consumption of the animal or its milk (milk discard time). Implanted
growth-promoting agents which have hormonal actions given by implantation of a solid
pellet of the active principle under the skin of the ear because the ear is discarded at
slaughter, this make a continued problems for veterinarian and regulators.

Significance of drug residues in edible animal food products

I-Concerns for the potential danger to human health as follows:
1-May be toxic if large amounts ingested by human. These are dose related (toxic to
certain organs or inhibit fertility or adverse effects on fetus or may be carcinogenic)
2-May induce drug allergy e.g…milk contaminated with penicillin
3-Adverse effects of such drugs due to ingestion of residue of drug given to food
producing animals
36
II-Residues may also be of economic importance to the livestock producer:
As if samples of animal’s food products are found to contain unlawful amounts of a
drug, the product will be condemned and destroyed.
III-Veterinarian and/or livestock man may be prosecuted under the law if the drugs
were wrongfully used and led to a violative residue
IV-At present time, a very prevalent problem is treat and salvage:
Area of concern are dairy and beef cows and veal calves. Another area of concern is
sulphamethazine residues.
Monitoring of residues in food-animals
The use of drugs to control and treat animal disease and as growth promoters is a
common practice. Misuse of animal drugs can cause residues in the edible tissues of
slaughtered animals that could be hazardous to consumers. Tissue samples from
slaughtered animals for many chemical compounds are monitored such as:-
1-Antimicrobials…includes,sulphonamides,penicillins,aminoglycosides, tetracyclines,
erythromycin, neomycin, chloramphenicol
2-Other drugs…coccidiostats, growth promoters
3-Pesticides and industrial chemicals
4-Trace elements…copper, nickel, cobalt, zinc, iron and arsenic

The main goal of FDA residue program is to protect consumers from adulterated meat
and poultry products. The program can be divided into monitoring and surveillance

Detection of drug residues by thin layer chromatography (TLC), spectrophotometry

(SP), gas chromatography (GC), HPLC and radioimmunoassay. Also atomic absorption
spectrometry (AAS) and neutron activation analysis (NAA).
Control measures of drug residues
A-Legislation of authorization of veterinarians in supervising animal and poultry
farm.
B-Antibiotics used as growth promoters must be limited to four drugs only: zinc
bacitracin, flavomycin, virginamycin and avopracine. These drugs are contraindicated
to be used in treatment to avoid drug residue
C-Following the instructions of FDA in using veterinary drugs as follows:
1-Limitation of useing certain drugs to the nonfood producing animals as Novalgin
2-Contraindications to use coccidiostats for laying hens as well as certain antibiotics in
dairy cows.
3-Withdrawal period of drugs used in food producing animals or poultry must be limited.
4-The polluted meat, milk or eggs with drug residues higher the permissible limit
determined by FDA must be condemned.
Drug residue in fish
Fish lack glucuronic or sulphuric acid conjugating enzymes so are very
susceptible to poisoning by a wide range of chemicals and consequently toxic for human
consumers. The elimination time of antimicrobial drug flumequine. After oral and intra-
arterial administration in rainbow trout was extremely long (more than 0.3 ug/ml) after
12 and 25 days from administration. The long elimination time in the orally treated fish
was probably due to the slow absorption rate of the drug from the GIT. OTC was found
in the wild fish after 13 days of medication. The half-life of OTC was 9 days.

37
Autonomic Nervous
System

38
 Autonomic Nervous System
Nervous system

Autonomic Nervous system

The autonomic, involuntary, vegetative or visceral nervous system is so called
because it is widely distributed throughout the body, innervates the plain or
involuntary muscles, the visceral organs and glands, controlled and function below the
level of consciousness.
Anatomically:
It is composed of 2 divisions:
1-The sympathetic, adrenergic or thoraco-lumber outflow:
It originates from the nerves come from all the thoracic and first three lumbar
nerves of spinal cord. The chemical transmitter is adrenaline or noradrenaline or
dopamine.
2-The parasympathetic, cholinergic or cranio-sacral outflow
It originates mainly from III,VII,IX,X Cranial and 2nd,3rd,4th sacral nerves
of spinal cord.. The chemical transmitter is acetylcholine.
The two divisions are quite different in many of their anatomical and
physiological properties. Each division of the autonomic nervous system (sympathetic
or parasympathetic) is composed of preganglionic myelinated fibers, post ganglionic
non myelinated fibers and a ganglion in between where they establish synaptic
connection. The junction of postganglionic axonal terminal with its effector cell is
termed a neuro-effector junctions.

The difference between symp. and parasymp. nerves indicated as follows:

Item Sympathetic Parasympathetic
Origin Originated from all the thoracic Originates from the 3rd ,7th, 9th and 10th cranial
and first three lumbar nerves nerves and 2nd , 3rd and 4th sacral nerves
Preganglionic nerve fibers Short Long
Postganglionic nerve fibers Long Short
Distribution To effectors throughout the body Is much more limited

39
 Preganglionic terminal makes The number of pre- and postganglionic figers are
contact with large number of nearly equal sometimes 1 to 1, except in
postganglionic neurons, Auerbach;s plexus where a preganglionic fiber
sometimes the ratio is 1 :20 synapses with 8000 postganglionic nerve fiber
The adrenal medulla is homologue to sympathetic ganglion but does not contain
post synaptic neuronal cells. Adrenal chromaffin cells secrete epinephrine and nor
epinephrine (80/20%) directly into the circulatory system.
Definitions:
1-Neurotransmitters: These are chemical mediators that transmit nerve impulses across
junctions such as synapse.
2-Neuromodulator: It is a description for a substance with no intrinsic activity but
influence neuronal activity in a manner differs from that of neurotransmitter. This
substance originates from cellular and non synaptic sites yet influences the excitability
of nerve e.g…CO2, ammonia, circulating steroid hormones, adenosine, purines,
prostaglandins and nitric oxide.
3-Neuromediator: Is that substance that helps in election of the post synaptic response
to neurotransmitters e.g…cyclic AMP and inositol phosphate as a second messenger at
specific sites of synaptic transmission?
4-Neurohormones: They refer to substances secreted from peptide secreting cells
directly into circulation in a hormone-like fashion and mediate transmission at this site
e.g….oxytocin and vasopressin
5-Co-transmission: It is a non-adrenergic, non-cholinergic (NANC) transmission in the
ANS e.g…purines such as ATP and adenosine (ADO), (5-HT), nitric oxide (NO),
GABA, peptides (oxytocin, substance P, bradykinin and angiotensin).
General concepts of autonomic function
Many visceral organs are innervated by both sympathetic and parasympathetic.
1-The neurotransmitter at the ganglia both sympathetic and parasympathetic outflow at
parasympathetic neuroeffector junction is Ach e.g. erectile tissue of genitalia.
2-Norepinephrine (NE) or noradrenaline is the transmitter released at the majority of
sympathetic neuroeffector junctions and is considered to sympathetic neurotransmitter
3-Some sympathetic neurotransmitter junctions e.g.Ach is the transmitter as sweat glands
4-Nerves that release Ach are chemically classified as cholinergic nerves. Whereas nerves that
release NE are classified as adrenergic nerves.

40
 Central integration of autonomic activity
The afferent fibers and brain nuclei that influence peripheral motor function are
equally important when physiologic interactions of the autonomic nervous system are
considered. Afferent fibers transmit information concerning visceral pain,
cardiovascular activity, respiration and numerous other organ functions from peripheral
receptive areas to the central nervous system.
Afferent nerves are non mylinated and pass into the central nervous system along
autonomic nerve trunks such as vagus, pelvic and splanchic nerves.
An autonomic reflex involves passage of information along an afferent pathway,
reaction of CNS sites to the received impulse and resulting change in the efferent
discharge.Well known example involve the baroreceptor (pressue sensitive) that are
localized in the aortic arch and carotid sinus and the chemoreceptors localized within
aortic arch and carotid bodies. Information concerning blood pressure, blood oxygen
and CO2 and respiration is replayed from these sites via afferent fibers to CNS area.
Some drugs exert their pharmacological actions principally by alter afferent
receptor areas and afferent impulse traffic e.g. veratrum alkaloids
The hypothalamus is the principal supraspinal site involves in the modulation of
both sympathetic and parasympathetic outflow traffics. ANS participation in regulation
of B.P., body temperature, CHO metabolism, water electrolytes balance, sexual
responses, emotion and sleep in mediated through the hypothalamus pathways.
Pharmacologically motor nerves are classified into cholinergic and adrenergic
nerves; moreover cholinergic nerves are subdivided into central and peripheral
cholinergic
I-Cholinergic nerves:-
A-Central cholinergic nerves included:
1-Somatic nerves to the skeletal muscles
2-Splanchnic nerve to the adrenal medulla
3-All autonomic (symp. and parasymp.)Preganglionic nerves
B-Peripheral cholinergic nerves included:
1-All postganglionic parasympathetic nerves
2-Post postganglionic sympathetic nerve fiber to the sweat gland and certain blood
vessels of skin of face
II-Adrenergic nerves:
-They include all postganglionic sympathetic nerves except the cholinergic fibers of
sympathetic.
Neurohumoral transmission
Ach was found to be the chemical released from all sympathetic and
parasympathetic autonomic preganglionic fibers and postganglionic parasympathetic
fibers. NE is the neurotransmitter released at the majority of sympathetic neuroeffector
junctions. For convenience, it should be known that the chemical transmitters (Ach.,
adrenaline and NE) exist normally in the tissues in an inactive form and are only
liberated on stimulation of their nerves. The step of neurohumoral transmission could
be summarized as follows:

41
1-arrival of the N. action potential
2-release of Ach in all ganglia
3-release of Ach at cholinergic receptors
4-occupation of specific receptors
5-change of permeability to Na-K and Cl ions with depolarization or hyper-
polarization, producing an action
6-destruction or uptake of the chemical mediators
7-reverse of permeability and re-polarization.
Adrenergic neurohumoral transmission
Catecholamines:
Norepinephrine (NE), epinephrine (EP) and dopamine are endogenous cate-
cholamines. They are neurohumoral transmitter in most mammalian species.
1-NE and dopamine are believed to transmit impulse information in specific areas
within the CNS
2-NE is also the neurotransmitter at most peripheral sympathetic neuroeffector junction
3-NE is a hormone rather than a neurohumoral transmitter as a major hormone from
adrenal medulla
4-Catecholamines are stored in an inactive form within granular structure in adrenergic
nerve terminals and chromaffin cells.
Receptors of autonomic nervous system

I. Cholinergic receptors: They are subdivided into:

A. Muscarinic receptors: There are five muscarinic receptors (M1-M5).

-M1 receptors (neuronal) are found in CNS, peripheral neurons and gastric parietal
cells. They mediate excitatory effect through decreased K+ conductance and increase
gastric secretion is following the vagal stimulation.
- M2 receptors (cardiac) are found in the heart and presynaptic terminals of peripheral
and central neurons as autoreceptors. They induce inhibitory action by enhancing K+
conductance and is responsible for bradycardia following vagal stimulation

42
-M3 (glandular and smooth muscle) receptors mediate excitatory response resulted in
stimulation for glandular secretion, contraction of visceral smooth muscles and
stimulate release of nitric oxide which induce vasodilatation for endothelial cells
- M4 and M5 receptors are found in CNS
Drugs acting on muscarinic receptors
1-Muscarinic agonists are Ach and other esters,cholinergic alkaloids and
antichlinestrases
2-Antagonists for muscarinic receptors are classified into:
a-Selective muscarinic antagonist for M1, M2 and M3
b-Non selective muscarinic antagonist that block all muscarinic receptors (atropine and
scopolamine)
B-Nicotinic receptors:
Two different subtypes are found in skeletal muscle (NM) ,or autonomic ganglia
and brain(NN).
Nicotinic receptors blocking agents are:
1-Non selective blockers are d-tubocurarine and hexamethonium.
2-Selective blockers are mecamylamine, nicotinic agonists and nicotine in low
concentration while in high concentration block ganglia, methylcarbamylcholine,
dimethylphenylpiperazinium and epibatidine
II-Adrenergic receptors
They are subdivided into:-
1- α-adrenergic receptors:
-they include α1 postsynaptic and α2 presynaptic
- α1 subtypes (α1A, α1B and α1D) and subtypes (α2A, α2B and α2C). α2A serves as presynaptic
autoreceptors regulate release of adrenaline and nor-adrenaline.
α1Adrenergic receptors activate phospholipase and increased Ca released
intracellularly. α2 adrenergic receptors inhibit adenyl cyclase.
2-β-adrenergic receptors (β1, β2 and β3 receptors)
*The molecular mechanism for adrenergic receptor occurs through G protein coupling
activates adenyl cyclase.
Ach and congeners
Ach is a neurotransmitter which is released from cholinergic neurons at many
locations in the body. It acts on receptors in skeletal muscles, end plates, smooth muscle,
cells of secretory glands, ganglion cells of ANS, adrenal medulla and probably in certain
nerve cells of CNS.Ach receptors also found in smooth muscles that have no cholinergic
innervations e.g…..most articular smooth muscles.

43
 Organ Sympathetic Parasympathetic
Receptor Response Receptor Response
Eye
Radial muscle iris α1 Contraction (mydriasis) -- --
Sphincter muscle iris M3 Contraction (miosis)
Ciliary muscle β2 Relaxation for far vision M3 Contraction for near vision
Lacrymal glands Inhibition of secretion M3 Stimulation (lacrymation)
Heart
SA node β1  heart rate M2  heart rat (bradycardia)
(tachycardia)
AV node β1  conductivity M2  conductivity
Atria β1  contractility and M2  contractility
conduction
Ventricles β1  contractility and -- ----
conduction
Blood vessels
Skin, mucosa and α1 Vasoconstriction - Vasodilatation
viscera
Coronary and skeletal β2 Vasodilatation - Vasodilatation
Lung
Bronchial muscle β2 Bronchodilatation M2 = M 3 Bronchospasm spasm
Bronchial gland α1 Inhibition of secretion M3 Stimulation
Stomach
Motility-tone β2 Relaxation M2 = M 3 Contraction
Sphincters α1 Contraction M3, M2 Relaxation
Secretions α1 Inhibition M1 Stimulation
Intestine
Motility-tone α-β Decrease M2 = M 3 Increase
Sphincters α1 Contraction M3, M2 Relaxation ↓ Tone
Secretions Inhibition M3, M2 Stimulation
Gall bladder
Muscle duct β2 Relaxation M3, M2 Contraction
Sphincter oddi α1 Contraction Relaxation
Urinary bladder
Detrusor muscle β2 Relaxation M3 >M2 Contraction
Trigone and sphincter α Contraction M3 >M2 Relaxation
Uterus
Tone and motility α-β2 Pregnant contraction; α1 M Variable contraction
Relaxation β2
Nonpregnant relaxation
β2
Spleen
Splenic capsule α1 Contraction
Skin
Sweat gland α1 Localized secretion Generalized secretion
Pilomotor muscle α1 Contraction
Adrenal medulla M3 Secretion of EP and NE
Liver β2 Glycogenolysis&glucon Glycogen synthesis
eogenesis
Basal metabolic rate 150 %

Pancreas
Acini α1 Decrease secretion M3, M2 Secretion
Islets (β cells) α1 Decrease secretion
Fat cells β1 Lipolysis
Salivary glands αβ K+ & water secretion M3, M2 K+ & water secretion (+++)
(+) Secretion
Amylase secretion
Mental activity Increased dopaminergic
Sexual activity Ejaculation+++ α1 M3 Erection+++
Pineal glands Melanton β —
synthesis
Posterior pituitary Antidiuretic β1 —
secretion
Kidney
Renin secretion Decrease+; α1; β1 No —
increase++ innervation
Responses of effector organs to autonomic stimulation

44
 Autonomic drugs
These are drugs which affect the ANS and are classified in to:-
1-Cholinergic drugs which act on cell receptors of the tissues innervated with
cholinergic nerves
2-Adrenergic drugs which act on cell receptors of the tissues innervated with
sympathetic nerves.
Other classification:-
1-Mimetics: these are drugs which mimic the action of the mediators, occupying the
receptors or stimulating the release of mediators as sympathomimetics and
parasympathomimetics
2-Blockers: these are drugs which block the specific receptors or interfere with
synthesis, storage or release of mediators as parasympatholytics and anti-adrenergics.
Parasympathomimetics
Theses are drugs which help the access of Ach and related compounds to cholinergic
receptors or are a term used to an Ach-like effect on effector cells innervated by
postganglionic parasympathetic neurons.
Classification of cholinergic drugs
1-Peripheral drugs
a-Stimulants (parasympathomimetics) which includes :
i-Choline esters (as Ach, carbacol, bethanecol, methacholine)
ii-Alkaloids (as arecholine, pilocarpine, muscarine)
iii-Anticholinesterases(reversible as physostigmine, neostigmine or irreversible as
organophosphorous compounds)
b-Blockers (parasympatholytics)
As belladonna alkaloids (atropine, hyoscine, hyoscyamine, synthetic atropine)
2-Central drugs
a-Acting on ganglia which may be stimulants (as Ach, nicotine in small doses) or
blockers (which either competitive as hexamethonium or depolarizing as Ach, nicotine
in large doses)
b-Acting on skeletal muscles which either stimulant (as Ach, nicotine in small doses) or
blockers (which either competitive as curare and gallamine or depolarizing as
suxamethonium and decamethonium)

45
 Cholinergic synapse

Fig. (4): sites of drug action at cholinergic synapses (Modified after Cooper et al. ,1996)
(1): Ach synthesis blockers (2): Ach transport blockers
(3): Releasers and release blocker (4): Nicotinic and muscarinic blockers
(5): Autoreceptors agonists and antagonists (6): Anticholinesterases
(7) Reuptake blockers
Parasympathomimetics include
1-Choline esters: These are drugs which stimulate directly the cholinergic receptors.
As Ach., carbacol, methacholine and bethanechol

46
 A-Acetyl choline (Ach)
Synthesis and fate of Ach:
as in fig:4
Choline acetylase enzyme within cholinergic nerves
Acetic acid + choline Ach Stored in
axonal vesicles

Released Ach

Ach realesed from the nerve terminals

upon arrival of axonal action potential
depolarization of the nerve terminals
membrane cause Na++ influx with triggers
the release of large quantity of Ach from the
storage site (where present at autonomic ganglia)

Hydrolysis of Ach
by cholinesterase
Acetic acid + choline Ach

Relation of Ca++ and acetyl choline:

1-Ach is release on arrival of the action potential there increase of intraneuronal Ca++
infloux leading to exocytosis and release of Ach. Calcium deficiency reduces A.ch.
release from cholinergic nerves with failure of transmission.
Pharmacological actions of Ach:
Ach is typical para sympathomimitc drug acting on both muscarinic and nicotinic
receptors back to the table: 1 and write in details
I. Action on CNS
a. Acety choline induces excitatory action at (M1, M2, M3, M5 & NN).
b. Acetyl choline induces inhibitory action at (M2 & M4).
Both effects occur in number of neuronal tracts including cerebral cortex and basal
ganglia. Muscarinic receptors are abundant in dorsal surface of spinal cord, thalamus
and areas of CNS involved in pain transmission. So, the muscarinic agonist may be
effective as analgesic.
II. Peripheral action
(Heart , SMF, Exocrine glands)
a-On CVS:
Heart:
A negative inotropic and a negative chronotropic effect on the heart by acetyl
choline is mediated by action on M2 receptors and is due to the inhibitory effect of
increased K+ conductance.
BVs:-Vasodilatation action of A.ch. on the heart as the effects of vagal stimulation.
- Large I/V doses causes an increase in the blood pressure because it induces release
of catecholamines from the adrenal medulla and activation of sympathetic ganglia.
b-On GIT: Ach increases the motility and secretory activities (M1 & M3).

47
c-On smooth muscles:Ach contracts the smooth muscles in the uterus, ureters, bladder
and bronchioles and the constrictor muscles of the iris.
d-Ach stimulates exocrine glands eg bronchial, salivary, sweat and lacrymal glands.
e-On skeletal muscles: Ach stimulates skeletal muscle contraction by action on
nicotine receptors (NN) competitive and depolarizing for nicotinic receptors.
f-Effect on autonomic ganglia: Ach has a depolarizing and firing of postganglionic
neurons of both sympathetic and parasympathetic ganglia. This action is mediated
through (NN) nicotinic receptors. It is stimulated by nicotine and blocked by
hexamethonium.
Mode of action of Ach:
By occupying the receptor sites (muscarinic and nicotinic receptors). In general A.ch
evokes an excitatory response in some tissues (smooth muscles of GIT) where as it cause
inhibitory response to other tissues (myocardium). The excitatory effect of Ach is due to
depolarization of the post synaptic membrane leads to increases in the permeability of the
membrane to both Na+ and K+ ions. On the other hand the inhibitory effect is due to
hyperpolarization of the membrane caused by selective increase in the membrane
permeability to K+ not to Na+.
Therapeutic uses of Ach:
Ach is not used therapeutically due to the following:
1-It. has no selective therapeutic response.
2-It has short duration of action due to cholinesterase enzyme and adrenaline.
3-It has no effect when given orally due to its destruction in the alkaline media of the
intestine.
4-Ach is a valuable for pharmacological research.
Adverse effects and precautions for parasympathetic agonists:
1-Increase GIT motility, muscle paralysis and stimulation of glandular secretion.
Atropine can block these serious adverse effects.
2-They are contraindicated in patients with coronary insufficiency, hyperthyroidism,
peptic ulcer or bronchial asthma.
B-Carbacol-carbaminoyl choline (Doryl)
It is available as chloride salts, soluble in water.Completely absorped after oral
and S/C administration.
Pharmacological actions:
1-It has long duration as highly resistant to hydrolysis by cholinesterase enzyme.
2-It has a selective action on the smooth muscle of GIT and urinary bladder.
3-Its nicotinic action is more pronounced on the ganglia due to release of Ach from the
terminals of the preganglionic fibers.
Therapeutic uses of carbacol:
1-Neuromuscular purgatives.
2-Rumentoric (s/c in dose 2-5 mg for cattle, 0.5-1 mg for sheep).
3-Urine retention in large animals due to atony of urinary bladder (s/c in a dose of 0.5
mg).
4-Treatment of glaucoma as a miotic drug alternative to physostigmine.
5-It used as diaphoretic to remove edema.
C-Methacholine
It is a synthetic drug available in the form of chloride powder soluble in water.

48
Pharmacological actions:
1-Prolonged action than Ach because methacholine is less hydrolyzed by
cholinesterase. Only hyrolyzed by ture Ach .ase
2-The muscarinic action is predominant. This action pronounced on CVS.
Therapeutic uses:
1-Atrial tachycardia.
2-Peripheral vascular diseases given orally or by injection.
D-Bethanechol (urecholine)
Pharmacological action:
1-It is the most stable choline esters because it is not hydrolyzed by cholinesterases and
more prolonged action.
2-The muscarinic action mainly acting on GIT and urinary bladder.
Therapeutic uses:
1- Gastric retention post vagotomy,
2- Post operative urinary retention
3- Post operative abdominal distension.
Preparations:
1-Methacholine chloride s/c 10-25 mg.2-Carbacol (Doryl) s/c 0.25-0.5 mg.
3-Bethanechol 5 mg/ml.4-Bethanechol tablets 5-10 mg.

2-Cholinomimetics alkaloids
Naturally occurring alkaloids pilocarpine, muscarine and areocoline.
exert parasympathetic (muscarinic) effects without nicotinic activity.
Pharmacological actions:

49
1-parasympathomimetic effects by direct stimulation of the muscarinic receptors of the
cells innervated by postganglionic cholinergic nerves.
2-They do not destructed by cholinesterase enzyme and do not depend on release of
endogenous Ach.
A-Pilocarpine:
Pharmacological action:
It stimulates flow of secretion from exocrine glands. It causes contractions of GIT
smooth muscles. It constricts the eye pupil.
Clinical uses:
1-It causes miosis, papillary constriction when it used locally in 0.5-2 %,or systemic for
the treatment of glaucoma.
2-It used alternately with mydriasis to prevent synechiation (adhesion).
B-Arecoline
Pharmacological actions:
1-It activates muscarinic receptors of the cholinergically innervated effector cells of
glands, smooth muscles and myocardium.
2-It is more potent than pilicarpine.
3-It depresses the heart rate and blood pressure.
4-It constricting the bronchioles causes dyspnea.
5-It increases the secretion and peristalsis of the GIT.
6-it increases saliva.
7-It contracts the urinary bladder.
Clinical uses:
Arecoline HCl in a dose of 1 mg/kg used as a taniacide in dogs.
C-Muscarine
Pharmacological actions:
Its action is particularly on the cell receptors innervated by peripheral cholinergic
nerves. It is not used clinically.
Toxic symptoms of cholinergic alkaloids:
Colic, diarrhea, salivation, constricted eye pupil, dyspnea, depression of heart rate and
B.P.
Contraindications:
Not used arecoline and pilocarpine in animals with heart failure, depression or
disease of respiratory tract, spasmodic colic and during gestation.
Treatment of toxicity:
The treatment of toxicity occurs by atropine sulphate which is specific antidote to
toxic doses of arecoline, pilocarpine and muscarine.

50
 3-Cholinestrase inhibitors
They are divided into:
I-Reversible cholinergic inhibitors
e.g. physostigmine, neostigmine and edrophonium.
Mode of action:
They are compound that inactivate or inhibit Ach enzyme and
pseudocholinestrase leads to increasing the activity of endogenous Ach e.g.
physostigmine, neostigmine and edrophonium. They induce reversible inhibition of
cholinesterase. Neostigmine and other reversible inhibitors exert some direct effects
either agonistic or antagonistic on cholinergic receptors, in addition to inhibition of
cholinesterase. Stimulant effect of neuromuscular junction is due to direct receptor
activation as well as to cholinesterase inhibition of neostigmune.
II-Irreversible cholinergic inhibitors
Organophosphorus compounds
e.g. phosphorofluoridate.
Pharmacological actions:
1-Physostigmine and neostigmine cause contraction of the smooth muscle fibers
increasing motility of the GIT, while excessive motility leads to spasm (physostigmin
given s/c or I/M).
2-Cholinestrase inhibitors induce parasympathomimetic (muscarinic) effects and
induce post ganglionic parasympathomimetic impulses and activate Ach at nicotinic
sites. So these drugs induce the following:
-Stimulate post ganglionic muscarinic receptors of the effector cells, resulting in typical
parasympathetic activity.
-Stimulation of adrenal chromaffine cells to discharge catecholamine into circulation
initial stimulation and subsequent depolarization block of nicotine receptors of
51
autonomic ganglia and skeletal muscle fiber and marked CNS cholinergic effects. These
effects happened in excessive dose where as the therapeutic dose resulted in:
*Reversible compounds induce little CNS activity because it is poorly cross the blood
brain barrier.
*These compounds are relatively more active at nicotinic receptors of the skeletal
neuromuscular junction of the autonomic effector cells.
*Where as the tertiary amines and organophosphates are less lipophilic and cross the
blood brain barrier and evokes CNS effects. These compound are relatively active with
low dose at autonomic receptor sites than on voluntary muscles.
I-Reversible inhibitors
1-Physostigmine (eserine)
Source:
-Naturally obtained from the dried seeds of calabar beans.
-Synthetically physostigmine salicylates white crystals easily soluble in water.
Action and mode of action:
1-Physostigmine acts by inhibiting cholinesterase enzyme prolong the action of A .ch
in the end plate of the peripheral and central cholinergic nerves thus it produce action
similar to muscarine on smooth muscle fibers and secretory glands and action similar
to nicotine on striated muscle and autonomic ganglia.
2-Large doses of physostigmine induce stimulant effect flowed by a depressant effect
on CNS specially the respiratory center and cause death due to respiratory failure.
Therapeutic uses:
1-As miotic drug constricting the eye pupil in the form of eye drops 0.5 % solution for
treating adhesion of the cornea and iris of the eye.
2-As GIT stimulant and ruminetoric especially in cases of impaction in horses and cattle
given s/c in doses of 5-25 mg, but not used in case of impaction due to mechanical
obstruction.
3-Glucoma.
2-Prostigmine or neostigmine
Source:
Synthetically in the form of two salts:
a-Neostigmine methylsulphate, powder and crystals soluble in water. It is given by inj.
(Amp. 0.25-0.5-1 mg/ml).
b-Neostigmine bromide, powder and crystals soluble in water. It is given orally as
tablets(15-30 mg).
Action and mode of action:
1-The same action of physostigmine.
2-It is more powerful or effective on the skeletal muscle and intestine.
3-It induces severe colicy pain due to severe action on the intestine.
Therapeutic uses:
1-To induce Miosis.
2-Antidote for curare and atropine toxicity.
3-Myasthenia gravis.
4-Post operative atony of the intestine.
5-Post operative atony of the bladder.
Enzyme reactivators:

52
 They are chemical agents that can reactivate the cholinesterase. e.g.
(PAM) pyridine -2- aldoxime methiodide.
3-Edrophonium (tensilon)
Source:
It is formed synthetically.
Pharmacological action:
1-It stimulates the skeletal muscle in small doses.
2-Its action is very short as anticholinestrase.
Therapeutic uses:
1-It is used as diagnostic means for myasthenia gravis.
2-It is used as an antidote for curare toxicity.
II-Irreversible anticholiestrases
Organic phosphorus compounds
They are powerful inhibitors of the cholinesterase as they phosphorylate it and
form a stable substance which undergo hydrolysis only very slowly or not hydrolyzed
and forming irreversible inhibition of cholinesterase; hence their action is prolonged.
Various organic phosphorus compounds are used in veterinary medicine as insecticides
as parathion, malathion, asuntol and neguvon. Their effect may stay for few days.
Atropine sulfate is used as an antidotal treatment for acute poisoning with organic
phosphorus compounds.
e.g.- DFP (diisopropyl fluophosphonate).
Pharmacological actions:
It stimulates the skeletal muscles. Tremors, convulsions, paralysis and coma.
Muscarinic activities.
Therapeutic uses:
1-Treatment of atropine poisoning. 2-Glucoma.
Adverse effects:
The adverse effects or side effects include the following:
1-Miosis.
2-Increased bronchial secretions, profuse sweating and increased lacrimation
3-Anorexia, vomiting and involuntary diarrhea.
4-Bradycardia.
5-Weakness of all skeletal muscles especially those of the respiration.
6-Anxiety and convulsions followed by vasomotor depression.
Reversal of cholinesterase inhibition:
(Treatment of organophosphorus toxicity)
Action and mode of action:
The anticholinestrases bind forcibly with the estrase enzyme at its anionic site by
the alkyl substitutes on the N2 atom forming an enzyme inhibitor complex. Oximes as
PAM or pralidoxime form an oxime-phosphorylated enzyme complex.The oxime-
phosphate then split of the phosphorus from the estratic site on cholinesterase in such a
way that the enzyme is restored and reactivated, the effects of A.ch begin to disappear
reversing the effect of organophosphate anticholinestrase agents.
N.B.Treatment must be within hours, because the phosphorylated enzyme slowly
changes to an aged form that can not be reversed.
Parasympatholytics

53
 (parasympathetic depressant, cholinergic blocking or antimuscarinic agents)
They are drugs compete with A .ch for the muscrinic receptors at the end plate of
structure innervated with peripheral but not central cholinergic or nicotinc receptors.
They differ from nicotinic blockers as curare which is also depressant of the
parasympathetic but act as blocking agents on preganglionic cholinergic nerves.
These alkaloids are atropine, hyoscyamine and hyoscine. Atropa
belladonna alkaloids are organic esters formed by combination of an aromatic acid
complex organic bases.
1-Atropine
Atropine is an alkaloids obtained mainly from atropa belladonna. It does not
prevent the release of Ach but it acting by preventing its arrival to the cells by blocking
the post ganglionic cholinergic receptors.
All muscarinic actions of Ach on smooth muscle fiber, heart, muscles and exocrine
glands are prevented by atropine.

Pharmacological actions and therapeutic uses of Atropine:

A-Parasympatholytic actions
I-On cardiovascular system:
1-Therapeutic dose, it induces temporal bradycardia then tachycardia is due to that it is
counter acts the peripheral dilatation and sharp fall in blood pressure caused by
cholinesters.
2-Large dose of atropine increase the heat rate leading to tachycardia by blocking the
vagal effects on the S.A node.
II-On GIT:
1-Atropine decrease secretion and diminishes acidity of the stomach.
2-Inhibit motility of GIT so it used as sedative and used during the peptic ulcer
treatment.
3-It relax the plain muscle fiber of bile duct so it used in case of biliary colic
III-On the renal system:
1-Atropine relaxes the smooth muscle of the ureter.
2-It reduces the tone of the urinary bladder.
3-It is given with morphine in renal colic during passage of a stone down ureter.
IV-Other therapeutic uses:
1-It decreases sweat secretion so it is given for individual suffering from excessive
sweat secretion
2-It is given before administration of neostigmine during treatment of myasthenia gravis
to prevent the muscarinic effect of neostigmine.
3-used as a Preanesthetic medication for the following:
a-Abolish salivary and bronchial secretion
b-Protect the heart from excessive vagal stimulation
c-Stimulation of respiratory center
B-Actions on CNS
1-Small doses (0.5-1 mg) induce slight stimulation.
2-Large dose induce stimulant effect on the brain producing excitation and restlessness.
3-Toxic dose caused central stimulation followed by depression and death due to
paralysis of respiratory center

54
Dose of atropine:
Belladonna dry extract contain 1 % of the alkaloid. Tr. belladonna contains 0.3 %
w/v of alkaloids. In ruminants 30-60 ug/kg injection s/c or i.m 1/1000 as atropine sulfate

Atropine absorption, fate and excretion:

The absorption occurs after oral or parentral administration. Partial deoxidation in
the liver. Partially excreted unchanged from kidney

Adverse effect of atropine:

Rapid pulse, dilated pupil, dry mouth, flushed skin, restlessness,elvated body temp.

Treatment of atropine poisoning: Its antidote is physostigmine.

1-Administration of pilocarpine or methacholine at interval till mouth becomes moist.
2- Administration of respiratory and central stimulant
2-Hyoscine (scopolamine)
Source: is an alkaloid obtained mainly from hyoscymus nigra plant. Is an ester of tropic
acid and scopine.
Pharmacological actions:
It has the effect of atropine acting as parasympatholytic drug. But it differs from
atropine in the following:
1-It is a central depressant and can act as sedative.
2-It has a prominent effect on the eye and excretory glands,
3-It is less active and of short duration effect on heart, GIT and bronchial muscles.
Preparations: hyoscine hydrobromide (crystalline salts, water soluble)
3-Hyoscyamine
It is L-hyoscyamine while atropine is d-hyoscyamine
Source: is an alkaloid obtained from datura stromonium and atropa belladonna
Pharmacological actions:
1- It has same actions of atropine.
2-It has more antispasmodic effect than atropine.
3-It is used with irritant purgatives to counteract their colicy pain.
4- It is used as bronchodilator in case of asthma.
4-Synthetic and semi-synthetic atropine substitutes
They are synthetic derivatives of atropine selective in action. They include:
1-Antispasmodic group:
Act by preventing spasm and colic of GIT and urogenital tract e.g hyoscine
butylbromide (buscopan) and oxyphenonium (anternyl)
2-Antisecretory group decrease Hcl secretion selectively block M1 e.g. Telenzepine
and prenzepine
3-Mydriatic group e.g. Homatropine 24 h., eucatropine 4 h., cyclopentolate and
tropicamide 6h.
4-Anti-parkinsonism group e.g. benzatropine (cogentin) and trihexphenidyl (artane)
5-Bronchodilator group e.g. ipratropium (atrovent) and tiotropium
I-Ganglionic stimulants

55
 These drugs are of limited value in therapeutics. They include small dose of Ach.,
nicotine, lobeline,Trimethyl-ammonium( T.M.D) and Dimethyl phenyl piperazin
(DMPP). They are used mainly as experimental tools.

1-Nicotine
Source: it is colorless liquid alkaloid, obtained from leaves of tobacco plant
Actions and mode of action:
1-Direct action on ganglia (sympathetic and parasympathetic):
a-Small doses of nicotine stimulate the ganglia by depolarization
b-Large doses of nicotine induce persistant depolarization and prevent further
stimulation by preganglionic release of Ach called ganglionic blocker which does not
interfere with synaptic release of Ach.
2-The same effect occurs in the adrenal medulla which secrets adrenaline after internal
stimulation, then stop secretion after the paralysis of secretory process
3-Nicotine affect the skeletal muscles at the neuromuscular junction in a similar manner
(depolarization), stimulation for a short period followed by neuromuscular block when
the muscle becomes insensitive to the action of Ach, hence they are described as
nicotinic effect of Ach
4-Small doses stimulate CNS and induce tremors. While large doses of nicotine induce
convulsions which are blocked by anticonvulsants and hypnotics. Also it stimulates the
respiratory center,followed by depression then paralysis. Stimulation of vomiting
center)
5-Small doses of nicotine reflexly stimulates respiration through aortic and carotid
chemoreceptor bodies
6-Nicotine first stimulates the GIT inducing diarrhea due to stimulation of the
parasympathetic ganglia followed by inhibition of the tone leading to constipation.
Bronchial and salivary secretions increased which is followed by inhibition.
7-Nicotine used as insecticides.
Nicotine poisoning:
Nicotine poisoning appeared in the form of nausea, vomiting, abdominal pain,
diarrhea, dizziness, rise in the blood pressure followed by fall, the pupil becomes
constricted but soon dilates, cold sweat, stimulation then depression of the respiration,
convulsions then death from respiratory paralysis.
Treatment of the nicotine poisoning:
1-Gastric lavage with 1:10,000 potassium permanganate.
2-Respiratory stimulant as systemic treatment.
2-Lobeline
Souce:
Lobeline inflate (Indian tobacco).
Actions and mode of action:
1-Lobeline is similar as nicotine in its action but less potent without habit forming.
2-It is mainly used as respiratory stimulant.
II-Ganglionic blockers
This group of drugs blocks the ganglia by blocking only the preganglionic fibers
without interfering with the liberation of Ach.
They include:-

56
1-Depolarizing ganglionic blockers:
e.g.Nicotine, Ach and lobeline in large doses.They act by causing persistent
depolarization of the postganglionic membrane and render its inexcitable which
usually stimulate before the paralysis of the ganglia.
2-Competitive ganglionic blokers:
e.g. Hexamethoium, Pentamethouium and Tetraethylammonium.They act by compete
with Ach for the same receptors.
Pharmacological actions:
1-Blockage of the sympathetic ganglia leading to vasodilatation and hypotension with
improving peripheral blood flow. They used for the treatment of hypertension and
peripheral vascular diseases.
II-Blockage of the parasympathetic ganglia leads to decrease the GIT motility and
urinary bladder motility with uterine retention, mydriasis, dry mouth and skin,
bradycardia and failure of erection and impotence occurred.
*These effects depend upon which of ganglia are predominant. Sympathetic are dominating
blood vessels while parasympathetic controlling the remaining effects.
Therapeutic uses:
1-Trimetaphan camphor sulphate (arfonad) injection 50 mg/ml is hypotensive during
anaesthesia.
2-Ansolysin (pentolinium tartarate) is used in malignant hypertension tablets 20-100 mg.
Side effects and contraindications:
a-Rapid hypotension in peripheral vascular diseases is dangerous.
b-Augmented uterine activities are dangerous for fetus and mother.
Drugs acting on the skeletal muscles
1-Skeletal muscle stimulants
e.g: A ch, methacholine & anticholinesterase.
Action and mode of action:
After a motor impulse arrives the neuromuscular junction, A.ch is released at the
nerve ending and depolarizes the muscle end plate causing a transient electrical charge
called the end plate potential which excites the adjoining muscle fibers and causes
contraction of the muscle. This effect for short period because the released Ach is
rapidly hydrolyzed to choline and acetic acid by cholinesterase enzyme and the end
plate quickly returns to its resting polarized state and it is then ready to response to the
next nerve impulse.
2-Skeletal muscle relaxants
They are called neuromuscular blocking agents. They are used during surgical
operations of the abdomen. They are classified according to its site of action into:
A-Peripheral skeletal muscle relaxant.
1-Presynpatic skeletal muscle relaxant 2-Postsynpatic skeletal muscle relaxant
B-Central skeletal muscle relaxant.
A-peripheral skeletal muscle relaxant
1-Presynpatic
They include drugs that interfere with the propagation of axonal action potential
e.g.-Local anesthetics, release of A.ch., aminoglycosides antibiotics.

II-Postsynpatic

57
 They are drugs that which inhibit the transmission of the nerve impulses at the
skeletal neuromuscular junctions. According to the mode of action they classify into:
1-Competitive: e.g.D-tubocurarine and gallamine.
2-Depolarizing: e.g. succinylcholine and decamethonium.
B-Cental skeletal muscle relaxant
1-CNS depressant: e.g. General anesthesia, tranquilizers, hypnotics, narcotics.
They depress motor output from the central cortex and spinal cord, reducing the
tone of the muscles
2-Spinal cord interneuron blocking drugs: e.g. Mephensin, Meprobate.

Postsynaptic skeletal muscle relaxant

A-Competitive Postsynaptic skeletal muscle relaxant
1-Tubocurarine
Source: They are obtained as powder from plant alkaloids.
Pharmacological actions:
1-Inactive orally, poorly absorbed from GIT.
2- It blocks autonomic ganglia and liberates histamine leading to hypotension and
bronchospasm.
3-Its effect is potentiated in the presence of the aminoglucosides antibiotics.
4-Patients suffering from myasthenia gravis are more susceptible to small doses of this
drug.
Pharmacokinetics:
It dose not pass the placental membrane to any degree. The drug is biotransformed
by the liver. The drug metabolites are eliminated through bile and kidney.
2-Gallamine
Source: Synthetic
Pharmacological actions:
1- It has curarine like action.
2-It is less potent than d-tubocurarine and of shorter duration less than 30 min.
3-It blocks the muscarinic receptors in the heart leading to tachycardia.
4-It excreted unchanged through the kidney.
B-Depolarizing Postsynaptic skeletal muscle relaxant:
e.g. succinylcholine and decamethoium. They act by inducing depolarization as
Ach leading to initial twitches and muscle tremors then followed by persistent
depolarization leading to spastic paralysis.
1-Succinylcholine (suxamethonium)
Source: Condensation of two molecules of Ach.
Pharmacological actions:
1- Rapid onset of action I/V in 20-60 seconds.
2-Showing long duration of action in ruminants but in dogs and cats are intermediate.
3-Its action potentiated by cholinesterase inhibitors.
4-It has cholinergic effect on the heart leading to bradycardia.
5-Patients with myothenia gravis are insensitive to the succinylcholine.
Pharmacokinetics: It is rapidly biotransformed in the horse.
2-Decamethonium and suxamethonium

58
 They are depolarizing muscular relaxants given I/V in doses of 1.5 mg/kg body
weight to horse and 0.15 mg/kg in cattle. They induce immediate relaxation of muscle
and it more prolonged than succinylcholine.
Clinical uses:
1-Diagnosis of myasthenia gravis.
2-Therapy of muscle sprains and traumatic injuries.
3-Therapy of strychnine poisoning.
4-To increase muscle relaxation to facilitate surgical interference.
5-It is used during surgery with general anesthesia.
Preparations:
Tubocurarine 15 mg/ml.
Dimethyl tubocurarine 2 mg/ml.
Gallamine triethiodide 20-100 mg/ml (floxebil).
Succinylcholine 20-50 mg/ml (anectine.)
Decamethonium 5 mg/ml (syncurine).

Sympathetic nervous system

Synthesis of adrenergic transmitters(The metabolic pathway )

The nerve ending may take other amines than catecholamines to be stored. The nerve
impulses release nor adrenaline in the presence of A.ch that help the entry of Ca++ that
evokes nor adrenaline release from the chromaffin granules. Reserpine helps the
detection of the store granules so that the pharmacological action starts.
Fate of catecholamines:
1-Inhibition of MAO caused increase of NE in the intra-cytoplasmic only.
2-Reuptake of the noradrenaline after its pharmacological action into the neuron and its
re-storage by the cell membrane pump is blocked by cocaine and phenoxybenzamine.
Inhibition of uptake of noradrenaline occurs by reserpine, guanethidine and 6-
hydroxydopamine.
Nor adrenaline and adrenaline Mono amine oxidase 3,4 dihydroxy mandic acid
(MAO)Intracytoplasmic)
Noradrenaline
and adrenaline catechol ortho methyl transferase (COMT) Normetanephrine
Circulating blood and synapsis

59
 Sympathomimetics (adrenergic agents)
These are drugs which induce actions similar to stimulation of sympathetic nerves.
A-Drugs stimulate adrenergic receptors:
I-α-agonist:
1-α1 agonists are phenylephrine and oxymetazoline
2-α2 agonists are clonidine and α methylnoradrenaline. They cause fall in B.P by
inhibiting of noradrenaline release
II-β-agonist:
1-Selective β1 agonist is dobutamine, increase cardiac contractility
2-Selective β2 agonists are salbutamol, terbutaline and salmeterol. They are used mainly
as bronchial dilator.
3-Selective β3 agonist BRL 37344 induce lipolysis
B-Drugs block noradrenaline receptors:
I-α-antagonist:
1-Non selective antagonists e.g…phenoxybenzamine and phentolamine
2-Selective α1 antagonists are prazocin, doxazocin and terazocin
3-Selective receptor antagonists e.g…yohimbine and idazoxan
II-β-antagonist:
1-Non selective β1 antagonists e.g…propranolol, alprenolol, oxprenolol
2-Selective β1 antagonists e.g…atenolol
According to their actions, they include direct, indirect and dual actions, whereas,
they are classified into catecholamines and non catecholamines according to their
chemistry.
Classification of sympathomimetics
I-According to their action:
a-Direct action on α, β receptors .e.g…noradrenaline, adrenaline, isoprenaline
b-Indirect:
-by stimulating release of catecholamines e.g…amphetamine
-or by inhibiting their destruction by enzymes or reuptake e.g…cocaine
c-Dual (direct and indirect), by both mechanisms e.g….ephedrine
II-According to their chemistry:
a-Catecholamines: They contain catechol nucleus (dihydroxyphenol) as EP,
NE, dopamine, isoprenaline
b-Non catecholamines: Without catechol nucleus as ephedrine, tyramine,
amphetamine, iproniazide, naphazoline
Adrenaline or Epinephrine (EP) (α and β)
It is one of the hormones of the suprarenal gland and also found in the vesicles at
the end plate of the sympathetic nerves to which it acts as a chemical transmitter.
Source: synthetically or from acid extracts of suprarenal glands.
Pharmacological actions
Adrenaline acts on α and β receptors inducing sympathomimetic and other actions.
I-Sympathomimetic actions:
1-On circulatory system:

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a-Heart: it is supplied with β1 receptors which are excitatory in the heart only. It gives
+ve inotropic and chronotropic (increase in the force and rate of contraction)
tachycardia.
N.B.Adrenaline must not be given in case of cardiac shock during chloroform
anesthesia because chloroform causes cardiac irritability and when adrenaline given it
produces ventricular fibrillation which may stop the heart
b-Blood vessels: adrenaline acts on α and β receptors and cause constriction of blood
vessels of skin, mucous membrane and visceral blood vessels (α1),
increasing the peripheral resistance and dilatation of the skeletal and coronary blood
vessels (β2).
c-Blood pressure: increasing B.P resulted from (tachycardia + increasing peripheral
resistance), proportional to the dose injected, is followed by sudden fall before it comes
to normal due to stimulation of the vagal receptors.
2-Respiratory tract: It relaxes the smooth muscles of bronchi and bronchioles. Also it
decrease congestion of respiratory mucous membrane, hence it is used in bronchial
asthma and anaphylactic shock.
3-GIT: Adrenaline relaxes the smooth muscles of the stomach and intestine (α1 and β2)
and contractions of the sphincters.
4-Urinary system: It relaxes the muscles of urinary bladder (β2) and constricts the
sphincter (α1) leading to urine retention.
5-Uterus:
Variable according to the species, sex cycle and pregnancy. It relaxes the uterus of
guinea pigs, rats and non-pregnant cats.
6-Splenic capsule:
Injection of adrenaline causes contraction of the spleen (α1) results in release of RBCs
in circulation.
7-Eye:Adrenaline causes mydriasis by contraction of radiating muscle (α1). Locally,
slight mydriasis and conjuctival ischaemia (α1).
8-Skin & salivary glands: Adrenaline causes erection of the hair (α1) and scanty viscid
sweat secretion.
II-Other action:
1-Adrenaline stimulate release of ACTH, that enhance cortisone production.
2-Skeletal muscles facilitates neuromuscular transmission (α) with rapid recovery from
fatigue.
3-The adrenaline considers physiological antihistaminic agent.
4-Blood coagulation:
It accelerates blood coagulation by increasing the activity of the factor V.
5-CNS:Weak stimulation, restlessness and tremors.
6-Metabolism:
a-Adrenaline accelerate the glyconeogenesis and increase the depletion of the glycogen
deposits in the liver and the skeletal muscles and thus rise blood sugar and lactic acid
content in the blood. Thus leads to antagonize the insulin.
b-Increases BMR by increasing the O2 consumption and rise of the body temperature.
c-Increase the release of corticotrophine and increase excretion in 7- ketosteroids.
Mode of action on metabolism

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 Adrenaline stimulate adenylcyclase enzyme which stimulate formation of the
active 3,5 AMP cyclic from ATP required for biological and metabolic activities
transforming the inactive phyosphorylase to active physphorylase inducing
glyconeogenolysis.
Pharmacokinetics of adrenaline:
1-When adrenaline is administered orally it gives no effect or no systemic action because it
partly destroyed by GIT secretions and partly conjugated in the liver.
2-When it given S/C it absorbed slowly due to its vasoconstrictor action.
3-When it given I/M it absorbed rapidly because it dilates the blood vessels of the skeletal
muscles.
4-I/V injection of adrenaline induces ventricular fibrillation.
5-After absorption of adrenaline it is rapidly inactivated by conjugation in the liver and
degradation by oxidation in the tissues by C.O.M.T and M.A.O enzymes.
Contraindications:
It is contraindicated to use adrenaline in the following cases, chloroform
anaesthesia, hypertension, old ages, Heart diseases and hyperglycemia
Therapeutic uses of adrenaline:
Bronchial asthma S/C in small doses, allergic reactions, with local anaesthesia,
hyperglycemia due to insulin, local haemorrhages, cardiac arrest.
Preparations:
Adrenaline Hcl injection 0.1 % = 5 mg S/C.
Adrenaline Hcl injection 0.2 % in oil I/M.
Adrenaline Hcl inhalation 1 % as erosol.
Noradrenaline or Norepinephrine ( α )
Source:
1-It is the chief catecholamine released at the ending of the sympathetic post ganglionic
nerve fiber by about 80 %.
2-It is also produced in the adrenal gland by about 20.%.
3-It present in the brain.
Pharmacokinetics:
Sience noradrenaline is changed into adrenaline in the tissues hence it has the same fate
in the body.
Pharmacological actions:
1-It acts mainly on the α receptors (α agonist).
2-It is differ from adrenaline in the following:
a-It causes constriction of the peripheral and skeletal blood vessels.
b-It causes steady rise in the blood pressure (systolic and diastolyic pressure).
c-It dose not cause increase in the cardiac output.
d-It causes decrease in the heart rate reflexly following the increase the blood pressure.
e-It was weak bronchodilator.
f-It has less powerful effect on the plain muscle fibers.
Therapeutic uses:
1-It used to counter act the hypotension especially in the hypertension induced in the
spinal anaesthesia and postoperative collapse.
2-It is also used as haemostatic.
Preparations:

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 Noradrenaline bitartarate 0.2 % (equivelant to 0.1 nor adrenaline) given I/V
infusion (4 ml in 1 liter 5 % glucose or saline) 0.25-25 ml/min.
Adverse effects of nor adrenaline and adrenaline:
1-Anxiety. 2-Headache. 3-Central haemorrhages from the vasopressor effects.
4-Cardiac arrhythmia, especially in the presence of digitalis and certain anaesthetic
agents. 5-Pulmonary edema from the pulmonary hypertension.
Isoprenaline (isopropyl nor adrenaline) (β)
Soure:
Synthetic crystalline powder soluble in water.
Pharmacokinetics:
1-Absorption by injection or by inhalation but orally is unreliable.
2-It metabolized by COMT and MAO as adrenaline and nor adrenaline.
3-It excreted through urine.
Pharmacological actions:
1-Isoprenaline is selective β agonists. It acts mainly on β receptors.
2-Heart:
Isoprenaline is the most potent active on the heart causes relatively great increase in
the myocardial contraction force, heart rate and cardiac output than dose similar of the
adrenaline and noradrenaline.
3-Smooth muscle fibers:
It is more powerful in produce relaxation of the smooth muscle fiber (β2) present in
bronchi, intestine and uterus.
4-Blood vessels:
It induces vasodilatation of the skeletal muscle blood vessels, and partially for the
peripheral blood vessels.
5-Blood pressure:
Decrease the blood pressure especially the diastolic blood pressure by generalized
vasodilatation.
Therapeutic uses:
1-Acute bronchial asthma. 2- Heart block.
Preparations:
1-Subling tablets 10-20 mg. 2-Solution 1 % aerosol.
Adverse effects:
1-These are similar to the adverse affects of the adrenaline.
2-Over doses by inhalation can induce fatal ventricular arrythemia.
3-Tolerance to the desired effects occurs with over use in the asthmatic.
Dopamine(α , β, D1, D2 and D3)
Dopamine is precursor of adrenaline in nerve ending also it is a normal transmitter
in CNS. Dopamine deficiency result in Parkinsonism and treated by L-dopa as
dopamine can not cross brain barrier.
Pharmacokinetics:
It resembles adrenaline and noradrenaline in its pharmacokinetics.
Central dopamine receptors:
1-The central D1 receptors sits is excitatory and directly activates the adenylate cyclase
enzyme.

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2-The D2 receptor site is inhibitory in the same brain tissues and use CAMP as its
intracellular messenger. Pituitary related side effects of neuroleptics are mediated
through D2 receptors in the pituitary.
3-The D3 receptors are found in the limbic system and not found in the pituitary. It is
concerned with emotional and cognitive behavior.
Pharmacological actions:
1-Dopamine is direct agonist acting on β1 receptors and releasing nor adrenaline from
thew nerve terminals leads to positive inotropic effect on the myocardium.
2-It in low or moderate dose induces vasodilatation of the blood vessels of the mesentry
and kidneys mediated by receptors of the dopamine.
3-It increases the systolic pressure and has little effect on the diastolic pressure.
4-In higher doses resulted in vasoconstriction with decrease in the renal functions by
acting on α receptors.
Therapeutic uses:
In case of cardiac and septic shock, chronic refractory congestive heart failure.
Adverse effects:
1-Larg doses leads to excessive sympathomimetic activites.
2-May leads to angina, nausea and hypertension.
Non catecholamines
Ephedrine
Source:
1-Alkaloids obtained from ephedra plant.
2-Synthetically.
Mode of action:
Ephedrine is a mixed acting sympathomimetic agent, it has direct and indirect
actions (dual actions).
1-Its primary action is indirect, it cause release of nor adrenaline from its storage in the
nerve terminals apparently by competing with nor adrenaline for transport into granules
and by prevent the destruction of the adrenaline by MAO enzyme.
2-It is also produce direct stimulation of adrenaline receptors by acting on α and β
receptors (direct action).
Pharmacological actions:
Ephedrine is similar in its pharmacological action to adrenaline but differs in the
following:
1- Stability: Ephedrines is stable but adrenaline is unstable.
2-Origin: Adrenaline is animal and synthetic in its origin while the Ephedrine is plant
and of synthetic origin.
3-Duration of action: Ephedrine is long acting as not affect by MAO, while adrenaline
is short acting where it affects by MAO.
4-Routes: Ephedrine given by all routes but adrenaline is inactive orally.
5-CNS stimulants: Ephedrine stimulate, while adrenaline not stimulate.
6-Locally on the eye: Ephedrine induces mydriasis but adrenaline has no effect.
7-On uterus: Ephedrine stimulate, while adrenaline variable.
8-Tachyphyloxis: Ephedrine induced but adrenaline not induced.
Pharmacokinetics:
1-Absorption occurs by all routes even orally.

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2-It is resistant to COMT and MAO so its activity is prolonged.
3-Excreted unchanged by the kidneys.
Therapeutic uses of Ephedrine:
1-It is mainly used as bronchodilator against attacks of bronchial asthma in dogs, when
it is given orally in doses of 15-30 mg.
2-Mydriasis when used 1 % solution of Ephedrine sulfate.
3-Nasal decongest out in the case of rhinitis.
4-It is used with neostigmine in the case of myasthenia gravis.
5-It used to increase the blood pressure.
6- Antidote in narcoting poising because it stimulates the central nervous system.
7-As respiratory inhalant but Amphitamine is superior in this respect.
Adverse effect of Ephedrine:
1-As epinephrine.
2-CNS effect may occur.
3-It must be used with caution in patients with cardiovascular diseases or
hyperthyrodisim because it is powerful heart stimulant.
Amphetamine
Source: It is synthetically prepared liquid amphetamine sulfate and it commonly used
as powder or tablets.
Pharmacokinetics:
1-Amphetamine rapidly absorbed from the alimentary tract.
2-It inactivated partly in the liver.
3-Excreted unchanged by the kidneys.
Mode of action: Amphetamine acts indirectly by releasing of noradrenaline.
N.B
1-The dextrorotatory (d-) form is more active in the CNS than levorotatory (L-) form.
2-Amphetamine depresses the appetite and decreasing food intake by affecting the
feeding center in the hypothalamus.
3-It increases the metabolism to small extent.
Pharmacological actions:
1-It has addiction.
2-It stimulates the CNS.
3-It stimulates the respiratory center.
4-It activates the motor area and mental activity of the brain, so it used in race horses.
5-It stimulates the spinal cord transmission.
6-It increases the blood pressure.
Therapeutic uses of Amphetamine:
1-Motor activator in race horses. 2-As respiratory stimulant.
3-It is not recommended to control the obusity using amphetamine because tolerance to the
anorexic effects
4-In case of rhinitis. 5-In case of Parkinsonism.
Adverse effect of Amphetamine:
1-Tolerance to Amphetamine occurs within several weeks.
2-Prolonged use can lead to mental depression and fatigue.
3-Cardiovascular stimulation leads to tachycardia and hypertension.
4-Mydriasis and dry mouth occur.

65
5-It is contraindicated to be used in patients with cardiovascular diseases.
Salbutamol
Source: Synthetic.
Pharmacological actions:
1- It acts chiefly on β2 receptors.
2-More effective as bronchodilator than isoprenaline.
3-Has no effect on CVS.
4-Resistant to COMT so prolonged in its action.
Therapeutic uses:
Salbutamol used in acute bronchial asthma and bronchitis.

Other adrenergic drugs

Pasedrine  hydroxyamphetamine
Mephenteramine  wyamine
Antiadrenergic drugs
These are drugs which antagonize the adrenergic activities, and they grouped into:
1-Adrenergic receptors blocking drugs.
2-Adrenergic neurons blocking drugs.
1-Adrenergic receptors blocking drugs:
They are drugs which block α or β. They block the acess of catecholamines. These
drugs interact with adrenergic receptors of the effector cells and by occupying these site
not allow an adrenergic agonists access to the receptors. α receptor blocked by
phentoamine while β receptor by propanolol.
2-Adrenergic neurons blocking drugs:
They are not block the postsynaptic receptors, but they act presynaptically at the nerve
terminals to cause a decrease release of endogenous neurotransmitter nor epinephrine.
α-adrenergic blockers
1-Imidazoline derivatives (Tolazoline, Phentolamine).
2-Dibenzazepine derivatives (Azaperine).
3-Bera-Halo alkyl amines (Phenoxybenzamine, Dibenzamine).
4-Yohimbine.
5-Ergot alkaloids.
1-Imidazoline derivatives (Tolazoline, Phentolamine).
1-Tolazoline (Priscol)
Source: Synthetic.
Pharmacological action:
1-It is α- receptor blocker.
2-It induces a direct vasodilatation.
3-It increases the gastric secretion by histamine action.
4-It induces a hypotension.
5-It induces GIT stimulation and diarrhea.
2-Phentolamine (Rigitine)
Source: Synthetic.
Pharmacological actions:
1-It acts on α-receptor similar to the action of Tolazolin.
2-Its potency is 10 times more potent as α-blocker.

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Pharmacokinetics:
Phentolamine is less than 30 % active when given by mouth compared to injection.
2-Azaperine
Similar to Tolazoline.

3-Beta-Halo alkyl amines

α-blockers, slow in thir action by slow formation of reactive intermediate
compounds.
A-Phenoxybenzamine
Mode of action: It induces its action by binding to the α-receptor producing an
irreversible blockage. It is somewhat more potent in blocking α1 (postsynaptic)
receptors than in blocking α2 (presynaptic) receptors.
Pharmacological actions:
1-CVS:
a-Hypotension. b-Increases cardiac output. c-Depress total peripheral resistance.
2-Metabolim:
It does not have sihnificant metabolic actions (because it acts on α adrenergic receptors
and most metabolic effects of catecholamines are the result of their effects on β-
receptors).
3-CNS:
It stimulates CNS producing nausea, hyprventilation and loss of the time perception.
Therapeutic uses:
1-For acute hypertension caused by the use of sympathomimetics or MAO inhibitors or
by pheochromocytoma. 2-To reverse vasoconstriction in shock.
3-Torelieve vasospasm. 4-To control autonomic hyper reflexia.
Adverse effects:
1-Ejaculation may by inhibit.
2-Miosis and nasal stuffiness may occur.
3-Nausea and vomiting may occur with oral administration.
4-Injection causes local tissue irritation.
B-Dibenzamine
1- It produces a local tissue damage and CNS stimulation.
2-It has a slight direct depressant effect on the heart that may be involved.
3-It inhibits the pressor effects of catecholamines α-blocking drugs decrease the
inotropic effects of catecholamines in isolated heat muscles. This effect varies from
species to species.
Pharmacokinetics:
1-the Haloalkylamines and Imidazole are effective when given by mouth or by
injection. Haloalkylamine is absorbed in 20-30 % orally in an active form.
2-The onset of action of phenoxybenzamine and dibenzamine is prolonged after I/V
administration. These drugs may be converted into active intermediates which exert α-
blockers effects. Metabolism of α-blocking is not clarified, may stored in fat adipose
tissues because of their relatively high fat solubility.
4-Yohimbine
Souce: Natural alkaloids.
Pharmacological actions:

67
1- α-blocking effect with local anaesthetic effect.
2- 2-It is an aphrodisiacby genital vasodilatation.
3- 3-It releases the A.D. hormone.
5-Ergot alkaloids:
Source:
The natural alkaloids of ergot are ergotoxine, ergotamine and ergometrine.
Mode of action:
They induce their actions, which are α-blocking agents which prevent the effector
cells from responding to their stimulation of adrenergic nerves of the injection of
epinephrine but they do not prevent the liberation of the chemical mediator.

Pharmacological action:
1-Uterus: Stimulation of the uterus occurs in late pregnancy in case of ergometrine. It
induced faster and tonic contractions.
2-B.Vs.: They induce vasoconstriction leading to increasing blood pressure with
reduction in peripheral blood flow.
3- α-adrenergic blocking effects is antagonized by using dihydroergometrine.
4-Haert and Bvs.:Ergot alkaloids slows the heart rate but augment its contraction. Large
doses produce rise in blood pressure due to the peripheral vasoconstriction and
constriction of the blood vessels of the abdomen.
5-Stomach and intestine: In small doses, ergot alkaloids have little effect on the movement
because the sympathetic nerves are inhibitory. It causes vomiting and diarrhea.
6-Eye pupil: It causes slight dilatation but soon produce powerful constriction which is
not removed by atropine.
7-Respiration: Respiration is accelerated from stimulation of the center.
Therapeutic uses of ergot alkaloids:
1-Methylergotamine (Methergin):
It is used to help rapid involution of the uterus as well as for treatment and
prevention of post parturient haemorrhage.
2-Dihydroergotamine:
It is used for treatment of migraine.
3-Dihydroergotoxine:
It is used as hypotensive and in case of peribheral vascular disease.
Clinical uses of α-adrenergic blockers:
1-In cerain types or stages of shock syndromes have been reported to respond favorably
to an α-blocking agent. This is beliveved to be due to antagonism of catecholamines
induced peripheral vasoconstriction in visceral organs.
2-Phenoxybenzamine:
It is used for preventing ischemia of the microcirculation during shock in animals.
If hypotension occurs during α-blocking administration in shock, adequate fluid
replacementhas not achieved but blood or plasma expanders should be instituted prior
to continuing the infusion of the α-blocking agent.
3-Chloropromazine (2 mg/kg) and acepromazine (1 mg/kg):
They are administered I/V and have been shown tp prevent anaesthesia, induced
sensitization of myocardium to catecholamines and to decrease incidence of ventricular

68
fibrillation induced by administration of epinephrine and norepinephrine during
anaesthesia in dogs.
β-adrenergic blockers
Dichloroisoproternol (DCI) was the first drug demonstrated to cause a specific
blockde of β-drenerhic receptors.
1-Propranolol
It blocks all β adrenergic blocking agent. Propranolo is a non selective β-
antagonsists, it competes for both β1 and β2 receptors.
Pharacokinetics:
The drug absorbed then extracted in the liver before entering the systemic
circulation. The drug metabolized in the liver with wide variation among individuals
and different concentration in the plasma. It is bound to the plasma protein (90 %). The
elimination time 0.5-3 hours in small doses and prolonged in the large doses especially
in the presence of cirrhosis. A metabolic product, 4- hydroxypropranalol is active but
has short half life.
Pharmacological actions:
A-CVS:
Propranolol causes minimal depression of the heart rate, myocardial contractile
forc and cardiac output during normal condition since at rest the heart is not under
pronounced sympathetic tone. The drug prevents the positive inotropic and
chronotropic effects of catecholamines in the heart as a result of β-receptors blockade.
β-blocking agents affect blood pressure through their effect on the cardiac output rather
than by peripheral vascular effect, vasodilatation produced by isoproterenol or
epinephrine is blocked by propranalol. Propranolol causes antiarrythmic effect on the
heart. it causes prolongation of the A-V node conduction and causes quinidine like
effect as it csuse direct stabilization of the cell membeane.
B-Bronchi: Propranolol inhibits sympathetic bronchodilator activity and causes
bronchoconstriction which is harmful in the bronchial asthma by stimulating 3 ,5 AMP.
C-Metabolic activity: Propranolol causes prevention of the lipolysis and
glycogenolysis.
Clinical uses of Propranolol:
1-β-blocking drugs is used with vasodilator drugs that act on the smooth muscle fibers
of blood vessls to prevent the reflex tachycardia caused by the decrease of the peribheral
vascular resistant.
2-Propranolo used to control the angina attack.
3-β-blocking agents have been used to protect the heart from arrhythmia induced by
adrenergic agents.
4-In dogs slow I/V infusion of the drug 1-3 mg has been proposed fro the teatmentof
digitalis induced supraventricular tachycardia.
**The oral dose 10-40 mg every 8 hours.
Side effects:
1-It may precipitate heart failure.
2-It may exacerbate bronchoconstriction in the asthmatic patients.
2-Practolol or Eralin
Source: Synthetic.
Pharmacological actions:

69
1-It acts on β1 receptors.
2-Specific selective action on the heart.
3-Has no effect on the bronchial muscles.
Therapeutic uses:
1-It is used for the treatment of angina in the asthmatic patients.
2-It reduces the cardiac output.
3-Sotalol
Pharmacological actions:
1-It has the pharmacological actions of propranolol.
2-It has no quindine like effect.
4-Oxprenolol
Pharmacological actions:
1-It has the pharmacological actions of propranolol.
2-It has intrinsic sympathomimetic action used to increase the blood pressure.

5-Aloprenolol
Pharmacological actions:
1-It has the pharmacological actions of propranolol.
2-It has intrinsic sympathomimetic action used to increase the blood pressure.
N.B. (DCI) not used for patent intrinsic activity and pronethalol which is not
used as carcinogenic.
Preparations:
Propranolol (inderal) 10-40 mg tablets.
Practolal (eraldin) 200-300 mg tablets.
Oxprenolol (trosicar) 20 mg tablets.

Adrenergic neuron blocking drugs and catecholamines depleting agents

These are drugs which interfere with chemical transmitter at the post ganglionic
nerve ending either by depletion of the stores of mediator oe direct prevention of its
release.
Mode of action: They act by three ways:
A-Inhibiting the synthesis of nor adrenaline by false transmitter whtch replace nor
adrenaline with weak presser effect. e.g.α-methyl dopa.
B-By inhibiting the storage of adrenaline. e.g. reserpine.
C-By inhibiting release of nor adrenaline by nerve impulse. e.g. guanethidine.

α-methyl dopa
Source: Synthetic.
Pharmacological actions:
1-It depletes tissue storage of nor adrenaline through inhibition of decarboxy-lation of
dopa. 2-It also decrease the concentration of the dopamine and nor adrenaline in the
CNS and the peripheral tissues. 3-It directly dilates the peripheral blood vessels. 4-It
inhibits the rennin secretion. 5-It reduces the blood pressure by acting on the CNS.

Therapeutic uses: It used as hypotensive.

Preparations: *α-methyl dopa (aldomet) 250 mg tablets.

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 *Methyl dopate Hcl 250 mg/5 ml I/V injection.

Reserpine
It hypotensive and tranqulizer alkaloids that depletes nor adrenaline stores
reducing the effect of stimulating adrenergic nerves or drugs which act by releasing
catecholamines as ephedrine.
Mode of action: Impairment of Mg++ and ATP dependant capacity of interneuronal
vesicles to accumulate and store catecholamines.
After treatment with reserpine, amines are released from granular storage sites into the
neuronal cytoplasm, where they are metabolized by MAO.
Pharmacological actions:
1-Slow the heart rate and decrease the blood pressure.
2-Centrally it causes bradycardia, sedation and tranqulization.
3-The onset of action of the drug is very long 24-48 hours.
Therapeutic uses:
1-Reserpine used in the treatment of hypertension and psychic disorder in the human.
2-In dogs chronic daily treatment 26 µg/kg orally induces a marked decrease in the
concentration of NE in the hypothalamus, pons, M.O and heart.
Preparations: 1-Reserpine (Surposil) tab. 0.1-0.25 mg.
2-Reserpine (Surposil) inj. 2.5-5 mg/ml IM or IV
Side effects:
Sedation, abdominal cramps, GI ulceration, possible increased incidence of breast

Guanithidine
It is used as hypotensive in humans

Bretylium
it is an androgenic neuron blocking drug
Pharmacological actions:
1-Originally was used in attempts to control hypertension.
2-It exerts a local anesthetic like effect at the adrenergic nerve terminls by this
mechanism decreasing the amount of NE discharge from the nerve
Therapeutic uses:
Breytlium is used mainly as an antiarrhythmic agent; it is poorly absorbed when
given orally.
Adverse effects:
They include cardiac stimulation caused by the sympathomimetic effects of the
bretylium and strong hypotensin.

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 Autacoids

Autacoids "local hormones" are biologically active substances rapidly synthesized in

response to certain stimuli then rapidly degraded.

Unlike endocrine hormones, these agents are not blood-borne and so they act locally on the
tissue near to or from which they are secreted.

Effects of autacoids are primarily on smooth muscles.

Autacoids can be classified into the following categories:

1-Amines, including histamine and serotonin (5-HT or 5-hydroxytryptamine).

2-Eicosanoids, including prostaglandins, prostacyclins, thromboxanes and leukotrienes.

3-Endogenous peptides, including :

a-Vasoconstrictors, including angiotensin II, vasopressin, neuropeptide Y and endothelin .
b-Vasodilators, including kinins, vasoactive intestinal peptide (VIP) and substance P

4-Cytokines, including interferons and interleukin-1

A-Histamine

Histamine is a biogenic amine synthesized by decarboxylation of the amino acid L-histidine

by the action of the enzyme histidine decarboxylase.
-It can be synthesized in all body cells but it is mainly synthesized by three cell types :

1-Basophils and mast cells, where histamine represents a part of the immune reaction by
causing vasodilation and increased capillary permeability.
Antigens bound to IgE-loaded mast cells cause degranulation and excessive histamine
release.
Since histamine is also stored bound with heparin and acidic proteins, drugs like morphine
and tubocurarine increase histamine release by displacement of the latter from its bound
form .
2-Enterochromaffin-like cells (ECL cells) in the gastric mucosa, where the synthesized
histamine increases gastric acid secretion .
3-Certain neurons in CNS, where histamine is used as a neurotransmitter.

Histamine actions are mediated by three receptor subtypes, namely H1, H2 and H3
receptors:-
1-H1 receptors are present in
-Bronchial smooth muscles (bronchoconstriction and asphyxia)
- Vascular smooth muscles (vasodilation, increased capillary permeability
Extravasation (may lead to hypotensive shock)
-Vascular endothelial cells (contraction leads to edema) ,
-Nasal mucosa (runny nose)
- Vestibular system (nausea and vomiting)
-Sensory nerve terminals (pain and itching).
-Histamine receptor blockers:
These agents are either H1 blockers or H2 blockers .

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A) Histamine H1 receptor blockers :
These agents are either
1- First generation (have potent sedative effects, e.g. chloropheniramine, cetrizine,
benzatropine and diphenhydramine).
2-Second generation (non-sedating, e.g. Loratidine, astemizole, terfenadine and
fexofenadine) .
Some members also possess anticholinergic effects (diphenhydramine and benzatropine),
Anti-serotonin (cyproheptadine) or antiadrenergic alpha receptor blocking effect
(promethazine)

Actions include sedative effects:-

-First generation agents only, useful in insomnia.
- anti-allergic effect and anti-asthmatic effects
Useful in anaphylactic shock, allergic conditions, urticaria, drug hypersensitivity reactions,
runny nose, bronchoconstriction and edematous conditions.
-and anti-emetic effect (useful in motion sickness, especially when combined with
anticholinergic effect like diphenhydramine) .
-Some members may cause cardiac arrhythmia (astemizol).

Macrolide antibiotics (erythromycin) and ketoconazole inhibit metabolism of second

generation antihistamines leading to cardiac toxicity .

Other agents that interfere with histamine functions include agents that cause inhibition of
histamine release (cromolyn sodium)

or agents that cause physiological antagonism to histamine action (epinephrine) .

B) Histamine H2 receptor blockers:

These agents are used mainly to treat peptic ulcer (gastric and duodenal ulcers, an action
related to inhibition of HCl secretion), esophageal reflux and Zollinger-Ellison syndrome,
gastrin hypersecretory condition due to gastrin-secreting tumor. Examples include
Cimetidine, Ranitidine, Famotidine and Nizatidine.

Cimetidine is no longer used due to potent adverse effects and drug-drug interactions (liver
microsomal enzyme inhibition, anti-androgenic activity, male gynecomastia and female
galactorrhea).

Angiotensin (Hypertensin)

Angiotensin II is a vasoactive peptide synthesized in response to body need regarding blood

pressure and fluid load .
Angiotensinogen is a globulin that is produced constitutively and released into the circulation
mainly by the liver .It is also known as rennin substrate.
Angiotensin I is formed by the action of renin on angiotensinogen Renin is produced in the
kidneys in response to both decreased intra-renal blood pressure at juxtaglomerular cells, or
decreased delivery of Na+ and Cl - to the macula densa. If more Na + is sensed, renin release
is decreased.
Angiotensin I is converted to angiotensin II by the enzyme tissues. Angiotensin-converting
enzyme (ACE, or kinase), which is found predominantly in the capillaries of lung.

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Angiotensin II actions are mediated by binding to what is known as AT1 receptors .
Angiotensin II acts on the adrenal cortex, causing it to release aldosterone, a hormone that
causes the kidneys to retain sodium and lose potassium. Angiotensin II is degraded to
angiotensin III then angiotensin IV by angiotensinases that are located in red blood cells and
the vascular beds of most B.V

Drugs that interfere with angiotensin activity and actions:

1-Angiotensin converting enzyme inhibitors (ACEI's) :
Examples of these agents include captopril, enalapril and lisinopril. By inhibition
of ACE, these agents have antihypertensive and diuretic effects in addition to potassium-
sparing potential.
These agents are used mainly to treat hypertension and congestive heart failure.
Adverse effects includes
Cough, bronchospasm and proteinuria (elevated bradykinin levels) as well as hyperkalemia
(potassium-sparing effect).
2-Angiotensin II receptor blockers:
These agents include losartan, valsartan and saralazine .
These act by blockade of AT1 receptors causing similar effects to ACE inhibition but with
fewer side effects as they do not inhibit the breakdown of bradykinin.
Pharmacological actions:
1-Vasoconstriction: It increases blood pressure 40 times as nor adrenaline.-It dcreases
glomerular filtration leading to electrolyte retension.
2-Releases catecholamines.
3-Release aldosterone.
Therapeutic uses:
It is a hypertensive agent: 1-In cases of collapse and shock. 2-in case of counteracting α
adrenergic blockers hypotension.
Sid effects:
1-Headache. 2-Dizziness. 3-Coronary insufficiency. 4Bradycardia. 5-Urticaria.
Preparation:
Angiotensin I/V inj. (perfusion) 2.5 mg.

5-Hydroxytyptamine (5-HT)

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 (Serotonin, Enteramine)

Serotonin is synthesized from the amino acid L-tryptophan by the action of the enzyme
tryptophan hydroxylase (forms 5-hydroxytryptophan) followed by the action of aromatic L-
amino acid decarboxylase (forms 5-hydroxytryptamine).

- 5-HT is metabolized by monoamine oxidase (MAO) into 5-hydroxyindole acetic acid

which is secreted in urine in an amount reflecting serotonin synthesis level in the body

Source:
1-Animal tissues. E.g. blood platelets, mast cells and alimentaey tract.
2-Plants. Banana, tomatoes, plums, an various nuts.

Seven families of serotonin receptors are known (5HT1 - 5-HT7)

About 90 % of all body serotonin is secreted in the GIT where it regulates gastrointestinal
motility through 5-HT3 receptors .
Stimulation of 5-HT3 receptors in the gut by irritant foods (that increase serotonin release
from enterochromaffin cells that coat the gut) increases gastrointestinal motility causing
diarrhea .

Additionally, action of serotonin on 5-HT4 receptors in the gut increases acetylcholine

release and causes a prokinetic effect .

On blood vessels, serotonin has a potent vasoconstrictor and platelet aggregator effect via 5-
HT2 receptors, except in cardiac and skeletal muscle blood vessels (vasodilation).

Centrally, serotonin is a neurotransmitter that regulates many functions (sleep, mood,

vomiting, appetite, body temperature and pain) .
Serotonin action on 5-HT2C receptors on dopamine-producing cells in the brain increases
dopamine release and decreases appetite.

Some drugs that modulate serotonin function

1-Buspirone: 5-HT1A agonist, used to treat anxiety (anxiolytic) .
2-Ketanserin: 5-HT2C blocker, used as an antihypertensive drug .
3-Ondansetron: 5-HT3 blocker, used as a potent antiemetic agent .
4-Cisapride: 5-HT4 agonist, used as a prokinetic agent to suppress vomiting .
5-Triptans, e.g. sumatriptan: 5-HT1B and 5-HT1D agonist, causes cerebral vasoconstriction
and treats migraine.
Prostaglandins (PGs)

Four main series are known E, F, A and B Only E2 and F2α are of therapeutic value. They
are formed in seminal vesicles from unsaturated fatty acids.Prostaglandins are a group of
fatty acids (14).
Phamacological actions:
I-On reproduction:
1-Uterine contraction post coital being absorbed from semin.
2-Contraction of uterus in pregnancy during abortion and help parturition in late pregnancy.
3-Promote ejaculation
4-Luteolytic by PGF2α
5-PGs decrease release of FSH and LH.

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II-On cardiovascular system:
i-PGA & E act as hypotensive by their vasodilating.
ii-Increase cardiac output
iii-Antagonize the vaspressor effects induced by noradrenaline, vasopressin and angiotensin.
III-On smooth muscles:
1-Contraction GIT. 2-relaxation of bronchi
IV-PGE & PGPE2: has histamine like effect in inflammatory
V-PG increase the sensitivity of pain receptors leads to pain & headache
VI-PGs stimulate or inhibit CAMP under hormonal influence.
Therapeutic uses:
1-Diagnostic in peptic ulcer, hypertension and asthema.
2-In obstetrics and gynecology using PGF2 and PGF2 α for: Abortion, Induction of labour in
late pregnancy, Luteolytic and synchronization of oestrus.
Side effects:
1-Uterine over stimulation.
2-GIT disturbance.
3-Phelbitis at the site of inj.
Antinflammatory drugs
Tese are drugs which alleviate the effects of substance released at the site of inflammation
characterized by pain, redness, swelling and heat such as…histamine, 5-HT, bradykinines and
PGs (F and E).
Classification of anti-inflammatory drugs:
1-Antipyretic and analgesic 2-Adrenocortical hormones
Antipyretic and analgesic
e.g…salicylates, phenylbutazone, indomethacin, flunixine
Mode of action:
They act by inhibiting the enzyme synthesize PGs from arachidonic acid
Adrenocortical hormones
e.g…corticotrophins, glucocorticoids, synthetic glucocorticoids (prednisone,
prednisolone, dexamethasone, betamethasone, flumethasone)
Mode of action:
1-degradation of collagen by increasing synthesis of certain proteases
2-stabilization of the cellular and lysosomal membrane results in:
3-inhibition of variety of hydrolytic enzymes
4-preventing formation of inflammatory substances in area of inflammation
Corticophin: It is the hormone of anterior pituitary that stimulates the release of
corticosteroid (cortisone and cortisol) from the adrenal cortex. They are not used because of:
rapidly destroyed and they have mineral and glucocorticoid effects
Cortisone and cortisol
They are natural glucocorticoids frm the adrenal cortex. They are synthetized from
cholesterol and induce their anti-inflammatory action after conversion into cortisol in the liver.
Cortisol is more effective and suitable for local application and effective on skin or eye by
direct local action.
Side effects of corticoids:
1-On CHO metabolism:
Increase glycogen synthesis, decrease glucose utilization in liver and induce
hyperglycemia and glucosuria
2-On protein metabolism:

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 It reduces amino acids available for protein synthesis leading to : reduction of antibody
production, growth retardation, wound healing retardation, osteoperosis and bone fractures,
myopathy of skeletal muscles and eosinopenia and lymphocytopenia.
3-On mineral metabolism:
It caused: loss of Ca++, K+ and Ph., retension of Na+ and water and edema.
Precautions in corticoid therapy:
1-in case of infection, large doses of suitable antibiotics is necessary for the treatment as
corticoids leads to suppress the inflammatory response that help in the spreading the infection
2-gradual stoppage or withdrawal of corticoids therapy is necessary because the sudden
stoppage gives the same symptoms as adrenaline insufficiency by suppressing corticotrophin
release by feed back mechanism, this effect leads to Na++ and water loss with
haemoconstriction and easily affected by stress factors and infection.
3-large doses are contraindicated in the pregnant animals
Doses: Dogs (2 mg divided in 3-4 times), horse and cow (1000-1500 mg daily im)
N.B. Orally: capsules as cortisone acetate
Injection: 50-250 mg in the tendon sheath in cow and horse
Synthetic corticoids
They are prepared synthetically, analogues to natural corticoids
Pharmacological characters:
Used systemically and more potent as anti-inflammatory agents. Given by all routes and
absorbed by all routes. Effective in small doses. Metabolized by conjugation in the liver, which
delayed in liver diseases, starvation or pregnancy. Reduce side effects of corticoids especially
salt and water retension.it has no cumulative effect with half-life 20-30 min. the precautions
are the same as for natural corticoids.
Prednisone and prednisolone
They are synthetic drugs analogues to cortisone and corrtisol. They are more effective (4-
5 times their potency). Prednisone metabolized in the liver to prednisolone to be more effective.
It is similar to cortisol, could be used locally on skin and eye
Dose: dogs (0.5 mg/kg orally and 1-2 mg subconjuntival), Horse and cow (100-300 mg daily
IM and 50-250 in bursa) N.B….contraindicate to use large doses in pregnant animals
1-Triamcinolone and Flumethasone
They are synthetic corticoids contain fluorine atom. Their characters are: more potent
than prednisone and prednisolone also have no mineralocorticoid activity.
Dose: Triamcinolone: 0.05-0.1 mg/kg (dog) and 10-30 mg IM (cattle) and 6-30 intraarticular
(horse) Flumethasone: 0.06-0.25 mg/kg (dog), 1-5 mg IM (cattle and horse)
2-Betamethasone and dexamethasone
They are synthetic corticosterids. More potent than cortisone 25 times by presence of fluorine
atom at position C9. They have no mineralocorticoid activity. Used as other synthetic
corticoids. Larege doses are contraindicated in pregnant animals.
Dose: 0.1-1 mg daily (dog), 2-5 mg IM, 5-10 orally (horse) and 2-20 mg orally (cow)
Therapeutic uses of corticoids
1-Allergic conditions (skin disease as eczema-dermatitis-conjunctivitis-inflammation of skin,
eye and joints)
2-Arthritis 3-Induction of parturition 4-Postparturent ketosis
5-Pregnant toxaemia 6-Cystic ovaries or irregular estrus cycle
Contraindication:
1-in vaccination due to their immuno-suppressive effect
2-Eye infections with corneal ulcer.
Other autacoids:Plasma kinines (kallidine& bradykinine).,Substance (P).,Eledoisin,in
snake venums , and Slow reacting substance of anaphylaxis (SRS-A).
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Central Nervous
System

78
 Pharmacology of Central
Nervous System
Anatomical parts of this system includes:

1-Brain: includes…..

A-Cerebral cortex: Contains motor and sensory areas and higher centers. Stimulation
of motor areas induce restlessness and convulsions. Stimulation of sensory areas and
higher centers (site of consciousness) lead to sharpness in sensation, relief mental &
physical fatigue, and increase capacity to perform work and induce walk fullness.While
over stimulation leads to excitation. Depression of the sensory areas leads to sedation
and decrease emotion. While it’s over depression leads to loss of consciousness.
B-Thalamus:-Contains pain center & act as relay station for sending and receiving the
impulses to sensory areas of brain.
C-Hypothalamus:-Contains heat regulating center.

II-Medulla: Contains respiratory, vasomotor, vomiting, and vagal and cough centers.
III-Spinal cord: It act as reflex center. It contains sexual centers (ejaculatory & erection
centers) and sweat centers.

N.B.: Hypothalamus is concerned with all the nervous mechanism which keep the
internal environments of the body constant as heat regulation, metabolism, sleep….etc.
It is also contains a nucleus connected to the sympathetic system. Stimulation of these
nucleus produces similar effects to these resulting from stimulation of the sympathetic
nerves as rise of B.P., miosis and inhibition of intestine.

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Histology
The CNS contains hundreds of millions of neurons. Neurons are a special type of
cell that carry information between the brain and other parts of the body. Neuron send
and receive information via chemical signals. These chemicals are called
neurotransmitters. Some drugs resemble neurotrans-mitters. As a result, these drugs can
either mimic or block the action of the neurotransmitter they resemble. Drugs that
mimic these actions are called agonists and those block action are called antagonists or
blockers.

Five neurotransmitters
1-Acetyl choline (present in motor cortex and nucleus basalis).
2-Nor epinephrine (present in reticular formation, hypothalamus, limbic system,
thalamus alertness, focus, positive emotion and analgesia.
3-Dopamine (present in the limbic system).
4-serotonin (present in the same areas of nor epinephrine.
5-GABA (present throughout the brain). GABA is an inhibitory neurotransmitter that
is found extensively throughout the brain. An excess of GABA in the basal nuclei may
occur in Parkinson's disease. Alcohol and barbiturates mimic the effect of GABA.

Mechanism of action of centrally acting drugs

1-Modifying the synthesis of monoamines:
a-Inhibiting the synthesis (false transmitters). Methyl dopaforms the false transmitter
methyl nor adrenaline leading to sedation and depression while treating hypertension.
b-Increasing the synthesis. Levodopa forms dopamine after crossing the blood brain
barrier.

2-Blocking the reuptake of monoamines:

e.g cocaine and amphetamine.
3-Modifying storage of monoamines:
a-Depletion of monoamines. Act on depletion of (nor adrenaline), dopamine and 5-HT
reduced motor activity. As reserpine and tetrabenzine.
b-Depletion of dopamine from corpus stratum leads to parkinsonism.

4-Promoting the release of monoamines from the nerve terminals:

Release monoamines without depleting the stores as ephedrine, amphetamine and
tyramine.
5-Modifying the breakdown of monoamines:
By inhibiting MAO enzyme concerned with the breakdown of monoamines in the nerve
terminals e.g imipramine.

6-Blocking the post synaptic receptors of monoamines:

e.g Phenothiazines block alpha and dopaminergic receptors.
7-Stimulating monoamines receptors:
These result indirect stimulation of receptors in the CNS as amphetamine.

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 CNS transmitters:
Ach., Nor adrenaline, Dopamine, 5-HT., Histamine, Inhibitory amino acids (as GABA
and Glycine), Excitatory amino acide (as L-glutamic A and L-aspartic A) and
Prostaglandins (type E&F)

N.B.: CNS receptors that are involved in walk fullness or depression:

1-Post-synaptic receptors. These are 3 types:
a-Alpha1-------nor epinephrine is stimulatory agonist.
b-Dopamine---dopamine is stimulatory agonist.
c-Serotonin-----Serotonin is an inhibitory agonist.
2-Pre-synaptic receptors as excitatory nerve endings.
Alpha2: xylazine,detomidine and medetomidine are agonists. When stimulated, the
nerve ending is inhibited, and no excitatory neurotransmitters are released.
CNS receptor antagonists or drugs that are receptor blockers:
1-At alpha1 and dopamine receptors:-
Phenothiazine derivatives, Tranquilizers and Butyrophenone tranquilizers are blockers.
2-At alpha2 receptors: Yohimbine and Tolazoline are blockers.

Scheme for interrelation ship of the synaptic neurotransmitter receptors and

stimulation and inhibition of the reticular activating system (R.A.S.):

If dopamine or nor epinephrine is caused to be released, they will mesh with the post-
synaptic excitatory receptor and the RAS activity level is increased. A wake--- aroused--
- excited---mania. Sedation or sleep may be produced if dopamine or nor epinephrine are
not released or the excita-tory receptors are blocked or the release of the inhibitory
neurotransmitter serotonin is increased.
I-Cerebral stimulants
Definition: These are drugs which increase the mental activity of the brain and walk
fullness in man. Also they decrease physical and motor fatigue.
They includes:
A-Xanthine group

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 The members of this group are caffeine, theophylline and theobromine.
Source: They are methylated alkaloids. Caffeine present in caffee seeds and tea leaves.
Theophylline present tea leaves and theobromine in cocoa and coffee.

Pharmacological action:
They differ markedly in the intensity of their actions on various organs but in
common they stimulate CNS, act on the kidney as diuretics, stimulate cardiac muscle
and relax smooth muscles especially the bronchi.

Caffeine
Pharmacological actions:
1-CNS
a-Cerebral cortex: caffeine stimulate cerebral cortex leading to rapid and clearer flow
of thought, decreases drowsiness and increases the motor effects of conditioned reflexes
stimulating the neuromuscular transmission .It increases sensory stimuli and motor
activity.
b-Medulla: caffeine stimulate respiration, vasomotor and vagal centers when given by
injection only.
c-Spinal cord: caffeine with large doses stimulate the spinal cord leading to convulsions
and death.
2-Circulatory system:
xanthines produces antagonizing actions on different parts of the circulatory system.
a-Heart:
Caffeine in therapeutic doses stimulate the myocardium and increases the force, rate
and output of the heart, meanwhile it stimulates the vagal center which decreases the
heart rate. These two opposing actions result in slight increase or decrease or no change
at all in heart rate. Caffeine in large doses the myocardium stimulation overcomes the
vagal stimulation leading to tachycardia (increase heart rate).
b-Blood vessels:
i-Caffeine dilates the general systemic B.V. by direct action on the vascular
musculature, on the same time stimulate the vasomotor center in the medulla
(vasoconstriction) but the vasodilator action is predominates.
ii-It dilates the coronary and pulmonary B.V.
iii-It constricts cerebral B.V. resulted in decrease in cerebral blood flow.
iv-It increases the formation of prothrombin in the liver, increasing the the circulatory
prothrombin, fibrinogen and so decreasing blood coagulation time.
c-B.P.:
Caffeine slightly increases the B.P. as a result of its central vasomotor and direct
myocardial stimulation which favor an increase in B.P.which is counteracted by central
vagal stimulation and the peripheral vasodilatation which favor a decrease in B.P.
3-Smooth muscles:-
Caffeine relax the smooth muscles of bronchi and bile ducts. G.I. muscles are stimulated
by dilute solution of caffeine and depressed by high concentration.
4-Skeletal muscle:
Temporally increase capacity for muscular work. The drug make the muscle less
susceptible to fatigue. Possible mechanisms, increased release of Ach at neuromuscular

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junctions; increased production of cAMP---glycogenolysis ; increased level of the free
Ca++ in the myoplasm; central stimulation.
5-GIT:-
Caffeine in moderate concentration increases the gastric secretions (both acid and pepsin) and
thus it helps digestion but it is not recommended in cases of gastric ulcers.
6-kidney:-
Caffeine acts as a diuretic for its mainly causes a direct vasodilatation of the renal B.V.
and its ability to decrease the reabsorption of water from the tubules to the blood
inhibiting the secretion of ADH.

Theophylline and theobromine

1-Theophylline is less active and theobromine is the least active CNS stimulant
2-It is more effective as respiratory and circulatory stimulant (increasing cardiac output)
3-It is the most effective in relaxing smooth muscles especially of bronchi and billiary
ducts
4-It increases the rate and depth of respiration
Mechanism of action:
1-Xanthines potentiate catecholamines and augment AMP. They inhibit the enzyme
phosphodiesterase which convert cAMP into inactive form. So they increase the
phosphorylase activities mediated by cAMP.
2-Xanthines stimulate the neuromuscular transmission by liberating Ca++ from the
muscles.
**Action potential  sarcoplasmic reticulum
**Myocin + actin  contraction

Pharmacokinetics:
Caffeine is readily absorbed from digestive tract or from the site of injection in
small animals. It is partially demethylated and about 80 % is metabolized to urea.
Excretion in the urine.

Therapeutic uses:
1-Caffeine is used in treatment of CNS depressants poisoning as morphine (caffeine
and Na benzoate i.m.).
2-Caffeine also used in the treatment of headache with salicylates or with ergotamine
in migraine.
3-Aminophylline is used in the treatment of heart failure, angina pectoris and coronary
thrombosis (i.v.).
4-Theophylline used in the treatment of bronchial asthma, biliary colic and as diuretic

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 B-Amphetamine (Benziderine)
Pharmacological action:
1-Amphetamine stimulates the CNS and sympathetic nerves
2-It increase the mental and muscular activities
3-It causes a rise in B.P. (stimulate sympathetic)

Therapeutic uses
1-It is used in cases of barbiturate and narcotic poisoning as antidote
2-Illegally it is used as motor activity for race horses to increase their capacity for run
3-It is used in the treatment of obesity in human being

C-Ritalin
It is a chemical compound which acts on the cerebral cortex producing similar
actions to those produced by caffeine causing an increase in mental activity and
wakefulness so it is used to counteract the depressant effect of narcotics. It has no effect
on the B.P.

Toxicity of cerebral stimulants

Cerebral stimulants in toxic doses produce restlessness, dizziness, tremor,
irritability and insomnia. Cardiovascular. Symptoms are arrhythmia, hypertension and
excessive sweating. GI symptoms as nausea, vomiting, diarrhea, abdominal pain and
cramps. These symptoms are followed by fatigue, depression and hypotension
terminates in convulsions and coma from cerebral hemorrhage.
II-Medullary stimulants
Definition: drugs which stimulate the medullary centers called analeptics because they
are capable of a waking anesthetized animals by stimulating the brain and the medullary
centers.
Drugs used as medullary stimulants act either:
1-directly on the medulla as picrotoxin, nikethamide (coramine), bemegride,…
2-reflexly from the external irritation of the sensory nerves of the nose as by ammonia
vapor, of the skin as by camphor or of the stomach as by alcohol

Picrotoxin
Source:
It is obtained from the seeds of anamirtacocculus (alkaloid)
Action:
It increases the depth and rate of respiration so it is effective as respiratory stimulant. It
stimulates vasomotor center so raised the B.P.
Mode of action:
It produces its stimulatory effects by blocking the inhibitory transmitter gama amino
butyric acid (GABA) which is secreted in the cerebellum, medulla and spinal cord
inhibiting the presynaptic transmission.
N.B.: Picrotoxin historically used to poison fish.

84
Therapeutic uses:
1-It is used to overcome depressed respiration as in cases of narcotic and hypnotic
poisoning.
2- It is indicated in the treatment of acute ivermectin intoxication
Doses:
Horses and cattle (60 mg i.v), dogs (1-5 mg i.v)…repeated every ¼ h till recovery
Toxicity: over dosage produces convulsions especially in cats
Antidote: by barbiturate as Nembutal or by inhalation of volatile anesthesia

Nikethamide (coramine)
Source:
It is asynthetic drug (is diethylnicotinamide). It is converted in the body to nicotinamide
(B-complex vit)
Action:
Respiratory medullary stimulant. Peripheral chemoreceptor stimulant. It has no effect
on the heart
Mode of action:
It produces its effect either by acting on the chemoreceptors of the carotid body or
directly on the respiratory center by  its sensitivity to CO2.
Doses:
It is given in 25 % solution by mouth 10-25 ml for horse and cattle and 1-3 ml for dogs
or by injection i.m or i.v 0.5-1 gm

Bemegride (megimide)
It is a powerful stimulant to CNS. It is used to antagonize medullary depression
caused by barbiturates
Dose: 50 mg for dogsi.v or i.p repeated every 10 min till muscular tremors are seen

Cardiazole or leptazole
Source: synthetic compound
Action and uses:
It is a powerful cerebral and medullary stimulant. It is the best analeptic (arousing) drug,
counteracting the depression produced by hypnotics as barbiturates

85
Doses:
It is given in 10 % solution as 5-10 ml for horses and cattle and 0.5-1 ml for dogs as
medullary and respiratory stimulant

Camphor
Source:
Plant origin and synthetic prepared. It is a volatile crystalline substance having a
powerful characteristic odor.
Action: local and medullary stimulant
Mode of action:
After s/c injection it produces irritation which refelxly stimulate the medullary center
and after absorption it affects the medulla directly and acts as respiratory and circulatory
stimulant.
Uses:
1-as medullary stimulant (respiratory)…reflex expectorant
2-externally acts as counter irritant for rheumatic pains in the form of camphor
linament….carminative
Doses:
As respiratory stimulant…1-2 gm (horses and cattle), 0.1-0.2 gm (dogs)….given s/c or
i.m in 10 % sol. As reflex expectorant….1-4 gm (horses and cattle), 0.1-0.5 gm (dogs)

III-Spinal cord stimulants

Definition:
These are drugs which stimulate the spinal cord producing increase in muscular activity
and quicken the reflex excitability to any external stimuli.

Strychnine
Source: It is an alkaloid obtained from the seeds of strychnusnux vomica beside another
alkaloid brucine. Strychnine sulphate is soluble in water.
Action:
1-Spinal cord:
a-It stimulate the sensory and motor areas of the spinal cord (selective action on spinal
cord).
b-It stimulate the sexual centers (erection and ejaculatory centers).
c-In arge dose produce convulsions of the skeletal muscles and diaphragm.
2-Brain:
It stimulates the sensory area of the cortex increasing the sharpness of all special senses
(touch, sight, smell, hearing and taste). While in therapeutic dose no effect on medullary
centers.
3-Heart:
In therapeutic dose no effect on the heart.
4-Digestive system:
It acts as bitter stomachic and increase the intestinal movements in case of atony as it
stimulates Aurbach's plexus.
Mode of action:

86
Nux vomica and strychnine produce excitation of all parts of CNS in an ascending
manner by selecting blocking inhibition. Strychnine and glycine interact with the same
receptor complex, although probably at different sites. Strychnine binding may be
associated with the ionic conductance mechanism for Cl- in glycine receptor.
Therapeutic dose of the drug increases the reflex excitability of the motor and sensory
portions of the spinal centers. This decreases the reaction time to stimuli and hasten the
response to sensory impulses. Stimulation of the sacral region in the spinal cord
produces erection of the penis
Pharmacokinetics:
Nux vomica preparations are readily absorbed from the GIT and parentral sites. It is
carried in the plasma and RBcs. Then it leaves the circulation to its site of action in
specific tissues. Then it is metabolized in the liver, about 80 % destroyed in it. Excretion
of the metabolites starts after few minutes and continues till 2 days and about 20 %
excreted in the urine
Therapeutic uses:
1-Strychnine used in case of dyspepsia as bitter stomachic
2-Also used as aphrodisiac in case of sexual impotency in male animals given s/c in a
dose of 15-60 mg for horses and cattle. In dogs 0.3-1 mg
3-It is used as general tonic and nerve tonic
4-Illegally it is used as motor activator for race horses to increase their energy and
capacity for run
Toxicity:….Symptoms:
1-Intoxic doses causes convulsion due to contraction of all skeletal muscles. As the
extensor are stronger than the flexors, the limbs become stretched rigidly and the back
become arched and the head derived up and back (opsthotonsus). Convulsions are
followed by periods of rest of muscle relaxation
2-Small toxic doses causes short period of convulsion followed by longer interval of
rest. The animal becomes very sensitive to any external stimuli (as sudden light or noise)
which leads to the onset of convulsions
3-Large toxic doses produces prolonged periods of convulsions with short period of
rest. Death from strychnine poisoning occur from asphyxia as a result of stoppage of
the respiratory movements due to prolonged contraction of the diaphragmatic and
intercostals muscles. Dogs are very sensitive to strychnine poisoning.
Treatment:
1-Poisoned animal should be kept in dark place far from external stimuli or noises.
2-Barbiturates, tranquilizers or chloral hydrate are given i.v. Inhalation of ether is also
used.
3-Mephensin is a specific antidote act on the inter-neurons of the spinal cord.
4-Pot.permanganate 0.5 % or tannic acid 2 % or tr. iodine 1/150 for precipitating
strychnine alkaloid and preventing its absorption.
N.B*Opisthotonsus = defects. (Legs extended, arched neck and back).
*Strychnine is the principle alkaloid obtained from seeds of the tree (strychnusnux
vomica) native to India. It is used as a poison for the control of rodents. Dogs and cats
can be poisoned by eating rodents or birds that were poisoned by strychnine.
Toxic dose:
Acute oral lethal doses of strychnine salts (mg/kg) in various animals are:

87
horse and cow (0.5), swine (0.5-1.0), dog (0.75), cat (2.0), rat (3.0), fowl (5.0),
humans (1.0). These dosage can be reduced 2-10 fold if parentral route of administration
used. The number of convulsions and the time to death vary in relation to strychnine
dose. A large oral dose of strychnine may be lethal in 20-30 minutes and produce only
one convulsion.
CNS Depressants
Definition:
These are drugs which decrease the activity of the different parts of the CNS.
Classification of CNS depressants according to type and degree of depression into:-
I-Sedatives
Definition:
These are drugs which quiten convulsion and spasms in animals without
producing loss of consciousness or sensation except when given in large doses.
e.g bromides & chloral hydrate.
Bromides
Bromides includes sodium, potassium and ammonium bromides.
Mode of action:
It is suggested that bromides act by replacing the chlorid ions in the extracellular fluid
of the tissues specially in the nerve cells. This replacement weakens the activity of the
CNS producing sedative effect. The motor area of the cerebral cortex is selectively
depressed by bromides but the sensory area is not affected, therefore, bromides are
unable to remove pain except with large doses.
Therapeutic uses:
1-Sedative to reduce convulsions (in small doses).
2-Hypnotics when sleeplessness is not due to pain. And due to pain(in large doses).
3-Anaphrodisiacs to depress sexual excitability in dogs as bromides can depress the
sexual centers of the spinal cord.
4-In case of epilepsy.
Dose:
0.3-1 gm for dogs as sedatives while larger doses can act as hypnotics.
Pharmacokinetics:
Bromides are cumulative drugs for they are slowly excreted by the kidneys. They
are rapidly absorbed from the GIT.

Chloral hydrate
Definition:
It is a white colored crystalline substances with aromatic odor and burning taste.
1-It is one of the oldest sedative-hypnotics.
2-Chemically it is derivative of ethyl alcohol.
Chloral hydrate because of its irritant effect should be given highly diluted to prevent
gastric irritation.
Pharmacokinetics:
Chloral hydrate is readily absorbed from the GIT., reduced to trichloroethanol then
conjugated in the liver with glucuronic acid forming urochloralic acid excreted in urine.
Some trichloroethanol is oxidized to trichloracetic acid. It is a strong acid which bind
firmly to plasma proteins lasting in the body for some days.

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Pharmacological actions (CNS responses):
1-After changes into trichloroethanol it produces sedative effects. Larger doses
produces hypnotic effects resembling natural sleep which passes after 5-8 hours. In still
larger doses it produces anesthesia with absence of reflexes, loss of consciousness and
sensation, relaxation of the muscles, slow respiration and pulse rate but it is a dangerous
and unsafe anesthesia.
2-Narrow safety margin when used alone as an anesthetic.
3-No analgesia without anesthesia.
4-Respiratory center depression occurs at larger doses.
Therapeutic uses:
1-Orally and I.V sedative and hypnotic and light anesthesia, depth is dose dependent.
2-It is commonly given with turpentine oil and linseed oil as an anodyne, antizymotic
and antispasmodic compound in spasmodic and flatulent colic.
3-It is given as pre-anesthetic to decrease the amount of anesthesia and shorten the
period of excitation.
4-With bromides it is given in cases of epilepsy.
Doses:
10-60 gm orally and 0.1-0.2 gm/kg i.v for horses and cattle and 0.3-0.1 gm orally for
dog.
Toxicity:
1-Large doses result in hypotension, hypothermia, cardiac and respiratory depression
leading to cyanosis and death.
2-After prolonged anesthesia, fatty changes occur in the liver, heart and kidneys
resulting in death after 3 days.
N.B. Chloral hydrate very good drug for induction of sedation in large animals (horse),
used also for its hypnotic(horse) and anesthetic effects. Anesthetic doses of the drug
severely depress the respiratory and vasomotor centers. It stimulate vagus and produce
bradycardia so atropine must be given with chloral hydrate in pre-anesthetic medication.
Death from chloral hydrate is due to depression of the respiratory center. The margin of
safety is narrow in small animals (do not use).
Anticonvulsant or anti-epileptic drugs

These agents are used in symptomatic treatment of epilepsy.

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 II-Tranqullizers (Ataractic)
Definition:
Drugs relieve anxiety and mental tension in man without interfering with the
consciousness. Tranquilizers are used in veterinary practice to calm viscious animals
and facilitate their handling during clinical examination and as a pre-anesthetic to
prolong the duration of volatile anesthetic used e.gmeprobamate (quitan), comblene,
chlorpromazine (largactil) and hydroxyzine.

A-Phenothiazine derivative tranquilizers

Mechanism and site of action for CNS responses are by blocking dopamine
receptors in cerebral cortex induce tranquilization but in the basal ganglia induce side
effects (restlessness, excitement which may induce from large dosage).
Clinical uses:
1-Animals are easier to handle.
2-Pre-anesthetic medication for local or general anesthesia
3-Antiemetic 4-Anti-pruritic 5-Anti-tussive 6-Anti-stress
7-Has a calming effect in hyper-excitable sow.
8-May have a beneficial effect in long standing shock by producing an increase in the
blood flow to the kidney via alpha adrenergic blockade.
9-To reduce the stress of aggression and fighting in young pigs

1-Chloropromazine (largactil)

Action and uses:

1-This drug inhibit a large number of enzymes, producing depression of the CNS. It inhibits
the hypothalamus, the reticular formation and chemoreceptor trigger zone.
2-It prevents vomiting and has antihistaminic effect
3-It has anticholinergic, antispasmodic and hypotensive effects
4-It produce muscular relaxation and hypothermia
5-Large doses result in respiratory failure
6-It is used as a pre-anesthetic medication
Dose:0.5-2 mg/kg i.m
N.B Chloropromazine prolongs the sleeping time of barbiturates due to its effect on
the microsomal enzyme which destroys the barbiturates in the liver.
Pharmacokinetics:
Administered by i.m or i.v routes. Absorption is slow. Is highly lipophilic agent and
highly protein bound. Accumulation in brain, liver and kidneys. Easily enter the fetal
circulation. Metabolism by hydroxylation in 3,7 position  7-OH chloropromazine is
active metabolite. Conjugation with glucuronicacid. Chloropromazine is an inducing
agent of P-450 system and drug interact-tions are frequent. Excretion is slow (urine,
bile and faces). Biological half-life in dog is about 6 hours; horse 96 hours. In food
producing animals drug residues may persist in edible tissues for long periods.
Tolerancedevelops for sedative and hypotensive effect.

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 2-Promazine (Sparine):
Similar to chloropromazine but weaker and more hypotensive. It is popular in veterinary
practice.

3-Trimeprazine (Vallergan):
Similar to chloropromazine but has stronger antihistaminic action. It is more
reliable as ataractic and antipruritic in cats and horses.

4-Methotrimeprazine:
Similar to trimeprazine.

5-Acepromazine:
Similar or even of greater potency than chloropromazine and more popular in used
for horses.

6-Trifluomparzine:
More potent than chloropromazine as anti-emetic and sedative.Used mainly in dogs and
cats.

7-Promethazine:
It is mainly used as anti-histaminic with ataractic properties.

B-Rauwolfia derivatives

Reserpine is the main alkaloid of Rauwolfia serpentine plant.

It is mainly used as hypotensive, also it is ataractic resembling chlorpromazine but with
no antihistaminic, anticholinergic or α adrenergic blocking effects.

C-Butyrophenones

These are drugs act as neuroleptics. Chemically related to the morphine substitute
pethidine.

Mode of action: They binds to and blocks the dopamine receptors in the brain.
Pharmacological properties:
1-They have sedative-analgesic and tranquilizing action.
2-They have anti-emetic effect.
3-They induce an alpha adrenergic blocking activity.
4-They inhibit vasomotor center leading to hypotension.
e.g. 1-Azaperone-----used for pigs to prevent fighting-----has hypothermic
effect and induce hypotension.
2-Haloperidol and droperidol-----are butyrophenones used in dogs.
D-Neuroleptics

These are drugs which has the properties of ataractic and narcotic properties.
e.g.

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1-Phencycline HCl: used for primates only. used for immobilization of wild animals.
induce excitement in equine.
2-Xylazine: sedative, analgesic (15-30 min.), muscle relaxant of central origin,
hypnotic effect (1-2 hour), induce initial hypertension followed by prolonged
hypotension in cattle, when given i.m or i.v first it induce respiratory depression,
bradycardia and AV-block. used for horse, cattle, dog and cat.
E-lmidazole derivatives
This group includes Metomidate of hypnotic activity used in pigs and horses for
induction of anesthesia in combination of azaperone.
F-Cannabis indica

It is the oldest drug of addiction and habit forming in man. It was used as a hypnotic in
horses but new synthetic substances may be more reliable.

G-Benzodizepine derivatives
*e.g. Diazepam----is labeled for drugs . They act by Stim.GABA( A) receptor.
*Pharmacological properties are: mild sedative with anti-anxiety, good muscle relaxant,
slight respiratory depression, induce excitement in cats.

III-Hypnotics
Definition: These are drugs which produce sleep by depressing CNS begins with the
cortex and descends with increasing dosages to the medulla. In large doses some of
hypnotics act as narcotics (produce deep sleep) and general anesthesia. Hypnotics can
not produce sleep if sleeplessness is due to pain. The duration of sleep differs according
to the dose and hypnotic drug given.
*e.g barbiturates, chloral hydrate, chloretone and overtin. The most important group is
the barbiturates.

Barbiturates
These are sodium salts of barbituric acid from the combination between urea and
malonic acid.
Pharmacokinetics (barbiturate metabolism):
After oral, rectal or intravenous administration the drug is absorbed and is found in the
blood. They redistributed throughout the body tissues depending on their degree of
ionization, lipid solubility and protein binding. The greater the lipid solubility and the
greater their protein binding. The long acting group are less soluble than the short group
and so have a slow onset of action to cross the brain barrier. Metabolic degradation
mainly in the liver through oxidation. Excretion of barbiturates is renal depending on
pH of the urine. Increased pll increases ionization and rate of excretion.
Mode of action:
Barbiturates produce their sedative and hypnotic effect by enhance GABA
transmission. They have no effect on the cardiovascular system except with toxic doses
producing lowering of the blood pressure due to depression of the vasomotor center.
They can relax the plain muscles of uterus and GIT.
Classification of barbiturates:

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According to the duration of hypnotic action barbiturates are classified into:
1-Long acting barbiturates: which produce depression of the CNS for 12-24 hours as
they are slowly detoxicated in the body. They are rarely used as hypnotics for they tend
to have cumulative effect. Includes:
*Phenobarbital sodium (luminal)----dose 30-120 mg.
*barbital sodium (vernoal or medinal).
2-Medium acting barbiturates: which produce sleep for 6-12 hours. Includes:
*amobarbital sodium (amytal)-------dose 100-200 mg.
*hexabarbital sodium (ortal).
3-Short acting barbiturates:which acts for 3-6 hours. Includes:
*pentobarbital sodium (Nembutal)------dose 100-200 mg.
*secobarbital sodium (seconal)
4-Ultra-short acting barbiturates: which produce a very short period of central
depression for about ¼-2 h when given i.v as they are rapidly detoxicated in the body.
This group includes:
*Thiopental (pentothal)
*Thialbarbital sodium (kemithal)---dose 200-400 mg., given 25 % solution
Actions of barbiturates:
1-Depress CNS 2-Enhance the analgesic action of salicylates
3-Potent respiratory depressants and depress sensitivity of the respiratory centers to Co2.
4-In normal doses they have no action on the cardiovascular system or GIT.
In anesthetic doses result in hypotension and decreased tone and motility of GIT by
direct action
5-Do not affect uterus but can cross the placenta depressing the fetus

N.B.
1-Tranquilizers potentiate the hypnotic action of barbiturate as it inhibits the
microsomal enzymes in the liver which is responsible for detoxifying most of the
barbiturates
2-Starvation or administration of drugs which destroy the liver cells as carbon
tetrachloride or inhibit the formation of the microsomal metabolic enzymes in the liver
as largactil (microsomal enzyme inhibitors) potentiate the action of barbiturate
3-Certain long acting barbiturates as phenobarbitone and other drugs (microsomal
enzyme activators) can activate the formation of these microsomal enzymes and so they
shorten the duration of action of other barbiturates.
4-Tolerance can develop to barbiturates (cross-tolerance occur between various
barbiturates)
5-Species differ in metabolizing barbiturates due to variation in liver enzymes. Calves
poorly metabolize barbiturates and anesthetic time is very long e.g…pentobarbitone
action is very short and thiopentone is much shorter in horses and sheep for their high
level of oxidative enzymes

Toxicity of barbiturates:
1-Symptoms: toxic doses of barbiturates causes respiratory depression, sluggish
reflexes, weak pulse, low body temperature and coma. Death may occur due to
respiratory failure

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2-Treatment: analeptics as picrotoxin or coramin i.v in repeated doses every 15-30 min
till recovery. Barbiturate increasing pH, are used in the treatment of barbiturate
poisoning
IV-Analgesics (anodynes, antinoceptives)
Definition: these are drugs which are used to treat pain by depressing the pain center or
sensory area of the brain. They are classified into:-

1-Narcotic analgesics: are drugs which produce narcosis (deep sleep) beside their
analgesic effect
2-Antipyretic analgesics: are drugs which produce antipyretic effect beside their
analgesic effect
A-Narcotic analgesics (opiate analgesics)
These include morphine and related synthetic analgesics. They are effective in all
types of pain. In animals is suitable for dogs. They may produce addiction and tolerance
in man if given for a long period.

Opium
Source and active principles: it is dried exudates obtained by incision of the unripe
oriental poppy fruits. It is oldest analgesic known. It contains morphine, narcotine,
papaverine, codeine and thebaine.
a-Phenantherinic derivatives (morphine/codeine/thebaine)
1-Morphine

Pharmacological actions:
1-CNS: it depress the higher functions of the brain. It stimulates then depress the
medullary centers. It stimulates the spinal cord.
In large doses it produces analgesia, sleep and coma in dogs, rabbits and birds. In
cats it causes delirium while in horses, ox and pigs the effect is unreliable, sometimes
narcosis and sometimes excitement.
2-CVS and respiratory S.: it stimulate the vagal center slowing the heart.
Chemoreceptor trigger zone is first stimulated then depressed. Respiratory center is
depressed, large doses cause death by respiratory failure. Cough center is also
depressed. Cutaneous B.V dilated and loss of heat. Bronchial secretion stimulated then
depressed.
3-GIT: a-motility…stimulated by vagal stimulation then relax the muscles of
the gut leading to constipation
b-secretion…is reduced and defication is depressed
4-Urinary system: urine retention by contracting the U bladder sphincter
5-Eye:miosis
Pharmacokinetics:
Morphine absorbed from the gut or after injection. Some is conjugated and
excreted in urine but more is destroyed in the liver. About 30 % are excreted in feces.
Therapeutic uses: pre-anesthetic in dogs. Analgesic for animals suffering from
pain.Depressing the cough center in troublesome coughing.Used to treat diarrhea.
Dose: morphine HCl…15 mg orally or s/c

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Toxicity: in dogs (coma and cyanosis from respiratory depression and pin point eye
pupil), while in other animals (convulsions and excitement)
Treatment of toxicity: artificial respiration. Injection of nalorphine (lethidrone) and
naloxone (narcan) are used as antidote for morphine poisoning for they are competitive
antagonists to morphine

2-Codeine
it resemble morphine in its activity but less potent. Excreted in urine unchanged. It is
used to treat coughing in dogs, given by mouth as syrup of codeine phosphate.
b-Isoquinoline derivatives
Papaverine
It is a slight narcotic but a powerful inhibitor of plain muscles so used to treat
colic. Dose is 20 mg orally
c-Semi-synthetic morphine derivatives
1-Diamorphine (Heroin)
made by acetylating morphine and is much more active. It is absorbed from all routes
of administration including the nasal mucosa. It crosses the blood brain barrier
producing a rapid deterioration of molars and health addiction.
2-Apomorphine
it is prepared by treating morphine with mineral acids reducing its narcotic activity and
increasing the stimulant effect. It particularly stimulate vomiting center by acting on
the chemoreceptor trigger zone. It is used to induce vomiting in dogs by injection
(central emetic). Dose..0.08 mg/kg s/c.
d-Synthetic non phenentherine morphine substitutes includes
methadone (amidone), mepridine (pethidine), fentanyl, diethylthiambutane (themalon),
etrophine and dextromethorphan.
Antagonists of narcotic analgesics
1-Partial antagonists of nalorphine type
As nalorphine…..is chemically similar to morphine bu pharmacologically acts as a
competitive antagonist to morphine and its substitutes
2-Partial antagonists of morphine type as propiram
3-Purte antagonists as
-naloxone (narcan) which is competitive antagonist to morphine and nalorphine
-disprenorphine which is specific antagonist to etorphine
4-Weak antagonists as pentazocine
B-Antipyretic analgesics
These are drugs which lower the body temperature beside its analgesic effect.
They are used to treat pain as in case of headache, rheumatism…etc.
They differ from narcotic analgesics as they produce no addiction, not effective in
treating severe pain, not depress the respiratory center, less toxic and have anti-
rheumatic action.
They are classified according to their chemistry into:
1-Aniline derivatives…including phanacetine and acetanilide (antifebrin),
paracetamol,…etc
2-Pyrazolone derivatives…including antipyrine (phenazone), metamezole (novalgin),
phenylbutazone (butazolidine),….etc

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3-Salicylic acid derivatives….as Na. salicylates, acetyl salicylic acid (aspirin)
4-Miscellaneous….as indomethacin (indocid), fennamic acid,…etc

Phenacetin
Action and mode of action
It is an antipyretic analgesic producing its antipyretic effect by affecting the heat
regulating center and dilating the cutaneous B.V while as analgesic act by blocking the
pain center
Therapeutic uses:
Used in case of headache and neuralgia but does not treat severe pain. It is given
for dogs in doses of 0.1-0.3 gm. Usually combined with aspirin. Now replaced by
paracetamol.

Phenylbuazone (butazolidine)
Action and uses
1-It is an analgesic antipyretic commonly used for chronic rheumatism
2-It increases the excretion of uric acid in the urine (uricosuric drug0 so it is used for
acute and chronic gout. It is used for man and dogs in doses of 2 ml of 20 % solution
by deep slow i.m.
3-It is said to be a carcinogenic drug when taken for a long period.
4-It may affect haemopiotic system.

Metamezol (novalgin)
Action and uses
1-It is commonly used as analgesic antipyretic of treating muscular rheumatism,
sciatica, neuralgia and other similar painful conditions
2-It is usually given by mouth in mild cases but in severe pain it is injected i.m or slow
i.v in doses of 15-25 ml of 50 % solution for horses and cattle and 0.5-1 ml of the same
solution for dogs

Salicylates (salicylic acid)

Source:
Bark of willow tree containing the glycoside solicin. This glycoside yields salicylic acid
on hydrolysis. It is very irritant and so only used locally as a keratolytic. It is now used
as sodium salicylate, acetyl salicylic acid or methyl salicylates
Pharmacokinetics of salicylates:
These are rapidly absorbed, excreted rapidly unchanged in urine, partially
oxidized and partially combined with glucuronic acid and blocking this enzyme makes
salicylates use in cats is dangerous. Its half-life (time required for concentration in
plasma after i.v injection to fall to half its initial value) is 9 hours in horses and dogs, 6
hours in pigs and 36 hours in cats
Actions:
1-Salicylates produce their antipyretic action only in feverish animals. They act on the
heat regulating center in the hypothalamus, producing heat loss by peripheral
vasodilatation
2-Their anti-inflammatory properties are due to inhibition of PGs synthesis

96
3-They increase the urinary excretion of uric acid by reducing tubular re-absorption so
used in acute rheumatism, muscular and joint pain
4-Large doses results in vomiting, dyspnea, skin eruption and hemorrhage due to fall in
prothrombin
5-Salicylates stimulate respiration by direct effect on respiratory center and increasing
CO2 production by increased cellular metabolism

Pre-anesthetic medication
These are drugs administered before anesthetics to make the anesthesia more safe
and more agreeable to animal. They includes:-
1-Atropine:
It is used as a pre-anesthetic to reduce bronchial and salivary secretions and stimulate
the heart as chloroform causes increased salivation due to irritation of bronchial glands
and direct depression of cardiac muscle. Also atropine stimulate respiration by direct
stimulant effect on respiratory center in the medulla.
2-Muscle relaxants:
liketubocurarine and gallamine which are used before administration of general
anesthesia to ensure complete muscle relaxation
3-Tranquilizers:
As phenantherine derivatives
4-Hypnotics:
As barbiturates or chloral hydrate. They were used to produce deep sleep before
administration of general anesthesia to minimize the amount of general anesthesia used
so as to be far from its toxic dose
5-Morphine or mepridine in dogs
V-General anesthesia
Definition: These are drugs which produce loss of consciousness, sensation and
reflexes by depressing the brain and spinal cord without interfering with the vital centers
in the medulla.
Ideal anesthetic must be:
Easily to be administered,non irritant, rapid induction and recovery without
excitation and good muscle relaxant.

Classification of general anesthetics according to their physical characters:

1-Volatile anesthetics
Are volatile substances which are administered by inhalation to produce general
anesthesia. They are either:
a-Volatile liquid anesthetics as chloroform, ether,….etc
b-Gaseous anesthetic as nitrousoxide, cyclopropane, etc
2-Non volatile anesthetics
Arenon volatile water soluble anesthetic substances usually administered:
a-i.v as chloral hydrate, Nembutal, pentothal,….etc.
b-Rectally as avertin, paraldehyde, Nembutal,….etc

A-Volatile anesthetics
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This members includes:
a-Liquids such as chloroform, ether, trichloroethylene
b-Gases stored under pressure as nitrous oxide, ethylene, cyclopropane
Administration of volatile anesthetics:
-They are administered by inhalation
a-Cattle is less common than horses and dogs
b-Chloroform is used for horse
c-Ether is used for dogs
d-Trichloroethylene is used for small animals
Mechanism of action:
They first produce depression of sensory and motor areas of the brain followed by
depression of the spinal cord and finally with toxic doses the medullary centers are
involved.
Stages of volatile anesthesia:
1-Struggling stage:
-Beginning of inhalation until the animal begin to loss consciousness
-Accelerated heart
-Rapid respiration and dilated pupil (due to release of adrenaline from fear) appeared in
this stage
-Pre-anesthetic (atropine) is used to prevent the salivary and bronchial secretions which
resulted from inhalant irritant vapor of volatile anesthesia
2-Narcotic stage:
-The animal movement become sluggish and loss of consciousness and begins to sleep
but the reflexes and sensation are present.
-The respiration is irregular and eye pupils are widely dilated.
-Inhalation of high concentration of anesthesia may lead to death due to arrest of
respiration
-Pre-anesthetic administration (chloral hydrate, barbiturate or tranquilizers) shorten the
duration of narcotic stage
N.B
Induction period (1st and 2nd stages) means the period which begins from inhalation till
onset of anesthesia
3-Anesthetic or surgical stage:
characterized by:-
-Skeletal muscles of the body relaxes
-Various reflexes gradually disappear (tail and corneal reflexes are the last to disappear)
-Slow and regular pulse and respiration
-Eye pupils are constricted
*during this stage the operations can be performed and the anesthesia gradually increase
in depth beginning from light, moderate then deep anesthesia.
*maintaining in this stage till the end of operation by inhaling small amounts of the
anesthetic and the anesthesia should not be allowed to be more than the medium
anesthesia
N.B

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 Recovery period means the period which begins from the end of anesthesia till the
animal return conscious. Recovery begins from deep anesthesia to medium light then
return of sensation and the animal begins to move till it is able to stand on its feet.
4-Dangerous or paralytic stage:
This stage appeared in the inhalation of larger amounts of the anesthesia is
continued. Characterized by paralysis of medullary centers leading to weak and
irregular respiration and pulse. Respiration may stop suddenly and the beginning of
asphyxia is indicated by cyanosis of tongue and mucous membranes of the mouth and
eyes and sudden dilatation of eye pupils. Urination and defecation may occur as a result
of control on sphincters.
Excretion of volatile anesthesia:
It is rapidly excreted from the lung in the expired air and so recovery from volatile
anesthesia is more rapid than with non volatile anesthesia

Members of the volatile anesthetics

commonly used in veterinary surgery are:

1-Chloroform

It is a volatile liquid oxidized easily by oxygen to phosgene, it is the most

dangerous anesthetic used, given 2 % in inspired air.
Pharmacological properties:
1-It reduces the oxygen carrying capacity of the blood
2-It depresses the vasomotor center producing fall in B.P.
3-It depresses the respiratory center
4-It results in death during induction by ventricular fibrillation and cardiac arrhythmia.
The fibrillation is prevented by atropine while the arrhythmia can be controlled by
propranolol.
5-It results in death during prolonged anesthesia by myocardial depression or cessation
of respiration
6-Delayed chloroform poisoning occurs 24 hours after anesthesia and is mainly due to
liver damage. It resembles acidosis (vomiting, acetonurea, coma and death). In horses
there is loss of appetite, jaundice, coma and death.
7-Chloroform produces fatty changes in the liver, kidney and heart
8-It has no effect on the uterus and cesarean operation can be performed under
chloroform anesthesia
9-Chloroform produces relaxation of the skeletal muscles of a good degree

Therapeutic uses:
1-Nowadays chloroform is rarely used for anesthetizing animals due to its toxic effect
on heart and liver
2-Chloroform water 0.04 % is given by mouth as GI sedative and as a carminative in
cases of colic

Contraindication:
Chloroform contraindicated in lung and heart diseases, in diabetes and hemorrhages.

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Advantages:
It is not inflammable and can be indicated when firing is used, most potent volatile
anesthetic, its induction and recovery duration is short, not expensive and easily
administered and produce good muscular relaxation

2-Ether (Diethyl ether)

It is a volatile liquid, boils at 35 Co and is highly inflammable and explosive with

air. It forms peroxide in light and air which are irritant and toxic. It is used 6 % in
inspired air.

Pharmacological properties:
1-It is weaker than chloroform and 4 times are required to produce anesthesia as it is
more soluble in blood. Induction is slow and difficult.
2-It stimulate the sympathetic centers increasing the B.P, pulse rate, blood sugar and
cardiac output. It depresses the myocardium.
3- It increases the bronchial and salivary secretions. Ether produce neuromuscular
blockage.
4-It is excreted in the expired air but some is metabolized to ethanol and acetaldehyde.

Advantage of ether:
1-It is the safest general anesthetic. It has 1/3 the depressant action of chloroform on
respiration.
2-It has 1/25 the toxicity of chloroform.
3-It does not influence the different systems and recovery from anesthesia is quick.
4-It provides good surgical anesthesia in small animals.
5-It is not expensive and is readily stored.

Disadvantages:
1-Stage of induction is long.
2-It is more irritant thus it produces increased salivary and bronchial secretions.
3- It does not produce complete muscular relaxation and need pre-anesthetic atropine
and muscular relaxant.
4- It is not potent. It has low boiling point and its vapors are inflammable.

Therapeutic uses:
As anesthetic. Orally ether is given diluted with water or as spirit of nitrated ether (spt.
etherinitrosi) as carminative and sedative in case of GI colic.

3-Trichloroethylene (Trielene)

1-It is a clear non inflammable, volatile liquid with chloroform like odor.
2-Colored blue to distinguish it from chloroform.
3-It has a potency below that of ether.

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4-It is used for small animals when general anesthesia of a short duration is required as
in case of manipulation of fractures.

4-Ethyl chloride

1-It is a clear liquid with ether like odor.

2-It has a very low boiling point (12.5 Co). as it is highly volatile it is kept under
pressure in bottles as spray. When inhaled it produces general anesthesia for 2 min so
used for operations of short duration in small animals and birds.
3-It act as local anesthetic by reducing the temperature of the part to freezing leading
to loss of sensation for short duration

B-Non volatile anesthetics

Most non volatile anesthesia administered i.v called intravenous anesthetics. They
are used alone or as a pre-anesthetic to produce basal narcosis before inhalation of
volatile anesthesia. They are used alone to produce general anesthesia. The most
common non volatile anesthetics used in veterinary practice includes:
1-Chloral hydrate for large animals
2-Short and ultra-short acting barbiturates mainly Nembutal, evipan, pentothal and
kemithal for small animals
3-Other anesthetics as ketamine, chloralose, alphaxalone and urethane for small animals
Disadvantages:
1-They are slowly detoxicated in the liver and this leads to a prolonged recovery period
which is usually accompanied with convulsions.
2-They can not reduce pain so they are usually combined with analgesics as morphine.
3-They are not good muscle relaxant so they are frequently used with tubocurarine or
other muscle relaxants
Advantages:
1-They produce anesthesia after a short time.
2- They are easily administered. They do not cause increased bronchial and salivary
secretions
Precautions:
1-They must be injected slowly and the animal fall a sleep suddenly.
2-They must be freshly prepared because their solution is rapidly destroyed.
Choice of anesthetic in veterinary practice:
Horse (chloroform), cattle (epidural or paravertebral nerve blocking with local
anesthetic is recommended in bovine), sheep (i.v barbiturates or if facilities with
cyclopropane), calves (halothane for induction and maintenance).
Examples for non non volatile (injectable) anesthetics:
1-Ultra-short acting barbiturates
They are used for minor operations or for induction of anesthesia and completed with
another anesthetics (thiopental and hexobarbiturates)
2-Ketamine HCl

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 It is used mainly for cats given with acepromazine i.m in a dose of 22 mg/kg. it is
short in its action. It causes stimulation for heart but depress respiration with presence
of coughing and swallowing reflexes. Eye still open.
3-Steroid anesthesia:
a-Alphaxalone :given i.m and i.v for cats but unsuitable for dogs due to its release
for histamine. Recovery is very rapid (3-5 min). dose 9 mg/kg i.v
b-α-chloralose :it is composed from glucose and trichloracetaldhyde. It resemble
chloral hydrate but longer in duration. Death may occur due to respiratory depression
and hypothermia. Dose 0.1 mg/kg 1 % solution i.v.
c-Urethane :it is carcinogenic. Dose is 0.6 mg/100 gm IP or IM for laboratory
animals. It is long lasting and the animal rarely recover.

Local anesthetics
Definition:
These are drugs which produce loss of sensation or loss of pain due to temporary
paralysis of the sensory nerves of the part to which it is applied.
Mechanism of action of local anesthetics:
1-Local anesthetics interfere with the permeability of the cell membrane to cations
increased by depolarization.
2-Local anesthesia block the conduction without depolarizing the nerves by competing
with Ca++ at the receptor sites.
3-Local anesthetics are water soluble salts forming slightly acid solution, neutralized
the tissues. They liberate the free bases decreasing the pH and penetrate the tissues
resulting in nerve block.
4-Local anesthetics block the unmyelinated sensory nerves more easily. They block first
the sensation of pain then cold and worm and lastly touch sensation.
Methods of application of local anesthetics
1-Surface anesthesia
direct application of anesthetic on the skin or m.m.
2-Infiltration anesthesia:
Injection of the anesthetic around the nerve that supply the area (ring block).
3-Regional anesthesia:
Infiltration of the nerve supplying a region with anesthetic. Para-vertebral block in cattle
anesthetize the flank areas which allow abdominal surgery with the animal in standing
position.
4-Spinal anesthesia (epidural):
Injection of the anesthetic sub durally passing the needle between the lumber vertebrae
or in the lumbo-sacral space piercing the dura and arachnojd.Injections is made into the
CSF. It is commonly used in cows but risky due to intercostals and phrenic nerves
paralysis and so respiratory failure.

Desirable properties of local anesthetic

Produce analgesia without damage to the nerves. Not irritant. Low toxicity after
absorption. Effective at low concentrations. Persist for a long time to perform surgical
interference. Rapid in producing its analgesic effect.

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 Methods of prolonging the effect of local anesthetics
The effect is prolonged by addition of a vasoconstrictor so delaying the absorption
into the circulation and reducing the systemic toxicity. Adrenaline or nor adrenaline 1 :
80,000 or 1 : 25,000 are commonly used.

General pharmacological properties of local anesthesia

1-Affect the CNS resulting in a stimulation followed by depression.
2-Block the autonomic ganglia.
3-Block the myoneural junction and muscle fibers.
4-Inhibiting conduction in the nerve fibers.
5-Toxicity result in death from respiratory failure.
6-Local anesthetics have quinidine-like actions on the heart treating arrhythmia by
stabilizing the potential of the nerve cell membrane. They decrease the electrical
excitability of the myocardium, increasing the refractory period.
7-They depress the intestinal muscles but are weak antispasmodic.
8-They are absorbed from surface of application or by injection.They are metabolized
by liver esterases and by plasma esterases (pseudocholine esterase). CSF has no
esterases. And by epidural or spinal injection they last till absorbed then metabolized.
Examples for local anesthetics:
Cocaine, procaine(novocaine), lidocaine (lignocaine/xylocaine), butocaine,
amethocaine (pontocaine, tetracaine), othocaine, benzocaine, cinchocaine (nupercaine),
proxymetcaine, butylaminobenzoate, prilocaine.
1-Procalne (Novocaine)
1-It is used for infiltration and epidural anesthesia.
2-Its solution not absorbed from m.m. It is used 1-5 % solution for injections usually
combined with adrenaline 1: 100,000 solution to prolong its duration of action as
adrenaline constricts the cutaneous B.V of the part and retards its absorption and it also
prevents hemorrhage in the operated part.
3-It has a quinidine-like effect so procaine and procainamid have anti-arrhythmic effect.
2-Amethocaine (pentocaine or tetracaine)
1-It is more potent than procaine. It is more toxic than procaine.
2-It is used for topical anesthesia in ¼-1 % solution as eye drops for corneal anesthesia.
As sedative ointment for burns, itching and severe inflammations of skin and m.m of
eye and nose.
3-Cinchocalne (nupercalne)
1-It is the most potent.
2-It is the most toxic local anesthetic.
3-It is used in 0.1 % solution for corneal anesthesia.
4- It is used 0.2 % solution for corneal anesthesia. It is used as sedative eye drops.
4-Lignocalne HCl (Lidocaine, Xylocaine)
1-It is very effective local anesthetic which replaced procaine.
2-Its solution is very stable.
3-Onset of effect is very short &long duration than procaine.
4- It is more effective as local anesthetic for the eye in 4 % solution.
5-It is used for its anti-arrhythmic effect.

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Pharmacology
Of
Cardiovascular
System

104
 Cardiovascular system

Terms of cardiovascular system:-

1-Stroke volume: the cardiac output divided by number of beats of the heart/min
2-Bradycardia: the decrease in heart rate, cardiac output and heart beat below 60/min
3-Tachycardia: the increase in cardiac output (heart beats above 90/min)
4-Atrial flutter: when heart beat 200-400/min or more (tachycardia), the atria are said
to be in flutter. Flutter = move about in a quick irregular way
5-Atrial fibrillation: When the atria as a whole are not beating this is an advanced
condition of atrial flutter. Atria beats 400-600/min
6-Absolute refractory period: means inability of the myocardium to respond to any
stimuli during contraction due to depolarization.
7-Relative refractory period: means the response to stimuli at the end of
depolarization (repolarization)
8-Extracystoles: means extra-contractions which occurs if the refractory period is
decreased
9-Rhythmicity: it refers to the propriety by which impulses generated from itself
10-Conductivity: propriety to transmit impulses e.g…(A-V) node
11-Distensibility or Extensibility: means the measure of resistance to strech (muscle
tension).
12-Positive chronotropic response: a term used when there is increase in heart rate
13-Negative chronotropic response:a term used when there is decrease in heart rate
14-Positive inotropic response: a term used when there is increase in force of
contraction of the heart
15-Negative inotropic response: a term used when there is decrease in force of
contraction of the heart
16-Bathmotropic: means change in the excitability.
17-Dromotropic: means changes in the conduction.

Normal E.C.G

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Central control of the heart
Action of the heart controlled through medullary center by:
A-Cardio-inhibitory cells from the dorsal nucleus of the vagus
B-Cardioaccelerator cells from the dorsal nucleus of the close to the vagus cardio-
inhibitory.

Drugs acting on the cardiovascular system: Includes the following:-

1-Drugs acting on heart (cardiac stimulants, cardiac tonics and ant-arrythmics)
2-Drugs acting on B.Vs. (vasoconstrictors and vasodilators)
3-Drugs acting on blood (anti-anemics, coagulants and anticoagulants)

I-Drugs acting on the heart

The cardiac muscle posseses the properties of contractility, rythmicity,
excitability, conductivity and automaticity. The activity of the heart is controlled
by cholinergic and adrenergic nerve supplies as follow:
*The vagus nerve (cholinergic, parasympathetic) when stimulated causes the
following effects on the heart:
1-Bradycardia due to depression of the sino auricular node
2-Slowing of conduction in the bundle of his
3-Reduced force of contraction of heart
4-Shortening of the refractory period of myocardium
5-Decreased myocardial excitability
*The vagus nerve may be stimulated by drugs which are destroyed less rapidly
than Ach as methacholine, carbacol or anticholinesterases (edrophonium) which
prevent the destruction of Ach naturally produced at the nerve endings
*The vagus nerve is blocked by atropine and similar drugs and to some extent by
quinidine. These drugs also protect the heart from the effects of cholinergic drugs
*The sympathetic division (adrenergic of the autonomic nervous system) when
stimulated has the following effects on the heart:
1-Tachycardia due to increased rate of discharge of the sino atrial node
2-Increased conductivity in the bundle of his.

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 3-Increased force of contraction (contractility)
4-Shortening of refractory period
5-Increased automaticity
N.B.It may be noted that the effects in the 2 lists above are not all opposites. All
the sympathomimetic drugs produce these effects to a greated or lesser degree.
Those with predominantly α effects (vasoconstriction) can also be used to
obtained reflex vagal stimulation by raising the B.P.
The parasympathetic (vagus) supplies only the atria whereas the sympathetic
supplies all cardiac tissues. There is a reflex control of the heart from the pressor
receptors in the aortic arch and carotid sinus. The activity of the heart is dependent
on the coronary circulation maintaining an adequate supply of oxygen and
nutrients.

A-Cardiac Stimulants
These are drugs which increase the heart rate and contractile power of the
heart muscle. They include the following:
1-Sympathomimetic amines (EP, NE, ephedrine and amphetamine)
2-Parasympatholytics (atropine)
3-Caffeine and theobromine…stimulate the cardiac muscle
4-Ammonia and alcohol…are reflex cardiac stimulant

1-Adrenaline
Adrenaline is used mainly as cardiac stimulant in cases of acute heart failure
as occur in anesthesia. It is contraindicated in chloroform anesthesia as the
increased concentration of chloroform weakness the heart muscle and sensitizes
it to the action of adrenaline
Dose: 2-4 cc for horses and cattle and 0.1-0.3 cc for dog from solution 1:10000

2-Atropine and hyoscine

They induce their action by vagal depressant action on the heart. They are
not used in veterinary practice due to its numerous side effects

3-Xanthine group (caffeine-theophylline and theobromine)

They have a direct action on the heart muscle, that increase the cardiac
output. Aminophylline used instead of theophylline in cases of cardiac
insufficiency in animals in doses 2-5 gm for horses, 50-100 mg for dogs, given
orally 2-3 times daily.
N.B……..Xanthine causes peripheral vasodilatation and some central stimulation
of the vasomotor and vagal centers which make them unsatisfactory for use as
cardiac stimulant.

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 4-Ammonia, alcohol and camphor
They are used as reflex stimulant for heart muscles in doses 30-100 cc for
horse and cattle, 4-16 cc for sheep and 0.5-4 cc for dog. Reflex stimulants are of
no value in anesthetic cardiac emergency except ammonia which is frequently
used in small animals.

B-Cardiac Tonics
These are drugs which improve the functional activity of the heart in
diseased conditions. Cardiac glycosides are the only cardiac tonics of medical
importance. They includes digitalis, strophanthus and squill plants

Cardiac glycoside
1-Digitalis (fox glove)

The glucosides of digitalis mainly digitoxin, gitalin and digoxin are formed
in the leaves of digitalis purpurea and digitalis lanata. They called cardiac
glucosides, due to their main action on the heart. On hydrolysis give sugar and
genins (aglycone). Genin or aglycone gives their effects on the heart.

2-The glucoside of strophanthus

The seeds of strophanthuskmbe and strophanthusgrats are the source of
glucosides that gives strophanthin and g-strophanthin (ouabain) as active
principles respectively

3-Squil bulb (urginea maritime or India)

The glucosides of squill (scilla) are obtained from the roots of
(urgineaindica and maritime). They give the active principle scillarin A and B.
scillarin B has no cardiac effect

Pharmacokinetics of digitalis:
Digitalis glycosides are quickly absorbed from GIT. In ruminant animals, it
destroyed in the rumen. After absorption they reached quickly to the heart and
skeletal muscles and fixed there to induce their effects after stoppage of drug
administration. So they has a cumulative in the body. They metabolized by
destruction in the body. Digoxin and gitalin are more water-soluble than digoxin.

Digitalis purpura Squil bulb

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Pharmacological actions of cardiac glycosides:
I-On circulatory system
In normal individuals cardiac glycosides augment the strength of
myocardial contraction.
In congestive cardiac failure they:
1-Act directly on the cardiac muscle augmenting its force of contraction, resulting
in increased cardiac out put and improvement of blood ciruiation, thus they
releave congestion and oedema by increasing urinary excretion. The digitalized
heart, thus can do the same work with less energy (oxygen utilization).Digitalis
therefore is called a cardiac tonics.
2-slow the heart rate by :-
a-Stimulating the vagal center reflexly through stimulation of the vago-receptors
in the carotid sinus.
b-Inhibiting the Sino auricular node. These two actions can be antagonized by
atropine.
3-it slows the conductivity between the auricle and the ventricle through acting
on auriculo ventricular node. Asresults of these actions, digitalis strengthens the
heart for it produces forcible systole and prolonged diastole, which causes the
ventricle to empty more completely and fills better.
4-the ECG tracing is changed by digitalis as follows:
a-P-R wave is prolonged. b-Q-T interval is shortened.
c-RST is depressed. d-T is diminished or even inverted.

(1) Normal (2) H. failure (3) Digitalized

5-On arterial B.P:

a-Theraputic doses of digitalis does not produce any significant changes in the
arterial B.P in normal animals.
b-In cases of congested heart failure, digitalis may cause an increase in B.P due
to increase in the force of contraction.
c-Toxic dose in animals may be rise in B.P due to :
i-Direct vasoconstriction of digitalis on muscles B.vs.
ii-Centeral stimulation of vasomotor center.
6-On the coronary circulation:
i-On normal heart, therapeutic dose induce no effect
ii-On congestive heart failure, the coronaries can fill more completely.
II-On the Medulla
i-Terapeutic dose stimulate the vagal center only.
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ii-On Toxic dose: stimulate respiratory, vomiting and vasomotor centers.
III-On the kidney
Secondary diuretics only in case of congestive heart failure.

IV-On GIT: Nausea and vomition.

*Mode of action of digitalis:- Digitalis increases the mechanical efficiency of
the diseased heart i.e. the heart can do more work with a certain given amount of
energy

1-Positive Ionotropic: It reversibly inhibits the Na-K ATPase enzyme, leading

to various beneficial effects (The Na-K ATPase enzyme functions to maintain
the intracellular environment by regulating the entry and exit of sodium,
potassium, and calcium (indirectly)). Na-K ATPase is also known as the sodium
pump. The inhibition of the sodium pump by digoxin increases intracellular
sodium and increases the calcium level in the myocardial cells, causing an
increased contractile force of the heart. This improves the left ventricular
ejection fraction (EF), an important measure of cardiac function.

2-AV Node Inhibition: Digoxin has vagomimetic effects on the AV node. By

stimulating the parasympathetic nervous system, it slows electrical conduction
in the atrioventricular node, therefore, decreases the heart rate.

The prolonged administration, the action of digitalis on the heart can be

classified into 3 stage:-
1-1ststage( therapeutic stage): Corresponds to the predominance of the direct
action of digitalis on the heart muscle increasing the efficiency and contractility
of the heat.
2-2nd stage (toxic stage): Corresponds to the predominance of central vagal
stimulation causing excessive slowing of the heart.
3-3rd stage (dangerous stage): Corresponds to the predominance of the effect of
digitalis on the excitability of cardiac muscles causing extrasystoles leading to
ventricular fibrillation

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Toxic symptoms of digitalis which are extension from their pharmacological
effects are:-
a-Bradycardia due to prolongation of the auriculo-ventricular conduction time.
b-Auricular fibrillation due to increased vagal action.
c-Ventricular extra systole resulting from increased irritability of myocardium.
d-Necrosis of the heart resulted from coronary vasoconstriction.
f-Death is due to ventricular fibrillation.

Treatment of digitalis poisoning:

A)1-Stopping of further administration of digitalis
2-Removal of any unabsorbed part of digitalis from stomach and intestine
with emetics or purgatives and give atropine to limit vagal stimulation
B) drugs given orally but when vomiting is severe give the drug IV
N.B…..during digitalis administration, it is dangerous to use (Ca++, adrenaline,
atropine and histamine). There is synergism between histamine and digitalis.

Therapeutic uses and doses:

1-Initial dose and maintenance dose due to its cumulative effects (initial dose
given at first few days)
2-Digitalis is rarely used in cats because of the danger of inducing vomiting by
stimulation of vomiting center. Powdered digitalis or tincture may cause local
irritation of the stomach leading to vomiting in small animals (dog and cat)
3-In ruminants, digitalis is largely destroyed in the rumen and it must be given by
IV injection
4-Tr. digitalis is given in doses of 8-15 cc for horses and 0.3-1 cc for dogs.
5-Digitoxin is given orally for dogs in doses of 0.1-1 mg as initial dose and 0.025
mg as maintenance dose for 5 days only per week.

N.B. establishing an appropriate dose requires a digitalization phase and a

maintenance dose because with normal renal function there is a 50 % loss of e.g.
digoxin in 23 hours

Fate of digitalis in the body:

The highest concentration is found in the kidney, gall bladder, jejunum and
colon. Cardiacglycosides reversibly bind to plasma albumin which delays onset
of & prolong the duration of action. It is excreted by the kidney primarily with
some showing in the biliary tract of the dog. It detoxified in liver.

2-Strophanthus
The pharmacological actions similar to digitalis but it differs from digitalis
in the following:
1-Strophanthus tincture is less irritant to the stomach, so no vomiting effect.
2-Absorption and excretion more rapid, so there no dangerous of accumulation.
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3-It has potent diuretic effect due to absence of vasoconstrictor effect.
4-Strophanthus,IV route is the better route due to irregularity of oral absorption.
Dose: 1-12 mg for cattle and horse and 0.25-1 mg for dog.

3-Squill (Scilla)
1-As cardiac tonic, it is rarely used due to its mild cardiac action.
2- It is used as expectorant due to scilla causes more irritant effect for stomach
and reflexly stimulates bronchial secretions.
Dose….8-30 cc for horses and cattle and 0.25-1 cc for dog.

C-Ant-arrythmic or antifibrillatory drugs

(cardiac sedatives)
These are drugs which are used to prevent or treat cardiac arrhythmia. They
include: quinidine, procainamide, propranolol and lidocaine.
Class I – blocker’s of fast Na+ channels:
 Subclass IA: characters:
Cause moderate Phase 0 depression
Prolong repolarization
Increased duration of action potential
Examples:
 Quinidine and Procainamide
1-Quinidine
It is an alkaloid found in cinchona bark. It is the dextro isomer of quinine
Mode of action:
It induce a direct myocardial depressant effect reducing the rate of
depolarization of the myocardial cell membrane by rendering it less permeable to
Na+ ions by blocking sodium channel.
Pharmacological actions:
1-Quinidine depresses the excitability of the myocardium and suppresses the
ectopic pace-makers especially SA node.
2-Quinidine slows the conduction in the AV node and the bundle of his and
prolongs the refractory period
3-It depresses the myocardial contraction, reducing auricular contraction
4-In cases of atrial fibrillation or atrial flutter quinidine restores the normal
cardiac-arythum
5-Quinidine induces ECG normal with prolonged P-R waves and a wider QRS
complex.

112
Pharmacokinetics:
Quinidine completely absorbed from GIT. Metabolized partially in the liver
by degradation. Excretion is renal.
Toxicity:
Hypersensitivity reactions.Tachycardia, ventricular fibrillation and hypotension.
Sudden death result from coronary embolism due to the formation of clots in the
auricular appendix.
Therapeutic uses:
Quinidine used for treatment of aterial fibrillation in dogs and horses. It is
better to use quinidine after digitalis therapy.
2-Procainamide (pronestyl)
It has anti-fibrillatory effect but overcomes all difficulties of procaine as:
1-it is not hydrolyzed by procainesteras so its action is more prolonged
2-it is absorbed readily and rapidly from GIT, so can given orally. It has a weak
stimulant action on CNS, so produces less side effects.
4-it gives good results in cases of ventricular fibrillation and less effective in
auricular fibrillation.
Toxicity:
AV-block.Ventricular asystole and fibrillation.Hypotension following parentral
administration.Depression of myocardial contractility.Shows additive toxicities
when given with quinidine.GIT disturbances.
 Subclass IB:characters:
Weak Phase 0 depression
Shortened depolarization
Decreased action potential duration
Examples:
1-Lidocane: (also acts as local anesthetic) – blocks Na+ channels mostly in
ventricular cells, also good for:-
a- Digitalis-associated arrhythmias
b- Ventricular arrhythmias occurring after mild cardiac infarction.
2-Mexiletine - oral lidocaine derivative, similar activity.
3-Phenytoin – anticonvulsant that also works as antiarrhythmic similar to
lidocane
 Subclass IC
Strong Phase 0 depression
No effect of depolarization
No effect on action potential duration
Examples
1-Flecainide (initially developed as a local anesthetic)
Slows conduction in all parts of heart,

113
 Also inhibits abnormal automaticity
2-Propafenone
Also slows conduction
Weak β – blocker
Also some Ca2+ channel blockade
Class II – β–adrenergic blockers
Mechanism of action: reduce cardiac contractility and heart rate due to block of β1
receptors .
Types:
a-Non- selective: as Propranolol induces bronchospasm contraindicated in bronchial
asthma.
b-Cardio-selective β1-Blockers: e.g. Atenolol ,metoprolol ,Nadolol,
Acebutolol,Pindolol,Stalol,Timolol and Esmolol are allowed in bronchial asthma .
Uses:
Stable and unstable angina but contraindicated in variant angina (because block of β2
receptors in coronary arteries lead to coronary vasoconstriction and aggravation of
angina)
Class III – K+ channel blockers
1-Developed because some patients negatively sensitive to Na channel blockers (they
died!).
2-Cause delay in repolarization and prolonged refractory period
Examples: Amiodarone ,Ibutilide ,Bretylium and Dofetilide
Class IV – Ca2+ channel blockers
Mechanism of action:They block Ca channels →inhibition of Ca++ influx into cardiac
cells and arterial smooth muscle cells resulting into depression of the myocardium →
↓myocardial oxygen demand and coronary vasodilatation.
Examples: Nifedipine (adalat – epilat), indapamide,Verapamil (isoptin), Diltiazem
Uses:
1-All types of angina .
2-Hypertension especially nifedipine
3-Arrhythmia -verapamil I.V
Side effects:
1-Headache, flush, Hypotension, ankle edema due to vasodilatation.
2-Heart: Bradycardia with diltiazem and verapamil, Reflex Tachycardia with nifedipine
3-Constipation with verapamil
IV-Miscellaneous Antiarrhythmic drugs:-
1-Adenosine

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  Adenosine activates A1-purinergic receptors decreasing the SA nodal firing and
automaticity, reducing conduction velocity, prolonging effective refractory
period, and depressing AV nodal conductivity
 It is the drug of choice in the treatment of paroxysmal supra-ventricular
tachycardia
 It is used only by slow intravenous bolus
It only has a low-profile toxicity (lead to bronchospasm) being extremly short acting
for 15 seconds only
2- Metabolic modulators e.g. Ranolazine: partially inhibit the fatty acid oxidation
pathway in myocardium.

Blood pressure (B.P.)

Physiologists and pharmacologists usually measure B.P in anesthetized
animal by inserting a cannula into a blood vessels and connecting it directly to a
mercury manometer. The systolic and diastolic pressure can not therefore be
determined directly with a mercury manometer.
Cardiac output = B.P/peripheral resistance
Nervous control of B.P.
Vasomotor nerves:
-the vasomotor Ns are principally from the sympathetic division of the ANS.
Blood vessels of head and neck supplied by the postganglionic fibers from the
superior cervical ganglia
-excitation of the sympathetic nerves to B.Vs. of the skin and abdominal viscera
produce vasoconstriction for these nerves. In some species sympathetic-
cholinergic dilator nerves supply the to B.Vs of the skeletal muscles.
-the sympathetic nerves to the coronary B.Vs contain both adrenergic and
cholinergic fibers. Therefore, the effects produced by stimulating these nerves are
thus complex and may be influenced by change in the contraction and metabolism
of ventricular muscles
-B.Vs in general do not receive fibers from the parasympathetic N.S ;an exception
is the nerve supply to the erectile tissue, in which stimulation of the sacral
parasympathetic N produces dilatation of the arteries and constriction of the veins
so that the tissues become engorged with blood.
Central control of the vasomotor activity:
The activity of the vasomotor nerves and regulation due to CNS. The sympathetic
pre-ganglionic nerves in the lateral horns of the spinal cord connected with other
nerve fibers to form spinal vasomotor centers. The spinal centers are controlled
by impulses descended from the brain. But in spinal animals and paraplegic
patients a few reflexively induced responses of B.V persist including local
vascular change associated with control of body temperature and erection.

115
-The main vasomotor center in the medulla, in the floor of the 4 th ventricle, a
secretion through the stem below this center results in a fall in B.P and loss of
most vasomotor reflexes. The medullar vasomotor center is in turn under the
control of the cerebral cortex. During sleep, the B.P is lower than during
wakefulness.
Carotid sinus pressor reflex:
-At the origin of the internal carotid artery in the neck, the common carotid trunk
is enlarged to form the carotid sinus. The wall of the carotid sinus contains
baroreceptors, that is receptors sensitive to pressure. The sensory nerve running
from these receptors is called the nerve or simply the carotid sinus nerve.
-Baroreceptors in the wall of the aortic arch are aggregates of receptors known as
arortic bodies
-Baroreceptors of the heart endothelium and sensory fibers from them gain the
depressor nerve. Stimulation of the depressor nerve cause a fall in B.P
-Moderation of the output of the vasomotor center by that of baroreceptor form
an example of feed-back control loop.
-Chemoreceptors through the vascular system in the carotid body are connected
principally with respiratory reflexes
-Stimulation of the chenmoreceptors in the heart and aorta, leads to slowing in
the heart, as well as peripheral B.Vs are dilated giving fall in B.P.
-Vasomotor center is excited rhythmically by impulses irradiated from the nearly
respiratory center in the medulla
Humoral factors acting on circulation:
Carbon dioxide (CO2) dilates peripheral B.Vs by direct action, where as
release a drenaline from the adrenal medulla acts centrally to increase vasomotor
tone. Also adrenaline acts on the heart and B.Vs. Hormones of the adrenal Cortex
also have an effect on B.P by altering the sensitivity of the cardiovascular system
to other agents. The secretion of the posterior pituitary has marked effects on B.P
Antidiuretic hormone (ADH) causes constriction of B.Vs increasing the B.P.

II-Drugs acting on blood vessels

The B.Vs are supplied by vasoconstrictor & vasodilator nerves by the action
of these nerves on the arterioles, the general B.P. is maintained. All B.Vs in the
body with the exception of cutaneous B.Vs. are under the control of the
vasomotor center in the medulla. The cutaneous B.Vs are under the control of the
theromogenic center in the hypothalamus.

A-Vasoconstrictors and Hypertensive drugs

1-Drugs acting on vasomotor center (VMC):
a-Directly: as by caffeine, cardiazol, amphetamine, picrotoxin, coramin, ect.
They only cause rise of B.P. when used in large darge doses & when B.P is
abnormally low. CO2: has a direct stimulant action on VMC but peripherally it

116
has a vasodilating action. In therapeutic conc. (5-7 %) the centeral action
predominates.
b-Reflexly:
*Lboeline----stimulate chemoreceptors of the carotid body and reflexly stimulate
the vasomotor center.
*Alcohol----stimulate the sensory nerve endings in the mouth & stomach reflexly
stimulate VMC, but after absorption, cause vasodilatation to B.Vs of the skin due
to depression of heat regulating center.
*Anaesthetics: During the struggling stage of the volatile anaesthetics there is
arise of the B.P due to release of catecholamines, but in large dose they depress
the VMC.
2-Drugs acting peripherally:
1-By stimulating the sympathetic nerves supplying to the B.Vs:
A-Drugs acting directly on the adrenergic recoptors as EP and NE
B-Drugs acting indirect by:
i-Protecting the adrenergic mediators by:
a-Inhibiting the enzyme MAO such as ephedrine & amphetamine
b-Inhibiting the enzyme catechol-o-methyl transferase as catechol, pyrogallol.
ii-Liberating adrenergic mediators (nor adrenalin) from sympathetic nerve
terminalis as ephedrine& amphetamine.
C-Drugs acting by both mechanisms as ephedrine.
2-By stimulating directly the musculature of the B.Vs
a-Pitutrin it causes rise in B.P. due to the presence of vasopressin. It acts on
splanchenic BVs & cutaneous BVs.
b-Digitalis in large doses  act directly upon the smooth museles of arterioles.
c-Natural alkakoids (ergotoxin, ergotamine &ergonovine) they cause rise in the
B.P due to direct vasoconstriction of peripheral B.Vs & coronary & renal B.Vs
constriction.
NB: Nicotine in small doses elevates B.P., this rise in part is due to stimulation
of sympathetic ganglia, and mainly due to discharge of adrenaline & nor
adrenaline from the adrenal medulla, also nicotine causes peripheral vasocons-
triction due to release of nor adrenaline from sympathetic nerve endings.
D-Angiotensin pressor action is due to its direct action on smooth muscle fiber
& stimulation of centeral sympathetic structures.

Atihypertensives and vasodilators

It is Sustained elevation of arterial blood pressure (BP) above the normal.
Causes:
1-Primary (Essential) of unknown cause (the most common)
2- Secondary caused by diseases as pheochromocytoma or renal disease or Drugs as
cortisone
Drug strategy:
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 1- Reduce Total Peripheral Resistance (TPR ),
2- Reduce Cardiac output (CO) ,
3- Reduce body fluid volume
Antihypertensive drugs:
1- Diuretics:
a-Thiazide Diuretics are commonly used in the management of hypertension
e.g. hydrochlorothiazide (HCTZ) and chlorthalidone.
b- Loop diuretics: Several loop diuretics are used in refractory hypertension come in
IV and oral forms.
1-Furosemide is available in oral tablet form in 20, 40, and 80 mg dosages. Injectable solutions
come in 10 mg/mL doses. Oral solutions come in either 8 or 10 mg/mL doses.
2-Torsemide is available in tablet form in 5, 10, 20, or 100 mg doses. Injectable solution is 10
mg/mL dosing.
3-Bumetanide: Available in oral tablets of 0.5, 1 and 2 mg doses. IV solution is 0.25 mg/mL.
4-Ethacrynic acid: Available in oral tablets of 25 mg and powder form for injections at 50 mg
c- Potassium sparing diuretics: They are weak diuretics usually prescribed in
combination with other types of diuretics. Spironolactone, Amiloride, Triamterene and
Eplerenone.
2-Angiotensin-Converting Enzyme Inhibitors (ACEIs) and Angiotensin-
Receptor Blockers (ARBs):
a-ACEIs: e.g. Captopril, Lisinopril (and other “−prils”)
Block formation of angiotensin II, Resulting in prevention of AT1-receptor stimulation,
↓ aldosterone, vasodilation and prevent bradykinin degradation
b-ARBs: e.g. Losartan (and other “−sartans”)
Block AT1 receptors, Same results as ACEIs on BP mechanisms and ARBs do not
interfere with bradykinin degradation
c-Renin inhibitor :e.g. Aliskiren
Blocks formation of angiotensin I , Same results as ACEIs on BP mechanisms and
Aliskiren does not interfere with bradykinin degradation.
Uses:
1- Mild-to-moderate hypertension (all)
2-Protective of diabetic nephropathy (ACEI/ARBs)
3- CHF (ACEI/ARBs)
Side effects:
1- Dry cough (ACEIs) due to increase in bradykinin level 2-Hyperkalemia
3- Acute renal failure in renal artery stenosis 4- Angioedema
Contraindication: pregnancy

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3-Calcium-Channel Blockers Calcium-channel blockers (CCBs) block L-type
Ca2+ channels in heart and blood vessels.
Results in ↓ intracellular Ca2+ Causes ↓ CO (verapamil and diltiazem), ↓ TPR (all
CCBs) • Drugs: verapamil, diltiazem and nifedipine.
Ca2+-channel blockers
Heart B. v.
Verapamil Diltiazem Nifedipine
• Uses:
1- Hypertension (all drugs) 2- Angina (all drugs) 3-Antiarrhythmics (verapamil,
diltiazem)
• Side effects: a- Reflex tachycardia and Gingival hyperplasia (Nifedipine)
b-Constipation (verapamil)
4-Drugs block sympathetic activity:
a- β-Blockers
Side effects:
1- Cardiovascular depression 2-Fatigue
3- Sexual dysfunction 4- ↑ LDLs and TGs
Cautions in use: Asthma ,Vasospastic disorders , Diabetics (alteration of glycemia
and masking of tachycardia due to hypoglycemic events)
b-α1 -Blockers ( Decrease arteriolar and venous resistance , Reflex tachycardia)
Drugs: prazosin, doxazosin, terazosin
Uses: 1- Hypertension
2- BPH: ↓ urinary frequency and nocturia by ↓ the tone of urinary sphincters
Side effects: “first-dose” syncope, orthostatic hypotension, urinary incontinence.
Advantage: good effect on lipid profile (↑ HDL, ↓ LDL)
c- α 2- Agonists: e.g. clonidine and methyldopa (prodrug)
- α2 stimulation: ↓ in sympathetic outflow; ↓ TPR but also ↓ HR
Uses: 1- Mild-to-moderate hypertension (both).
2- Hypertensive management in pregnancy (methyldopa).
d- Sympathetic transmitter release inhibitors e.g. guanethidine.
e- Deplete catecholamine stores e.g. reserpine.
f- Inhibit synthesis of transmitter e.g. α- methyl dopa.
5-Direct acting vasodilators:
Classifcation of vasodilators according to site of action:_
a- Arterial: Hydralazine, Diazoxide, Minoxidil.

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b- Arterial + Venous: Sodium nitroprusside.
c- Mixed Arterial + Venous :Nitrates
Classifcation of vasodilators according to mechanism of action:-
a-Drugs Acting Through Nitric Oxide
1-Hydralazine – ↓ TPR via arteriolar dilation
Use: moderate-to-severe hypertension
Side effects: SLE-like syndrome and slow acetylators; edema; reflex tachycardia
2-Nitroprusside – ↓ TPR via dilation of both arterioles and venules
Use: hypertensive emergencies (used IV)
Side effects: cyanide toxicity (co-administered with nitrites and thiosulfate) Drugs
Acting to Open Potassium Channels
b- Open K+ channel, causing hyperpolarization of smooth muscle and Results in
arteriolar vasodilation
Drugs: Minoxidil and diazoxide
Uses: 1- Insulinoma (diazoxide) 2- Severe hypertension (minoxidil)
3-Baldness (topical minoxidil)
Side effects: 1- Hypertrichosis (minoxidil)
2-Hyperglycemia (↓ insulin release diazoxide)
3- Edema 4- Reflex tachycardia
6-Adjuvants to Antihypertensive Therapy: Sedative e.g. phenobarbitone, and
tranquillizers e.g. diazepam

III-Drugs acting on the blood

Drus acting as antianaemic and antileukaemic
A-Antianaemic drugs
1-Hamorrhagic anaemia: treated by blood transfusion & iron rich diets.
2-Microcytic anaemia or iron defficiecy anaemia or due to inability to absorb
iron.Treatment by iron preparations given orally after meal.
a-For large animals (horse&cattles):Ferrous salts (sulphate, phosphate,
carbonate or gluconate) 4-15 mg .
b-For small animals: scaly preparations of iron as iron ammonium citrate, iron
quinine citrate and iron strychnine citrate. They are less irritant & astringent than
ferrous salts. Dose 0.3-0.6 gm orally.

NB: Animals unable to absorb iron, it can be given by I/V, injection as ferivenin
or by I/M. injection of iron dextran.

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3-Macrocytic anaemia (pernicious anaemia): due to deficiency of exrensic factor
vit. B or the intrinsic factor which is a mucoprotein in the gastric juice. This type
of anaemia can be treated by vit B12 orally or by injection as liver extract rich in
vit B12. Folic acid is of value in treating this type of anaemia. The dessicated hog
stomach preparation as substitute for the intrinsic factor is also given.
4-Aplastic anaemia: Occur due to depression of the bone marrow by poisons or
radioactive substances is treated by removing the cause, vit B 12 and iron.
5-Haemolytic anaemia: Occur due to destruction of red cells by bacteria, parasites
or toxins & treated by preventing the etiology &supplementation with B 12&iron.

B-Antileukaemic drugs
Leukaemia means type of cancer for WBCs .It might be treated by the
antineoplastic drugs including the alkaylating agents as cyclophosphamide
(Endoxan) orantimetabolites as Methoutrexate.
C -Coagulant drugs
Blood coagulation is completed by formation of prothrombin from its
precursor vit K in the liver. Prothrombin in the presence of Ca++is transformed to
thrombin by the help of the enzyme thromboplastin. Thrombin which helps the
agglutination of blood platlets aids the convession of the plasma protein
fibrinogen to fibrin which froms a net work trapping the agglutinated platlet&
forming the blood colt.
1-Drugs as coagulant, which help the rapid formation of clot or stop bleeding or
haemprrhages, locally. The drugs, which precipitate proteins as ferric chloride or
tannic acid can be used as haemostatic or styptic.
2-Vit. K (Menandionbisulphate) or konakion injected I/M are of value in
controlling heamorrhages. Ca++ salts as gluconate, lactate or chloride (2-5 %)
injected S/C or IV are of value in helping the conversion of prothrombin to
thrombin.
D-Anticoagulants drugs
These are drugswhich delay coagulation of the blood in vivo or in vitro.
They are important in blood transfusion, treating thrombosis and for preserving
blood samples. In vitro: oxalic A, 0.1 % Na or K oxalates, di Na salt of EDTA or
Na fluoride unit with blood Ca preventing its coagulation. Na citrate 0.4 %
reduces the ionization of Ca and so used in blood transfusion.

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1-Heparin:
Heparin used in vivo and vitro. Its action as anticoagulant by interfering
with the conversion of prothrombin to thrombin by antagonizing thromboplastin.
It also prevents thrombin from acting on fibrinogen to form fibrin and also it
prevents the agglutination of platelets by decreasing thrombin formation. Heparin
by iv injection 1-10 units 1 ml produces its effect in 1o min and is destroyed by
heparinase enzyme in few hours. Excessive doses of heparin are counteracted by
the injection of protamin.
2-Dextran sulphate:
It is an anticoagulant but less potent than heparin
3-Dicoumarol (dicoumarin):
It is ana anticoagulant given orally. It is chemically related to vit K. It act
only in vivo by reducing the amount of prothrombin formed by the liver as
preventing the use of vit K. It also reduces the adhesiveness of platelets. It is
converted to salicylic acid which act as anticoagulant in 1-2 days and last for 3-
7 days and so not used in emergency and heparin is preferred. Its toxicity is
counteracted by injecting vit K I/V.
4-Warfarin Na:
It is an anticoagulant similar to dicoumarol antagonizing vit K also used as
a rodenticide.

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 Pharmacology
Of
Respiratory System

123
 Pharmacology of respiratory system

The respiratory system is one of the most important organ systems. The primary function
of the respiratory system is to bring oxygen into the body and to remove carbon dioxide. The
physiology of the respiratory system involves two main processes: ventilation and respiration.
Ventilation is the process of moving air into and out of the lungs. The process by which gasses
are exchanged is called respiration.
The respiratory tract is divided into the upper and lower tracts. The upper respiratory tract
contains nose, nasal cavity, pharynx and larynx. The lower tract consists of trachea, bronchi,
bronchioles, alveoli and alveolar-capillary membrane. Bronchioles are lined with smooth
muscle that controls the amount of air entering the lungs. The movement of respiratory muscles
(intercostals and diaphragmatic muscles) are under the control of respiratory center that located
in the medulla oblongata.
Drugs affecting the respiratory system includes:
1-Respiratory stimulants 2-Respiratory depressants

Respiratory stimulants
*Stimulation of respiration is urgent requirement for treating all emergency states
associated with respiratory failure.
Definition:- Respiratory stimulants are agents which stimulate the respiratory rate and
depth through stimulating the respiratory center.
Therapeutic uses:- Used for treating respiratory failure in cases of anesthesia,
asphyxia, morphine or barbiturate poisoning. Also, in some respiratory diseases that
depress respiration.
Includes:-
1-Direct stimulants of respiratory center

*Act by stimulating the respiration directly through stimulating the respiratory center.
i-Carbon dioxide
Is a natural, direct respiratory stimulant and also act reflexly. Used as 5 % with
oxygen (carbogen). Ineffective when respiration is depressed.
ii-Medullary stimulants (Analeptics, Arousing drugs)
Are drugs which stimulate the CNS and awaken anesthetized patients and produce
convulsions when administered in large doses. They stimulate the respiratory center and
other centers in medulla and brain. In normal patients, they have no effect on respiration
but in cases of depressed respiratory center, they cause marked stimulation of
respiratory center and respiration.
*Includes: Picrotoxin, Leptazole (Cardiazole), Megimide (Bemegride)
and Coramine (Nikethamide).
iii-Competitive antagonists of narcotic group of respiratory depressants
*Includes blockers of morphine, methadone and meperidine
e.g Nalorphine and Naloxone
iv-Pre-anesthetic medications
*Counteract the respiratory depressant action of morphine
e.g Atropine and Hyoscine

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 2-Reflex stimulants of respiratory center
*Act by irritating the skin and mucous membrane of respiratory tract causing reflex
stimulation of medullary centers including respiratory and vasomotor centers resulting
in respiratory and circulatory improvement.
*Includes: a-S/c inj. of camphor in 10 % oily sol. b-Inhalation of ammonia

Respiratory depressants
Definition:- Are agents or drugs which depress the respiration by depressing the
respiratory center.
Includes:-
1-Respiratory center depressants e.g Morphine and Diamorphine
2-Depressants of sensitivity of respiratory center to carbon dioxide e.g
Barbiturates

Cough
Cough is a protective reflex intended to remove irritants, accumulated secretion and
foreign materials from the respiratory airway.
Types of cough:
i-Productive (moist) (useful) cough :which is effectively expel the present
secretions (sputum) and exudates from the respiratory passages
ii-Non productive (dry) (useless) cough: as smokers cough

Treatment of dry, non productive, useless cough

Cough center depressants
(Cough sedatives)(Anti-tussive drugs)
These are drugs inhibiting cough reflex by suppressing cough center in medulla.
They are used for symptomatic treatment of dry unproductive cough due to stop or
decrease frequency of dry painful cough.
1-Peripheral anti-tussives
Act by blocking the cough reflex at the level of sensory nerve ending in pharynx, larynx
and upper respiratory tract.They suppresses the irritated sensory nerve endings which
initiate the cough reflex.They includes:-
a-Demulcents : Drugs used when cough arises due to irritation above larynx as sore
throat and pharyngitis. They increase salivation and produce protective soothing effect
on inflamed mucosa.-e.g Syrups, Logenges, Linctuses or liquorice.
b-Steam inhalation
1-For cough due to tracheo-bronchitis
2-Half a liter of boiling water to which added a teaspoonful of e.g.Tincture benzoin or
Menthol.
3-Promotes the secretion of protective mucous.

c-Drugs with a local anesthetic action -e.g Benzonatate (Tessalon)

1-It is a peripherally acting cough suppressant and chemically related to local
anesthetic tetracaine.

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 2-Acts on the pulmonary stretch receptors.
2-Central anti-tussives
*Act at the level of cough center in the medulla oblongata i.e suppress the medullary
cough center.
i-Narcotic anti-tussives:
a-Relatively non addicting group e.g Codeine phosphate (methyl morphine)
Codeine:
1. Cough center suppressant effects.
2. Cause mild CNS depression.
3. Constipation by decreasing intestinal movements.
4. Should be avoided in children and asthmaticus.
5. Administered orally, mild analgesic, less addiction.
b-Addicting group
e.g.Methadone HCl (synthetic morphine), Morphine sulphate and Heroin (semi-
synthetic morphine)
-Not commonly used as anti-tussives due to their addicting and respiratory
depressive properties
ii-Non narcotic (non addicting) anti-tussives:
-e.g Dextromethorphan hydrobromide (romilar), Narcotine and Noscapine
1-Pholcodeine:
1. Similar action as codeine
2. No analgesic.
3. No addiction liability.
4. Administered orally.
5. Has long duration of action.
2-Noscapine:
1. Opium alkaloid.
2. Potent antitussive effect.
3. Useful in spasmodic cough.
4. No analgesic effect.
5. Does’t cause constipation, CNS depression or addiction
6. Side effects are nausea and headache.
3-Dextromethorphan:
1. Centrally acting antitussive agent.
2. No analgesic property.
3. Does’t cause constipation and addiction; mucuciliary function is not affected.
iii-Antihistamines:
Diphenhydramine, chlorpheniramine, promethazine are useful in cough because:
1. Sedative, antiallergic, anticholinergic effects.
2. Produce symptomatic relief in cold and cough associated with allergic
condition of respiratory tract.

Treatment of Moist( productive or useful cough)

1-Expectorants
Expectorants are drugs which facilitate removal respiratory tract secretions
(sputum) by expectoration through coughing.
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Therapeutic uses:- For treatment of cough, bronchitis (acute and chronic), pneumonia
and bronchial asthma
Classification and mode of action
1-Ingested expectorants: Act after their oral administration
a-Alkaline expectorants:
Alkaline expectorants transferred in the body into alkaline compounds and during
their excretion through bronchial glands increased secretion of these glands. They
dissolve the viscid mucous secretion and sooth the inflamed bronchial mucosa. They
are effective in the early, dry stage of acute bronchitis in which there is a dry painful
cough because the bronchial mucosa is congested and coated with thick mucous
e.g 1-Sodium bicarbonates 2-Ammonium carbonate
b-Emetic (nauseant or reflex) expectorants:
1-Emetic expectorants caused irritation of the sensory nerve endings of oral, pharyngeal,
esophageal and gastric mucosa reflexly stimulate saliva and bronchial secretions ,also
Stimulate the activity of cilia to expel the respiratory secretion by aid of cough.
2-These agents are considered expectorants in small doses but emetics in large doses
3-They are effective in the early, dry stage of acute bronchitis.
e.g. i-Tincture ipecac (ipecacuanha roots) which contain two irritant
alkaloids (emetine and cephaline)
ii-Senega (polygala roots)(infusion senega) which contain an irritant
alkaloid (saponin or senegine)
iii-Squill (scilla, tincture scilla or syrup scilla) which contain an
irritant alkaloid (scillarine)
iv-Liquorice v-Tartar emetic vi-Tincture tolu
c-Direct (saline) expectorants:
Direct expectorants absorbed after their oral administration and during their
bronchial excretion caused direct irritation and increased secretion of bronchial glands.
Also, they help liquefying of the thick and tenacious bronchial secretions and thus they
are used mainly in chronic bronchitis
e.g. i-Potassium iodide ii-Sodium iodide
Iodides are contraindicated in cases of
i-Acute bronchitis, where iodide ions are too irritant to bronchial mucosa.
ii-Tuberculosis, because iodides may dissolve the fibrous connective tissue around an
old tuberculous lesion which may become reactivated.
Toxicity of iodides:Sialadenitis (inflammation of salivary gland), rhinitis, gastritis,
conjunctivitis, headache and allergic manifestations

2-Inhalant expectorants:
By inhalation of steamed water containing expectorant agents, where the inhalant
expectorant drug powdered on to hot water and the patient animal allowed to inhal the
medicated vapor which contain the inhalant drug. After absorption and during its
excretion, the inhalant drug irritate the bronchial glands and stimulate their
secretions.Difficult in large animals. Small animals may exposed to steam for repeated
short periods or exposed to aerosols using mask or small enclosed cage. effective in
chronic respiratory diseases and supported by suitable chemotherapeutic agents
e.g. a-Oil of Eucalyptus plant (has a characteristic pungent odor)

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 b-Terebens (is a refined fraction from turpentine oil)
c-Benzoin vapour d-Iodine vapour

2-Mucolytics
Mucolytics are drugs which facilitate liquefying (dissolving) and decrease
viscosity of viscid and thick sputum (pulmonary secretions) thus, they enhance the
therapeutic efficacy of expectorants (i.e improve expectoration) but they are not true
expectorants.
1-Bisovon (Bromohexine HCl): Used orally.Acts by destroying the mucopolys-
accharide which forms the ground substance of bronchial secretion.
2-Acetylcysteine: used as 20 % solution, orally or inhalation. Liquefy the viscid tracheo-
bronchial secretions.
3-S-carboxy-methyl cysteine (Mucodyne): Mucolytic and also decrease the mucous
gland hyperplasia which is usually associated with chronic bronchitis.

Bronchial secretion reducers

They are drugs or agent which reduce the bronchial glands secretion. Used
therapeutically as a pre-anesthetic medications to prevent patient suffocation during
anesthesia because the volatile anesthesia caused irritation, increased activity and
secretions of the bronchial glands
e.g Parasympatholytic drugs (as atropine or hyoscine)

Pharmacology of bronchial asthma

*Bronchial asthma is an allergic disorder of respiratory tract characterized by:-
Inflammation of respiratory airway, difficult respiration (breathing) or dyspnea, edema
and swelling of bronchial mucosa (narrowing of bronchi), cough due to contraction of
bronchial SM, accompanied by viscid and sticky secretions, increased numbers of
various types of inflammatory cells, most notably eosinophils but also basophils, mast
cells, macrophages, and certain types of lymphocytes, can be found in airway wall
biopsies and in bronchoalveolar lavage fluid from asthmatic patients.
It is possibly due to an antigen-antibody reaction which liberate pharmacologically
active substances including histamine, PGs, kinins and SRS-A in the bronchial SM
leading to bronchospasm (allergic asthmas). Other types of bronchial asthma are present
and considered non allergic asthma
Lines for treatment of bronchial asthma
The pharmacological therapy of asthma employs drugs aimed at reducing airway
inflammation (i.e., antiinflammatory agents) and drugs aimed more directly at
decreasing bronchospasm (i.e., bronchodilators).
I-Bronchodilators:Are drugs which relax bronchial SM spasm .
a- β2- adrenergic agonists: both short acting (SABA) and long acting (LABA).
b-Methylxanthines : theophylline derivatives e.g. aminophylline.
c-Muscarinic receptor antagonists: Ipartropium and tiotropium.
d-Direct SM relaxants (Spasmolytics):
1-Nitrites:
i-Amyl nitrites: Used by inhalation. Of rapid onset of action, thus used in acute
bronchial asthma

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 ii-Sodium nitrites: Uused orally. Of slow onset and prolonged duration of action,
thus used in chronic asthma
2-Papaverine:
-An alkaloid obtained from opium and used orally or parentrally
II-Mast cell stabilizers :
These drugs are not bronchodilators or anti-inflammatory only effective if given
before exposure to the antigen. They prevent release of histamine e.g. Disodium
cromoglycate (Cromolyn sodium, Intal), Ketotifen (Zaditen).
III- Corticosteroids:(Mainly used Inhalation rarely Systemic): Not act as
bronchodilator but they:
a-Reduce the response of the antigen -antibody reaction.
b-Anti-inflammorty inhibit production of inflammatory cytokines.
c-Potentiation of β agonists effects by preventing β receptors down-regulation .e.g.
Beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, mometasone, and
triamcinolone.
IV- Anti-lukotriene drugs:
1-Leukotriene (LTD4) receptor antagonists: e.g.
a-Zafirlukast (Accolate) b-Montelukast (Singulair)
2-Leukotriene (5- lipo - oxygenase enzyme inhibitor) synthesis inhibitors:e.g.
Zileuton (Zyflo)
V-Antihistaminics (H1-blochers)
Used to prevent the action of histamine on H1-receptors of bronchial SM.
VI-Immunoglobulin antagonists: Anti- IgE monocolonal antibodies e.g.
Omalizumab (Xolair).
VII-Expectorants:
These drugs reduce the viscosity of bronchial secretion found in the lumen of the
bronchi, and to help its expectoration .e.g. Potassium iodide or tincture ipecacuanha.
VIII-Sedatives and tranquilizers:*Used to promote sleeping of the patient at night.
e.g. diazepam

IX-Improve oxygen supply:

Indicated in severe cases of acute bronchial asthma and in cases where inhalation of
inspired oxygen is difficult and the patient become hypoxic. A mixture of 80% helium
and 20% oxygen inspired daily because helium has a low density.

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129
 Pharmacology
Of
Digestive System

130
 Pharmacolgy of Digestive System
The pharmacology of gastrointestinal tract (GIT) differs in various animals depending on
the anatomical and physiological variation e.g…ruminant animals differ from the monogastric
animals.
Drugs acting on the mouth and pharynx
I-Gustatory stimulants
These are drugs which stimulate the taste buds:
a-Volatile oils:(peppermint, carium, anise and cinnamon). They are given as infusion,
decoction, tincture or flavoring agents to mask unpleasant taste and stimulate the taste
buds.
b-Simple bitters: (Quinine and Strychnine), that have bitter taste and reflexly increase
the salivary and gastric secretions when given before meal directly.
c-Pungant substances: (ginger), induce irritation of sensory nerve endings in the mouth.
Excess of them caused irritation and gastritis.
d-Sweeting agents: (glucose, dextrose, lactose, sucrose) they stimulate the taste buds
and increase the salivary secretion

II- Sialagogues-(Salivary gland stimulants)

These are drugs which increase the salivary gland secretions and causing improvement
of appetite and food digestibility.
*Secretion of saliva can be stimulated by psychic stimuli as seeing or smelling of food
in case of hungry (in carnivores as dog and cat), Eating and rumination (in ruminants)
and Mastication (in equine).
1-Direct sialagogues: Increased salivary secretion directly by direct action on
secretory cells of salivary gland.e.g. Potassium iodide.
2-Cholinergic stimulants:
a-Parasympathomimetics (Ach, eserine physostigmine, carbacol, pilocarpine).
b-Nicotine, Lobeline.
2-Reflex sialagogues:
Increased salivary secretion either:
a-Stomachics: Stimulating the sensory nerves of taste buds in the buccal mucosa e.g.
Ammonium carbonates or
b-Nauseant (Reflex) emetics:Stimulating the sensory nerves in the gastric mucosa
reflexly stimulate the salivary gland secretion.e.g.Ipecaquanha.

III- Anti-sialagogues (Salivary gland inhibitors)

These are drugs which decrease the salivary gland secretions and flow of saliva.It is
used during surgery in the mouth and for pre-anesthetic medications
1-Parasympatholytics -Atropine, Hyoscine, Hyoscyamine.
2-Demulcents, Astringents
3-Reflex action e.g.unpalatable food or drug
4-Ganglionic blockers
5-Others:Some neuroleptics,antihistamines and anticonvulsants when used in high
doses caused dry mouth as a side effect.

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 IV-Demulcents
These are drugs able to adhere to and form a fine coat on mucous membrane and protect
it from irritations. e.g.
a-Natural plant hydrocolloids (as gum acacia, tragacanth, agar, methylcellulose). b-
Sugars (as honey, syrups and treacle) ,Starch.
3-Glycerols (as glycerin),
4-Animal proteins (as gelatin and egg white "egg albumen"),Mineral oils (as liquid
paraffin) and Propylene glycol
Uses :
Inflammatory conditions of mouth, pharynx, stomach and intestine, diarrhea and
irritant poisons.

The esophagus
The structure of the esophagus varies between species and this is reflected in differing
responses to drugs. In horse esophagus consists of high proportion of smooth muscle
.Cholinergic drugs cause relaxation of the caudal esophageal sphincter and contraction of the
smooth muscles above. The sphincter relaxation is blocked by atropine. While adrenaline
causes contraction of the sphincter. Atropine has little effect on the esophagus of the ruminant
because the esophagus is largely made up of striated muscle that is needed for control of
regurgitation.The movement of esophagus is blocked by curare or decamethonium.
Esophageal obstruction:
In small animals the esophageal obstruction occurred by bones or other foreign bodies,
but in cattle with pieces of root vegetable. Drugs muscle-relaxing spasmolytic effects are often
useful e.g acepromazine and proquamazine fumerate, but motility enhancing drugs e.g
arecholine increase spasm.
The esophageal groove
The importance of the esophageal groove (fold of mucosa):
It can close and allow orally ingested fluids to pass directly from esophagus to the
abomasums by passing the rumen, reticulum and omasum (in young animals).
1-atropine partly abolish the closure of the groove
2-dopamine completely abolish the closure of the groove
3-stimulation of closure in young animals by milk and water (6 months in cattle and 3
months in water aged calves).
4-sodium bicarbonate close the groove at dose of 60 ml of a 10 % solution in most cattle up to
the age of 18 months, while the closure over this age is irregular.
5-copper sulphate 1 % is effective in sheep for closing the groove while sodium salts
are not. Copper sulphate was used to ensure that the drug passed directly to the
abomasums and was not diluted to the rumen
6-failure of the esophageal groove to close fully is a common cause of bloat in milk-fed
calves. The use of dopaminergic blocking agents e.g…domperictone treat this
condition.

Drugs acting on stomach and rumen

I-Stomachics (Bitters)
Are drugs which improve the appetite and reflexly increasing saliva and gastric
secretions. Bitter stomachics include:-
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a-Aromatic: e.g Orange peel, Lemon peel, Ginger, Cardamom
b-Simple infusion: e.g tr. of quassia, calumba and gentian
c-Alkaloidal: e.g quinine and strychnine……in small doses
d-Compound: e.g….Tr. of gentian

II-Drugs influencing the gastric secretion

1-Drugs stimulate or increase the secretion
a-Gustatory stimulants
b-Chemical stimulants…weak inorganic, organic or fatty acids increase the gastric
secretion. Alkaline carbonates, histamine phosphate, alcoholic solutions of less than 10
5 strength augmented gastric secretion
c-Nervous stimulants: Stimulation of parasympathetic nervous system (by exciting the
vagal nerve endings, physostigmine, pilocarpine) augment the flow of gastric juice.
Not used in therapy

2-Drugs inhibit or decrease the secretion

a-Reflex depressants….as unpalatable foods, mucilaginous materials
b-Chemical depressants…as acids in strengths above of 0.5 % HCl, fixed oils or fats,
strong alcoholic solutions
c-Narvous depressants…as atropine, hyoscyamine, hyoscine,

III-Drugs influencing the acidity

a-Hydrochlorhydria: when the gastric juice is deficient in acids as occurs in pernicious
anemia, rheumatoid arthritis and carcinoma dilute acids given during and shortly after
meals, is the natural method of supplying the defect
b-Hyperchlorhydria: it is the increased acidity of the gastric contents which may occur
in gastric or duodenal ulcers or be associated with chronic dyspepsia can be
counteracted by the administration of antacids.

IV-Anti-acids
Drugs used to control or neutralize the gastric hyperacidity. Chemical antacids are either
soluble salts acting locally and systemically after absorption as Na bicarbonate or not absorbed
and act only in the stomach as Mg, Ca and aluminum salts.
The common antacids are bases of either:-
1-Aluminum, magnesium, calcium:-
Examples : aluminum hydroxide (Al(OH)3), magnesium hydroxide (Mg(OH)2),
and calcium carbonate (CaCO3, e.g., Tums®). These drugs neutralize stomach acid through
a simple reaction to form water and a neutral salt. They have no systemic effects. In addition
to their acid-neutralizing ability, antacids may benefit patients by decreasing pepsin activity,
binding to bile acids in the stomach, and stimulating local prostaglandin (e.g., PGE2) synthesis.
2-Sodium bicarbonate acts both locally and systemic.
V-Drugs affecting the gastric movement
1-Drugs increase the gastric movement
a-Vagal stimulants
1-Vagal center (as digitalis) 2-vagal ganglia (as nicotine) 3-vagal endings (as
pilocarpine)
b-Gastric irritants as Mustard

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 2-Drugs decrease the gastric movement
1-Central depressants as general anesthetics
2-Vagal depressants as nicotine (large doses)
3-Depressant of vagal endings as atropine
4-stimulation of sympathetic endings as adrenaline
5-depressant of sensory nerve endings as cocaine
6-mechanical protectives as insoluble salts of calcium
7-morphine
N.B…in ruminants, the reflex closure of the esophageal groove enable the fluids to
enter the omasum and abomasums directly. 1 % copper sulphate or sodium bicarbonate
10 % stimulate this reflex.

VI-Emetics
Emetics are drugs which induce vomiting or emesis. Vomiting is a reflex act
controlled by a center in the medulla. It used to remove toxic material or removal of
foreign body. Emetics are classified according to their action into:-
a-Central emetics:
These are drugs which stimulate the vomiting center through their action on CTZ.
They are effective in small doses given by injection.
Apomorphine: It acts on the CTZ and produce emesis in 10 minutes. It is given by S/C.
Therapeutic and large doses of apomorphine are CNS depressants.
b-Local or reflex emetics:
These drugs which stimulate the sensory nerve endings in the stomach and
duodenum.
i-Copper or zinc sulphate and sodium chloride 1 % solution: These produce emesis in
few minutes.
ii-Ipecacunha: It contains the alkaloids emetine and cephaline to which it owes its
emetic properties. Emetine produces vomiting in 30 minutes. In sub emetic doses, it is
used as expectorant.
iii-Tarter emetic (Antimony potassium tartarate).

VII-Antiemetics
These are drugs which relieve vomiting. They are classified according to their
mode of action into:
Central:
i-Hyoscine: acts by depressing the vomiting center and labyrinth and their
antimuscarinic activity depressing the motor nerve endings in the mouth and stomach.
ii-Antihistaminics: act on vomiting center.
Diphenylhydramine  (benadryl); Dimenhydrinate  (Dramamine)
iii-Phenothiazine derivatives: They act on CTZ only.
e.g. largactil (chlorpromazine) and phenergan (promtheazine)
iv-Barbiturates: They depress CNS including CTZ and vomiting center.
b-Peripheral:
i-Protectives, adsorbants and demulcents act (e.g. Acacia, Tragacenth and pectin) by
coating the gastric mucous membrane.

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ii-Local anaesthetics as cocaine and Butacaine act by depressing the gastric movments
as ateopine.

VIII-The effect of drugs on the reticulo-ruminal movements

Treatment of ruminal stasis has centered on the administration of ruminotoric drugs
these drugs which were though to stimulate reticulo-ruminal contractions. It seems
likely that ruminotoric drugs may be helpful in the patient suffering from chronic or
prolonged subacute indigestion, induced or at least complicated by such conditions, as
traumatic gastritis, ketosis, refractory parturient paresis.
i-Physostigmine salicylate, U.S.P.(eserine salicylate)
This drug inhibits cholinestersse, which normally destroys A.ch. A dose of 30 to
45 mg of physostigmine salicylate injection S/C stimulate activity within 10 minutes
after the injection and lasted for an hour.
ii-Neostigmine methylsulphate, U.S.P.:
This synthetic derivative of physostigmine has a similar action upon the GIT and
is free of the undesirable side effects upon the heart and lungs.
iii-Carbachol, U.S.P. (lentin carbamylcholine chloride):
This drug is a synthetic derivative of A. ch. It stimulates both tone and motility of
the reticulo-ruminal musculature. The most favorable results in the cow from carbachol
follow the injection of 1 to 3 mg S/C the best results are obtained by repeating this small
dose at intervals of 30 to 60 minutes for two or three doses, if necessary. A single large
dose in the treatment of mild ruminal stasis is usually unsatisfactory. Large doses of
carbachol ranging from 4 to 8 mg. Markedly depress the rumen musculature and
stimulate the large intestine, which results in frequent defecation.
N.B. The treatment of severe and chronic rumen stasis requires repeated premeditation
with water, sugar and oils before carbachol is administrated.
After premeditation of chronic cases for two to three days. Carbachol should be
administrated in small repeated doses.
iv-Arecholine hydrobromide NF:
Small doses of this drug 4 to 8 mg stimulate reticulo-ruminal movements where
as large doses 15 to 30 mg inhibits the motility of the rumen in cattle. In sheep, archoline
causes only inhibition in a dose of 10 mg
v-Strychnyne, N.F.: Nux vomica used as rumenotonic drug in a dose of 3 mg.
vi-Antimony and potassium tartarate, U.S.P. (Tarter emetic):
It used in a dose of 8 to 10 mg orally.
vii-Barium chloride:
Not recommended because of the great danger of producing fatal cardiac block.
viii-Veratrine:
Intravenous of 5 mg Veratrine hydrochloride markedly stimulates the rumen in
sheep, beginning with 20 minutes and lasting for nearly two hours.

IX-Ruminal bloat
The excessive accumulation of gases within the rumen, bloat usually accompanies
rumen stasis. Severe bloat can lead to rumen stasis from over distention of the reticulo-
ruminal musculature. The traditional approach to the problem of treating bloat in

135
ruminants has consisted of promoting the escape of gases followed by the oral
administration of the antiferments and oils.
a-Antifermentative drugs:
These are agents where believed to decrease the bacterial metabolism in the
ruminal chamber and thereby to decrease the amount of gas produced by bacterial
fermentation.
e.g. choral hydrate (20-30 mg), ethyl alcohol (30-60 ml) in water.
b-Antizymotics:
These are drugs which kill or inhibit the rumen bacteria, leads to stopping
fermentation and consequently gas production.
e.g. Formalin 4 ml in 300 ml water, Turpentine oil 15-90 ml., Low concentration of
copper sulphate, Antibiotics as tetracyclines and streptomycin.
c-Carminatives:
These are drugs which facilitate the expulsion of gas from stomach They include:
Volatile oils as oil of turpentine, Volatile drugs as ether or alcohol, Ammonia
preparations as spiritus ammonii aromatics or spiritus etheri nitrosi.
d-Antifrothing agents:
These are drugs which increase the surface tension of the reticulo-ruminal fluid
and promote the escape of gas bubbles from throughout the ingesta.
e.g. cooking oil and turpentine oil. Silicons (Dimethicone).
Control of frothy bloat:
i-Spraying the pasture with antifrothing agents as mineral oil.
ii-Patent prepaeations must be added to drinking water such as pluronics (L 61-L64),
bloat quard (propaxolone, SKF) and Manoxol OT.

X-Digestants
These are drugs which are used for helping digestion. They include:
a-Diluted Hcl. b-Stomachics.
c-Pancreatin tablets that contain extracts. It is used in case of pancreatic enzyme
deficiency.

Drugs acting on the intestine

The drugs which diminish the secretions are of little practical value. Alkaloids
administered after meals decrease the pancreatic secretions and vagal depressants as
atropine diminish both pancreatic and intestinal secretions but have no influence on the
out of bile.
1-Intestinal absorption:
a-Drugs accelerate intestinal absorption: as volatile oils, pungents and alcohol.
b-Drugs retard absorption: as purgatives. astringent drugs by precititation the proteins
in the superficial cells of the villi. It is of importance that mechanical protectives to the
mucosa such as the insoluble salts of bisthmus, kaolin and powdered charcoal, will
hinder the absorption of toxins formed by bacteria.
2-Transmission of the intestinal contents:
Drugs which affect transmission of the intestinal contents are laxatives, purgatives
and astringents.
a-Laxatives

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 These drugs which facilitate the bowels and cause a soft motion without gripping
e.g…liquid paraffin that lubricate the intestinal mucosa in small dose and Mg sulfate in
small dose used as laxative. Methycellulose (bran) is suitable laxative for horse.
b-Purgatives
These are drugs which cause rapid rate of passage of digesta along the alimentary
tract. The purgatives include:-
I-Lubricant purgatives:
These act by softening the faces and lubrication, facilitating its passage. e.g. liquid
paraffin (Mineral oil).Liquid paraffin is non irritant and non absorbable. It acts by
lubrication and increasing the bulk.
Disadvantages of liquid paraffin:
1-Paraffin tends to leak through the anal sphincter. 2-Paraffin interferes with the
absorption of fat soluble vitamins. Dose: 10-30 ml.
II-Bulk purgatives:
These are drugs which cause stimulation of peristalsis by increasing the bulk of
the intestinal contents.
e.g.-Colloids and fibers:
1-Agar agar: Agar swells in the presence of H2O to form gel which is not absorbed
enhance peristalsis and facilitate evacuation . Dose: 1-4 gm. Suitable for dogs and cats.
2-Methylcellulose:
3-Bran:Contains 20%cellose used as laxative for horse.
III-Saline purgatives:
Mode of action of saline purgatives:They are salts not readily absorbed, therefore, it
maintains the osmotic tension of the content of the intestine thus prevent the absorption
of H2O as well as withdraw water from blood and other neighbouring tissues to the
inteastinal leumen increasing fluidity and bulk of the intestinal contents lead to
augmented peristalsis and more rapid transmission of the contents into the colon. This
responds to the bulky fluid mass by exhibited more active contractions, so that
evacuation soon occurs of stool, first of normal consistence and then of a profuse watery
character.
Thus it may cause a temporary heamconcentreation. When prescribed in this way, saline
purgatives may taken ten or mare hours to act.The commonly used saline purgatives are
Mag. sulphate is recommended for ruminants (sheep and cattle), and Sod. sulphate is
recommended for equines.
Magnessium Sulphate: It does not used in equines increase as delayed purgation may
result in absorbtion of Mg and heart block and death .Dose in ruminants250-500gm
Sodium Sulphate: It is saline purgative of chioce in equines.
IV-Irritant purgatives
a-Mild irritant purgatives:
These are drugs which produce mild irritation of the intestinal mucous membrane
and thus reflexly increased peristalsis and a more rapid transmission of the fluid
contents into the colon. They usually produce one or two soft, formed stools
unaccompanied by griping after 8 to 12 hours.
1-Castor oil: Contain ricinolic acid on hydrolysis by lipase into irritant sodium
ricinoleates, which mildly irritate small and large intestine enhance peristalsis. Castor
oil can irritate the colon and cause pelvic congestion.

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2-Sulphur acts as a mild purgative because it is convertedin intestine into alkali sodium
sulphides which are mild irritant to intestine.
b-Moderate irritant purgative
1-Anthracene purgatives:
They called anthracene purgatives,they contain anthraquinone(emodin and
crysophanic acid) combined with sugars to form glycosides that is absorbed and slowly
hydrolyzed rleasing irritant principle emodin or crysophanic acid in large intestine,
The irritant effect is exerted first in the colon, where they reflexly increase peristalsis
and cause varying amounts of griping, colic and pelvic congestion. e.g. Aloes ,Cascara,
Rhubarb, and Senna. They produce soft stools with moderate griping after 6-10 hours.
2-Phenolphthaline (Ph.ph.):Ph.Ph. given orally in dog and cat.It under goes hydrolysis
in presence of bile and sodium to form sodium phenolphthalinate which irritate intestine
and reflexly augments peristalsis causing purgative effect.
3-Mercurial purgatives:
e.g. Calomel (insoluble Hg salt).
Mode of action: when given the insoluble preparations, small amounts of soluble
albuminates are formed and these stimulate peristalsis in both the small and large
intestines with the result that in 4-8 hours a soft bulky stool is evacuated, usually without
much gripping. After large doses, the action may followed by several watery stools.
N.B…The mercurial purgatives have a special value in that may posses an antiseptic
action in the intestine.
c-Sever irritant purgative(Catheratics or Hydragogue or drastic purgatives):
e.g. Jalop, Scammony, Colocynth and Podophylum.
Mode of action:
These drugs contain glycosidal resins which in the alkaline intestine in presence
of lipase and bile, are hydrolyzed with liberation of irritant glycosides, owing to their
powerful irritant properties they greatly accelerate and augment peristalsis so that the
fluid contents of the intestine are hurried rapidly into the colon and discharged from
there before adequate time has elapsed for their concentration of water. They produce
effect within 2-6 hours, a copious watery stool, purgation is accompanied with griping,
coic and straining.
N.B. The term (Drastic purgatives) is applied to those which cause severe irritation in
increased secretion and congestion of the intestinal mucosa, resulting in increased
secretion of mucus or even catarrh inflammation, and repeated evacuation of liquid
stool accompanied with colic and straining.
V-Neuromuscular (hypodermic) purgatives
a-Stimulate the vagal receptor: e.g. pilocarpine, carbacol, arecholine
Mode of action: in the use of these drugs must be no mechanical obstruction, their use
in such conditions may be very dangerous. These drugs excite powerful peristaltic
movements and increased intestinal tone and secretion accompanied with gripping.
b-Increase the reflex excitability of Aurbach's plexus: e.g. Nux vomica, strychnine
Mode of action: it is merely increases the reflex responses of the intestine.
c-Direct stimulation of the smooth muscles of the intestine: as pituitrin
Enema
Solutions of NaCl or soap administrations per rectum to stimulate defecation.
Warm of glycerin enema is used for dogs and cats, or glycerin suppository can be used.

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 Intestinal sedatives
These are drugs which exert a sedative action on the intestine. They are classified
into:
a-Mechanical protectives: as insoluble salts of bismuth, kaolin and calcium
action and mode of action: they protect the intestinal wall from irritation by forming
over the mucosa a physical coating and thus they decrease reflex peristalsis, they are
therefore used in full dosage before meals to treat diarrhea.
b-Vagal depressants: they are drugs which paralyse vagal receptors, lower intestinal
tone and check spasmodic contractions without interfering the normal peristalsis. They
are valuable to check gripping or colicy pain e.g….atropine, hyoscyamine, hyoscine
and drugs containing them as belladonna, hyoscymus and stramonium.
c-Sympathetic stimulants: these are drugs which arrest for a short period the intestinal
movement but contract the sphincter e.g…adrenaline, tyramine and ephedrine.
N.B…it is not of practical value as it produce other side effects on other organs.
d-Reflex depressants: they decrease reflex peristalsis, delay the transmission of the
contents and induce constipation beside their contracting the pylorus and ileo-caecal
sphincters e.g…morphine, diamorphine and codeine.
e-Muscular depressants: volatile oils and chloroform exert a direct depressant action on
the intestinal muscles.

Intestinal astringents
These are drugs which act locally by precipitating the proteins in the superficial
cells of the mucous membrane and thus they check mucous secretion forming
protective coating decrease peristalsis. They includes:-
a-Metallic astringents: as lead acetate, soluble salts of iron, silver, alum and copper.
b-Tannic acid astringents: krameria, kino, catechu, albumin tannate and acetyl tannic
acid. They are crude vegetable drugs containing tannic acid

Intestinal antiseptics
(for treating bacterial infections)
a-Sulphonamides : as sulphaguanidine, sulphasuxidine and sulphathalidine are of
value in treating bacillary dysentery and other intestinal infections as they are hardly
absorbed from intestinal mucosa.
b-Antibiotics: as terramycin, streptomycin and chloramphenicol are of value against
intestinal bacteria. If antibiotics are given for long time, vitamins must be given
c-Amoebic dysentery treated with emetine, chinofon and acetarsol
Intestinal anthelmintics
For tapeworms, hook worms and thread worms in the chemotherapy
Drugs acting on the liver
Liver: is an important organ, the secretion of which (bile) is of significant value in
digestion
I-Drugs influencing bile secretion
1-Cholagogues: are drugs which increase the flow of bile such as:
a-Parasympathomimetics:by contracting the gall bladder and relaxing the sphincter of
oddi.

139
b-Cholecystokinin hormone:presence of fats in the duodenum leads to released this
hormone which contract the gall bladder
c-Mg sulphate 33 % (hypertonic solution)…..contract the gall bladder
d-Bile salts…..as dehydrocholic acid
2-Anticholagogues: are drugs which decrease the quantity of the bile secreted as opium
and lead acetate.
3-Choleritics: are drugs which stimulate the liver to excrete bile as Vitamine B12 or
secretin hormone which stimulate the bile secretion by the liver
---------------------------------------------------

140
Pharmacology Of
Urinary System

141
 Pharmacology of the urinary system
Renal function:
The kidneys are a major element in the regulation of the internal environment of
the body. Their contribution is in the regulation of the volume and composition of the
body fluids by : 1-they eliminate non volatile waste, ingested foreign substances and
desirable substances present in excess. 2-they play a major part in regulating the acid-
base balance and osmolarity and volume of the body water. Nephron in the kidney
induce filtration, secretion and resorption, each can modulated by drugs.
The tubule cells perform active secretory and resorptive functions and allow the
passive diffusion of solute in the direction appropriate to its concentration or
electrochemical gradient. Active transport systems in the non-luminal walls of the
tubule cells pump Na+ out of the cell into the renal interstitium and in this way create a
gradient which favors the movement of Na+ from the ultrafiltrate into the cells.
Hydrogen ions are transported into the filtrate along the whole nephron. The
proximal tubule resorbs about 80 % of the fluid and solute filtere at the glomerulus. It
absorbs all the glucose and amino acids, most of K+ and bicarbonate and much of Na+
and Cl-.
The resorption of water is passive and allows the osmotic gradient established by
active resorption of Na+ or Cl- in different segments of the tubule. Fluid resorption into
the interstitium is aided by the osmotic pressure of the plasma in the peritubular
capillaries along the length of the nephron. The filtrate leaving the proximal tubule is
more less isosmotic with interstitial fluid, as filtered water and chloride ions have
passively followed the actively resorbed Na+. at this stage more Na+ reabsorbed in
exchange for actively excreted H+ and NaHCO3 is about 90 % accompanied by water.
About 80 % of K+ and phosphate resorbed and the filtrate reduced to 20 %.
The descending limb of the loop of henle is permeable to water, while the
ascending limb is relatively impermeable. NaCl resorption by the ascending limb is
such that the filtrate entering the distal tubule is hypotonic and represents 10-15 % of
filtered volume. In the distal tubule further active resorption of Na and passive
resorption of Cl- occurs. The distal tubule under the control of ADH.

Antidiuretics
Some drugs have the ability to slow the rate of formation of urine as adverse action
e.g….by reducing B.P., by causing vasoconstriction in the kidney. By increasing output
of ADH.

Antidiuretic hormone (ADH):

This hormone non a peptide is synthetized in the supraoptic and paraventricular
nuclei of the hypothalamus and migrates in the storage granules to the neurohypophysis.
The signal for ADH discharge originates in the hypothalamic osmoreceptors which
react to the composition of the blood or baroreceptors which react indirectly to the blood
volume. The hormone causes marked. The synthetic hormone of ADH is called

142
vasopressin. Its physiological function is to increase the permeability to water of the
distal tubule and collecting ducts.
Mode of action:
The ADH act by increasing water permeability of the optic membrane of epithelial
cells. This action is accompanied by an increase in the intracellular cAMP
concentration.
ADH output is depressed by:
Ethanol or large water intake and glucocorticoids. PGE and F2α are released by
kidney cells and can diminish the effect of ADH on collecting duct permeability.
Diabetes insipidus occurs when ADH output is inadequate for genetic, pathological or
traumatic reasons.
Dose: vasopressin tannate in oil of about 0.2 units/kg. few drugs can inhibit ADH action
e.g…demeclocycline

DIURETICS
Diuretics are substances which increase the quantity of urine and electrolytes
excreted in a given period. Most diuretics increase urine volume by reducing the
efficacy of sodium resorbing processes and so increase obligatory water loss. Diuretic
drugs classified according to mechanism of action into:

Glomerulus Proximal Distal

Convoluted Tubule Convoluted Tubule H+ K+ Na+

Isotonic
Carbonic
Anhydrase-
Dependent Aldosterone- Collecting
NaHCO3 Dependent (5) and Duct
H2O
Reabsorption Independent (6) ADH-
Na+ Reabsorption
CORTEX Isotonic Responsive
NaCl and NaCl via Na+-Cl–
H2O Coupled Water
Transport Reabsorption
OUTER Diluting
MEDULLA Sites NaCl via H2O
Na+-K+
Water
Impermeable
3
Membrane
INNER C
HO HO ADH-
MEDULLA
H2O Responsive
Water
Reabsorption
Loop of Henle

Figure:( ) Functional for regulation of salt and water transport in an ephron.

Source:Thier1987.Reproducedwithpermission of Taylor & Francis.

143
1-Drugs acting on the cardiovascular system:
a-digitalis and xanthine derivatives b-colloidal plasma expanders
c-glucocorticoids in shock therapy
2-Osmotic diuretics (saline and non saline)
3-Inhibition of the re-absorption of sodium
a-organic mercurials b-carbonic anhydrase inhibitors c-thiazides
d-loop diuretics e-potassium sparing diuretics f-acidifying
agents…………urinary alkalizers
4-Simple diuretics
They inhibit the release of ADH from posterior pituitary e.g…water and ethyl
alcohol.  ADH   HOH reabsorption  HOH excretion

Cardiovascular diuretics
The 2 groups of cardiovascular diuretics are the cardiac glucosides (digitalis and
strophanthus) and xanthine derivatives. Cardiac glycosides can act on Na+/K+-ATPase
in the kidney. The extent to which this contributes to increased urine flow is not known.
Xanthines
Theophylline being the most mild diuretic.
Mode of action:
The diuretic effect arises from both extra-renal and renal action. Myocardial
stimulation and vasodilatation occur and are of value in edema of cardiac origin because
renal blood flow improve with theophylline, tubular reabsorption of Na+ and Cl- is also
diminished. The xanthines were used in combination with more potent, more toxic
agents such as the mercurials. Contraindicated to use as diuretic due to CNS stimulant
and arrythmogenic capabilities of xanthines.
Dose: aminophylline 10 mg/kg orally for 3 times/day for dogs.

Osmotic diuretics
I-Intravenous administration of isotonic or hypertonic solutions
Of which are nither metabolized nor reabsorbed, e.g…mannitol, glucose and urea
results in the appearance and persistence in the ultrafiltrate of osmotically active solutes
in increased concentration. The increased rate of flow of this dilute filtrate through the
nephron appears to reduce the absorptive and concentrating abilities and diuresis occur.
Drugs and doses:
1-urea…is unattractive as a drug substance and would be digested if given to ruminants
by oral route….12 gm for dogs
2-mannitol….must be given i.v. The dose for dog sol. 20 % 1-2 mg/kg.
II-Electrolyte osmotic diuretics:
The more powerful, more clinically effective diuretic is common use act by a
primary suppression of the ability of the kidney to reabsorb sodium. The increased loss
of Na+ is called

Mercurial diuretics
A-Organic mercurials: means mercury is bounded to an organic group e.g…Mersalyl
(salyrgan)

144
B-Inorganic mercurials: calomel or mercurous chloride. Not used today. But organic
mercurials used today as it prioduce less damage
Mechanism of action:
1-reduce tubular reabsorption of Na+ lead to increase Na+ in the filtrate and osmotically
decrease water reabsorption.
2-minute quantities of mercuric ions are realeased intracellularly. An increase in cellular
acidity enhances, alkalosis inhibits this release
3-it act on tubule cells by tying up sulphhydryl group of enzymes vital to furnishing
energy for the active transport of Na+
4-results is increased excretion of water, Na+ and Cl-
5-It induce synergistic action with ammonium chloride and theophylline. But
antagonized by alkalinizing salts or systemic alkalosis. Decreased loss and increased
accumulation of bicarbonate in the blood produces the alkalosis
Toxic effects:
Excessive use lead to electrolyte imbalances. High levels leads to necrosis of kidney
tubular cells. High levels induce cardiac arrythmias and ventricular fibrillation
***Contraindicated in renal insufficiency and nephritis.

Carbonic anhydrase inhibitors

e.g…acetazolamide-diamox
Acetazolamide chemically related to sulphonamides, well absorbed when used
orally and used IM
Mechanism of action:
1-inhibition (non-competitive) of tubule cell carbonic anhydrase enzyme (CA). also
inhibit CA of the eye
2-it resulted in less Na+ reabsorption, also less water reabsorption
3-it enhance K+ excretion by substitution of K+ intracellular for Na+
4-bicarbonate is trapped in urine and less returned to plasma

***Acetazolamide is eliminated unchanged in the urine. It has ability to reduce

intraocular pressure by inhibiting the rate of aquous humor formation

Benzothiazidine (Thiazides)

Thiazides synthesis as trials to improve duration of action of carbonic anhydrase

inhibitors so thiazides usefully moderate diuretic effect.
e.g…..chlorothiazides, hydrochlorothiazides and bendrofluazide
Pharmacokinetics:
After absorption, distribution occur extracellular fluids and bind to RBCs and
plasma proteins. Elimination occur both glomerular filtration and tubular secretion. The
drugs are active after one hour of oral administration and persist long enough to make
once daily dosage.
Mode of action:
The thiazides act as diuretics by inhibiting the reabsorption of Na+ and Cl- ions
mainly in the anterior distal convoluted tubule. Specific cellular mechanism is not well
understood but may include transport system inhibition as well as slight carbonic

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anhydrase inhibition. The excretion of Na+ can be such as to cause hyponatraemia. This
stimulate the release of aldosterone.
The advantage of thiazide diuretics (low toxicity and long duration of action).
Their usefulness is diminished in the presence of impaired renal function. Treatment
should be such as to allow the thiazides to enhance both the therapeutic and toxic actions
of the digitalis glycosides.
Dosage and administration:
Parentral / day……horse (100-200 mg iv or im), cow (100-250 mg iv or im), small
animals (12.5-25 mg im)
Oral / day………….horse and cow (500 mg initially followed by 250 mg), dog
and cat (1.25-2.5 mg/kg b.wt.)

Potassium sparing diuretics

e.g…spironolactone, aldosterone
chemically it is steroid, is an analogue of aldosterone
Mode of action:
The drug is competitive antagonist of aldosterone. It has no action in an
adrenolactomized animal. It increase excretion of Na+ and water but decrease excretion
of K+
Loop diuretics
e.g…furosemide, lasix, disol, diuride. The drug used for dogs, cats and horses. It
resemble the sulphonamide chemically.
Action and mode of action:
Inhibit tubular reabsorption of Na+ in the nephron but is primiraly is the ascending
limb of loop of henle. This may account for a high degree of efficacy and the rapid onset
and less water reabsorbed. These effects leads to excretion of Na+, Cl-, K+ and water.
Also the formation of volume of isotonic and less electrolytes loss urine per volume of
urine is increased. No effect on carbonic anhydrase activity also bicarbonate excretion
not altered
Pharmacokinetics:
The drug well absorbed from oral and parentral routes. Rapid onset of action 10-
20 min after iv or im and within 1 h after oral administration. Rapid renal excretion,
unchanged. Poor lipid solubility and no cumulative effect. Actively secreted into
tubules and excreted. The drug has a short duration of action, oral 5-6 hours, iv 3-4
hours.
Dosage:
a-Lasix…given iv to horse….4 ml dose (produce 4 liters of urine/40 min), 10 ml dose (produce
9 liters of urine/1 h), 40 ml dose (produce 21 liters of urine/2 h)
b-Furasemide…..given to horses 2 mg/kg iv.

Acidifying diuretics
e.g…ammonium chloride which:-
absorbed from GIT. It is converted by liver to urea and HCl which ionizes to H+
and Cl-. H+ combines with bicarbonate buffer to form carbonic acid which converts to
CO2 + HOH or H+ is excreted giving acid urine. CO2 is expired off and Cl- is left in

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extracellular fluid. Increased Cl- load to the tubules leads to escape reabsorption of Cl-
accompanying with amounts of cations (Na+) and osmotic amount of water are excreted.

Urinary alkalizers
1-sodium bicarbonate, acetate and citrate and potassium salts are effective equally but
more toxic. It is considered as osmotic diuretic.
2-acetate and citrate radicals are metabolized but excreted as bicarbonate which gives a
strong alkaline reaction to the urine
3-alkalization of urine increases the antibacterial activity of aminoglycosides in urinary
tract infections
4-urinary alkalizers make sulphonamides are more soluble so help in its excretion and
avoid the damage of the kidney from crystalluria. Also bicarbonate increase the rate of
excretion of salicylates and other weak acids by favoring their dissociation in
ultrafiltrate.
5-the alkalization of dog urine prevent recurance of cystine or urate stones.

Clinical applications of diuretics

Diuretic drugs are used to remove excess extracellular fluid (edema) such as:
increased B.P., decreased in plasma osmotic pressure, inflammation and traumatic
swelling, increased plasma levels of aldosterone, chronic renal insufficiency, chronic
liver diseases, congestive heart failure, lymph flow impairment, nutritional deficiencies
especially protein and endocrine disorders.

Urinary antiseptics

The urinary antiseptics are alternatives to sulphonamides and antibiotics. They are
used when bacterial resistance excludes the antibiotics. Examples:-
1-Hexamine:
It has the action of diuresis and urinary antiseptic. It make the urine pH below
5.5. hexamine slowly decomposes releasing ammonia and formaldehyde.
Formaldehyde exerts an antibacterial action. The drug is irritant to GI and urinary
tracts and may produce vomiting, albuminurea and haematurea.
Dose:…50 mg/kg b.wt. orally for all animals
2-Mandelic acid:
e.g….ammonium and Ca mandelate
It has antibacterial activity in the urine as pH below 5.5. ammonium and
Ca salts are self-acidifying compounds. Mandelic acid is irritant, not used more
than 14 days at a time.
Dose:….250 mg/kg b.wt. Ca mandelate for dog and cat.
3-Nitrofurantoin:
It is yellow nitrfuran. It is a broad spectrum bactericidal. In acid urine it is effective
against most urinary tract pathogens.
Pharmacokinetics:
well absorbed from the gut. about half is excreted unchanged.
Toxicity:

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 It cause vomiting, hypersensitivity reactions and damage to peripheral nerves. It
cause yellow coloration of permanent teeth.
Dose: for dog…4 mg/kg b.wt. 3 times daily
4-Nalidixic acid
It has antibacterial activity but bacterial resistance occurs. Its action not markedly
depends on pH. Its side effects are GI and/or CNS disturbances. Renal insufficiency is
contraindication for nalidixic acid.
Dose:…15-50 mg/kg b.wt every 24 h in divided doses for dogs
N.B…..old urinary antiseptics (historical) such as volatile oils and oleoresin (oils of
sandal wood and Buchee…etc) are now obsolete.

Uricosurics

These are drugs that stimulate uric acid excretion and treating pains of rheumatism
such as gout.
Mode of action:
They act by inhibiting xanthine oxidase enzyme such as allopurinol, inhibiting
uric acid re-absorption from renal tubules such as probenicid and are anti-inflammatory
drugs as colchicines.
Urinary sedatives

These are drugs which are used to induce sedation in the urinary tract by overcome
the filtration. These effects can occur by:
a-Remove the cause by using urinary antiseptics if the cause was infective agents
b-Changing the pH of urine using alkalizers as Na bicarbonate or acidifiers as
ammonium chloride that arrest infective agents multiplication or growth leading to
sedation.
c-local anesthetics e.g…tincture belladonna and spiritus etheris nitrosi.

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 Pharmacology Of
Reproductive System

149
 Pharmacology Of Reproductive System
The drugs acting on reproductive system are gonadotrophin releasing hormones,
gonadotrophins, sex hormones, ecobolics and uterine relaxants

Gondothrophine releasing hormones (GnRH)

It is a neuropeptide secreted from the hypothalamus transported via portal

circulation to the anterior pituitary attach to gonadotrophin secreting cell
receptors increases secretion of FSH and LH.

Synthetic forms of GnRH:

1-Gonadorelin
2-Fertirelin acetate (fertagyl), more potent than gonadorelin with 2.5-10 times.
3-Bruserelin (Receptal), more potent than fertirelin 10-20 times.

Therapeutic uses:
Induction of ovulation. Treating of cystic ovarian diseses (e.g granulose cell
tumour in bitch). Stimulate follicular development. Increasing libido in male dog
and tom cat at a dose of 2.2 mg/kg b.wt I/M once weekly for a month before
breeding season. Diagnostically to test the secretory ability of pituitary gonadal
axis.

Gonadotrophines

These are glycoprotein hormones secreted from anterior pituitary gland

under control of GnRH secretion from hypothalamus which is regulated by feed
back inhibition by sex steroids in plasma. They include:

1-Follicle stimulating hormone (FSH):

Which stimulate follicular development in female and sperm development
in male.
2-Luteinizing hormone (LH or ICSH):
LH in female is responsible for final maturation of the ovum, ovulation and
corpus leutum formation. ICSH (interstitial cell stimulating hormone) in male
stimulates leydig cells to secrete androgen hormone.
Gonadotrophines are secreted from tissues other than pituitary like placenta
or chorion. There are 2 types:

a-human chorionic gonadotrophines (HCG)…it is produced by chorion and

excreted in urine of pregnant women with mixed activity but mostly LH.

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b-Pregnant mare's serum gonadotrophines (serum gonadotrophines)
(PMSG)…it is secreted from endometrium of pregnant mare, reach serum at 50-
80 days of pregnancy . of mixed activity but mostly FSH.

N.B…urine of postmenopausal women is a source of FSH activity.

Mechanism of action of gonadotrophines:

The gonadotrophines act via specific receptors in gonadal tissue in ovary.
LH binds to receptors on surface of thecal cells, CL and large follicle granulose
cells, while in testis binds to leydig cells. FSH binds to surface of small follicle
granulose cells and sertoli cells in testis, this binding leads to increase
intracellular cyclic AMP increase mitochondrial enzymes that cleaves the side
chain of cholesterol which is the limiting step in conversion of cholesterol to
pregnenolone.

Indications (therapeutic uses):

1-Mare: Failure to come in estrus
a-mare with follicle: was given HCG 1500-3000 IU by S/C or I/M repeated after
2-3 days or SG 2000 IU I/M daily for 4 days repeated the treat after 14 days.
b-mare in an estrus with smooth or inactive ovaries: was given 3000-6000 IU S/C
or IM followed by 1500-3000 IU CG at time of service.
c-Nymphomania in mare: CG 1500-5000 IU I/V repeated after one month.
2-Male horse:
a-Cryptorchidism in foal LH 1500-5000 IU via IM twice weekly for 4-6 week
b-Inactive stallion administered LH to stimulate production of testosterone
c-Impaired spermatogenesis: SG 3000 IU by IM twice weekly for 3-6 weeks

3-Cattle:
a-Subestrus, ovulatory failure and early non specific abortion weekly IM for one
month dose 1500-3000 IU.
b-Nymphomania with cystic ovaries 1500-3000 IU I/M repeated after month. C-
Cryptorchidism in yearling calves HCG give 5000 IU by IM promote descend of
testicles.
d-Lazy bull 5000 IU, Im of CG.
e- Impaired spermatogenesis 1000-3000 IU SG possibly with equal dose of HC
twice weekly by IM for up to 6 weeks.
f-To induce superovulation single 2000 IU of PMSG.

4-Sheep and goats:

1-induction of superovulation to produce twining using SG single dose of 500-
1000 IU IM 12-15 day of the 3rd week of the cycle
2-cryptorchidism, impaired spermatogenesis and lack of libido as in other species
using 500 IU of CG
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3-induction of estrus using 1000 IU SG given IM repeated after 24 h., then 500
IM of CG at the day of service

5-In dog:
1-induction of ovulation with 500 IU SG via IM and repeated after 2 days
2-induction of estrus with 200 IU SG daily for 3 weeks followed by 300 IU of
CG at the day of service
3-failure of lactation treated with 500 IU CG IM repeated after 24 h
4-cryptorchidism is treated CG 500 IU twice weekly for 6 weeks
5-sluggish dog is given CG 400-800 IU IM twice weekly for 6 weeks

Toxicity:
Toxicity of FSH:
Over stimulation of the ovary can lead to uncomplicated ovarian
enlargement which may be resolved spontaneous or pass to hyperstimulation
syndrome characterized by ovarian enlargement, ascities, hydrothorax,
hypovolaemia even shock, hemoperitonium from ruptured ovarian cyst, fever,
arterial thrombosis and uterine cancer
Toxicity of LH:
Depression, edema, precocious puberty, rarely production of antibodies to
HCG it contraindicated in androgen dependent neoplasia and precocious puberty.
Sex hormones

All naturally produced androgens, estrogen and progesterone are steroid

synthesized in the body from steroid nucleus (cyclo pentane perhydro
phnanthrene nucleus) steroids can be derived from cholesterol via progesterone
which provides a common root for example:
Progesterone 17 α-hydroxylase testosterone

Androgens

Is the male sex hormone. The most potent is testosterone secreted from
interstitial cells of the testis (but in small amounts by the ovary& adrenal cortex
in both sexes) under influence of ICSH from anterior pituitary (responsible for
male sex characters "maleness")

Mechanism of action:
The testosterone 5α reductase 5 α dihydrotestosterone in target cells which
binds to cytosol androgen receptors target cells initiating series of events leading
to growth differentiation and synthesis of variety of enzymes and other functional
proteins.
Toxic effects of androgens:

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1-edema,retention of water and salts
2-jaundice especially with methyltestosterone was the first member discovered to
cause cholistatic hepatitis and jaundice.
3-hepatic carcinoma especially with 17 α alkyl substituted androgen for long
period
4-virialism in female, appearance of secondary male sex characters
Synthetic androgens:
1-methyltestosterone….is derivative of testosterone resistant to hepatic
metabolism with longer half-life. Can be given orally. Toxicity long duration of
administration may cause hepatic and renal failure. It is used as replacement
therapy in hypogonadism and to treat osteoperosis.
2-Fluoxymesterone and oxandrolone….they are anabolic steroids with a ratio of
androgenic to anabolic activity 1 : 1 used to promote weight gain after surgery or
chronic infection
3-Danazol….it is synthetic derivative with antiestrogen, weak androgen and
progestational activity mainly used to treat endometriosis but it is tratogenic not
used in pregnancy
Actions of androgens:
1- Appearance of secondary sex characters.
2-Aggressive male behavior.
3- Positive nitrogen retention, increase growth of muscle and body weight.
Increase bone growth.
4-Androgen is required for spermatogenesis.
Therapeutic uses:
1- Mammary gland tumor in bitch.
2- Pseudo-pregnancy in bitch 1-2 implant of 50 mg given s/c to be active for 70
days.
3- Oestrus suppression in bitch and queen cat.
4- Alopecia of hormonal origin.
5- Balanitis in castrated lamb and yearling sheep.
6- Cryptorchidism which has failed to respond to CG will sometimes respond
to testosterone especially when hypogonadism is also present.
7-lack to sex drive in adult stud animals
8-feminization in pubertal dogs
9-prevention of urethral calculi in castrated male cat
Dosage of androgens:
Bitch:methyltestosterone (5-30 mg daily in divided doses), testosterone
propionate (2.5 mg every 2-3 days), testosterone phenylpropionate (5-10 mg
every 7-14 days), implants (25-2x50 mg or exceptionally "mammary tumors" 100
mg 3x 100 mg).
Queen cat: methyltestosterone (5-10 mg daily) tosterone propionate (5 mg every
2-3 days), testosterone phenylpropionate (10 mg every 10-14 days), implants (50-
2x50 mg).
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Stallion and Bull: tosterone propionate (25-50 mg twice weekly), testosterone
phenylpropionate (20-25 mg every 7-10 days), implants (2x100-5x100 mg).
Ram, goat and boar:tosterone propionate (10-20 mg twice weekly), testost-erone
phenylpropionate (10-20 mg every 10-14 days), implants (25-2x50 mg).
Dog: methyltestosterone (5-30 mg daily or alternate days in divided doses)
tosterone propionate (2.5-5 mg twice weekly), testosterone phenylpropionate (5-
10 mg every 7-14 days), implants (25-2x50 mg).
Cat:methyltestosterone (5-10 mg daily) tosterone propionate (2.5-5 mg twice
weekly), testosterone phenylpropionate (5-10 mg every 7-14 days), implants (25-
2x25 mg).
Anti-androgens
There are several androgen antagonist used in treatment of prostatic cancer.
They act through inhibition of LH secretion, inhibition of testosterone synthesis,
inhibition of DHT synthesis by inhibiting the enzymes which give rise to the
active steroids and competing with endogenous androgens for their receptors.
a-Gonadotrophin releasing hormone analogues:
The continuous administration of GnRH reduce LH secretion and reduce
testosterone production by testis e.g…leuprolide used in treating prostatic cancer
b-Androgen synthesis inhibitors:
e.g…ketoconazole is antifungal inhibits cytochrome P450 enzymes including
those involved in steroidogenesis and also reduce corticosteroid synthesis
c-Androgen receptor antagonists:
1-Flutamide: it is steroidal drug compete with testosterone for androgenic
receptors. Used for treating prostatic cancer. Side effects produce gynecomastia
and reversible hepatic toxicity.
2-Cyproterone: steroidal androgen receptor antagonist used to reduce excessive
sex drive in male.

Oestrogens
It is a female sex hormones secreted from ovarian follicles and by placenta
in female and in small amounts by the testis (Leydig cell) in male under control
of gonadotrophines and by the adrenal cortex. Naturally occurring oestrogens are
oestradiol, oestriol and oestrone.

Actions:
1-responsible for development and maintenance of secondary sexual
characteristics of the female
2-increase the motor activity of the uterus and prime it for the action of oxytocin
3-increase growth of the duct system of mammary gland and maintain lactation
4-responsible for physical signs of oestrus
5-closure of epiphyseal plates of bones leading to cessation of longitudinal bone
growth

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6-anabolic activity causing retention of salts, water and nitrogen but less than
androgen
7-increase the coagulability of the blood.
Synthetic oestrogens:
Stilbosterol, dienosterol, methallenosterol and hexosterol
Therapeutic uses:
Treating pyometra. Induction of abortion and parturition. Treating prostatic
cancer. Anabolic in cattle and poultry to increase weight gain. Contraceptive
**Dose…..10-30 mg IM in large animals
Side effects of stilbosterol:
Rectal and vaginal prolapse. Abortion in cattle. Rarification of bone and pelvic
fracture in cattle.
Anti-estrogens
These are drugs which antagonizing the effect of estrogen. They include:
1-Clomiphene
Antagonizing estrogen at receptors in the hypothalamuic, pituitary and
ovarian. It increase secretion of Gonadotropin secretion caused increase FSH and
LH secretion and thereby induce follicular development and ovulation. Used to
treat anovulatory disorders.
Adverse effect…increase incidence of twining.

2-Tamoxifen
It is estrogen antagonist at estrogen receptors. Used for treatment of breast
cancer with positive estrogen receptor. Adverse effect…vaginal bleeding and
proliferation of endometrial cells.

3-Raloxifen
It is selective estrogen receptor modulator. Antagonizing receptors at both
breast and uterus.

Progesterone
It is hormone secreted from corpus leutum to maintain pregnancy, large
amounts are secreted by the placenta and can be synthetically prepared.
Actions:
Predispose the uterus for implantation of zygote. Increase thickness of
uterine wall. With help of oestrogen cause development of mammary gland.
Inhibit the effect of oxytocin on uterine muscle. Suppressive for LH secretion
from anterior pituitary.
Therapeutic uses:
Treatment of threatened or habitual abortion in animals. Suppression of
estrus in bitch. Synchronization of oestrus.
Synthetic progesterons

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 Are very potent and can be given orally….megesterol, medroxy
progesterone. Dose…50-100 mg in large animals.
Anti-progesterone
They are synthetic steroids act as progesterone receptor antagonists. Used
for induction of abortion in first trimester e.g…mifepristone
It senstitises the uterus to the action of prostaglandins.
Drugs influencing uterine contractility
Uterine stimulants
These are drugs which stimulate the uterine contraction either at term
(ecobolics) or induce parturition before full term (abortificients). They include:
a-Ergot alkaloids:
Are produced by claviceps purpurea fungus infecting rye grains or grass.
They was discovered as a cause of poisoning resulting in prolonged
vasoconstriction, gangrene and sloughing of extremities ergotism. They contain
ergometrine, ergotoxin and ergotamine
Ergometrine
Is the most powerful ergot alkaloids as uterine stimulant and cause abortion
during pregnancy although it is no longer favored to use ergometrine during
parturition as it may result in spasmodic contraction of the uterus and delays
parturition but it is used to cause rapid involution of uterus, control postpartum
hemorrhage and aid expulsion of retained placenta.
Methylergometrine
Is powerful ecobolic lacks vasoconstricting effect. Dose of ergometrine
maleate as tablet or injection is 10-20 mg (horse and cow), 0.5-1 (sheep and pig),
0.2-1 mg (dog) and up to 0.125 mg (cat).
b-Oxytocin
Is a hormone secreted from posterior pituitary (with vasopressin or
antiduiretic hormone), its release is greatly increased by afferent impulses which
originates from dilating the cervix or anterior vagina.
Action:
1-it causes powerful frequent uterine contraction at term and thus complete the
stage 2 of labor. The myometrium must be previously sensitized by estrogen
through controlling polarization of cell membrane of uterine muscle
2-oxytocine has a role in letdown of milk being released as response to suckling
by contracting smooth muscle fibers around the milk acini
3-synthetic oxytocine is free from pressor effect.
Therapeutic uses:
1-Uterine inertia with normal position& presentation of fetus and cervix is dilated
enough to hasten fetal expulsion.
2-Retained placenta and delayed involution of the uterus.
3-Uterine prolapse injected in uterine wall to facilitate its replacement.
4-After cesarean to speed involution and control bleeding.

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5-Functional agalactia to help letdown of milk.

Dose IM IV
Horse and cow 10-40 2.5-10 IU
Sheep, goat and pig 2.5-10 0.5-2.5 IU
Dog 1-10 up to 0.5 IU
Cat 0.5-5 IU

c-Prostaglandins
PGF2α is a powerful inducer of uterine contractions i.e it is ecobolic,
synchronization of estrus cycle by induction of luteolysis. The natural PGF2α is
rapidly inactivated with short half-life 1-3 min, synthetic analogues with extended
duration of action and restricted activity e.g…dinoprost tromethamine: induce
parturition in late pregnancy, the effect appear after long period after injection.
However of value in fetal over size or malformation.
Induction of estrus in subestrus lactating cow cloprostenol (synthetic PG)
given IM 500 mg also can terminate pregnancy 7-150 day, resolution of
pyometra. Cloprostenol may given as 2 treatments with 11 day interval. In mare,
fluprostenol administered as single IM injection of 250 mg for treatment of
infertility with persistent corpus luteum or in location anestrus.
Indications of ecobolics:
1-Uterine inertia with normal position presentation and dilated cervix.
2- Flaccid postpartum uterus to help its involution.
3- To control postpartum hemorrhage.
N.B.: many substances may have ecobolic action as drastic purgatives,
neuromuscular purgatives…..etc.(indirect or reflex uterine stimulant )

Uterine spasmolytics (relaxant or sedative)

These are drugs which relax the uterus and used in case of threatened
abortion, correction of fetal presentation or position or during embryotomy.
They include:
1-perphenazine and heroin: they directly relax the myometrial muscles and the
response is enhanced by pregnancy.
2-isoxuprine: it is non catecholamine mixed β adrenergic agonist used as uterine
relaxant, resist MAO and COMT enzymes thus has long duration of action. It is
given at a dose of 0.5 mg/kg in all species. Onset of effect after 15 min and lasts
for 2h.
3- Progesterone, atropine , asprine and barbiturate.
Side effects: tachycardia, peripheral vasodilatation and muscle tremors
3-clenbutrol: mainly used as bronchial dilator (β2 agonist in horse but in can
impede the uterine muscle contractility)

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 Cervical dilators
These are drugs which relax the birth canal especially when inadequately
dilated at birth.
1-proquamezine: a phenothiazine derivative with smooth muscle relaxing effect.
It is given by slow IV every 24 h
2-fenpiprane and fenipipramide: they are used to control server coordinated
uterine contraction, given by IM route. The effect occur after 15 min. if there is
no effect could be repeated after 30 min.

158
 Pharmacology
Of
Endocrine System

159
 Pharmacology Of Endocrine System
Definition

1-Endocrine gland : is a gland secreting active materials (hormones) in a very small

amount directly into the blood stream.

2-Hormone : is a messenger control the functions of tissue and organs or is a specific

chemical stimulus released in a very small amounts into the blood stream by an
endocrine or ductless gland

*The endocrine system is composed of the thyroid gland, ovaries, testicles, pancreas,
adrenal glands and other glands that produce hormones.

The negative feed-back mechanism

All endocrine systems are regulated by a feed-back mechanism in much the same
way as the temperature inside a house and a thermostat regulate the activity of a furnace.
In a house, the furnace produce heat until the thermostat detects that the interior
environment is warm enough and sends a signal that turns off the furnace. This signal
from the thermostat to the furnace to stop or inhibit its heat production is called negative
feed-back mechanism.

Pituitary gland

Pituitary is the master gland, under control of releasing hypothalamic hormones.

It secretes trophic or tropic hormones which control the functions of all endocrine
glands.

I-Anterior pituitary hormones (Adenohypophysis)

Definition:

*The adenohypophysis is a polypeptide hormones that stimulate the activity of other

endocrine glands secrete at least seven poly peptide hormones, four of which stimulate
the secretory activity of other endocrine glands.

They includes:

A-(1-4) stimulate other endocrine glands

1-Follicle stimulating hormone (FSH) 2-Lutenizing hormone (LH) or interstitial

stimulating hormone (ICSH) 3-Thyrotrophin hormone (TSH) 4-Corticotrophin
(ACTH)

160
B-(5-7) the hormones produce their effects directly at their appropriate targets

5-The growth hormone (GH) 6-Prolactin ….. see reproductive system

7-Melanocyte stimulating hormone (MSH), also known as intermedin

1-Growth hormone (GH) (Somatotrophin )(STH)

Definition

*GH is a polypeptide has molecular weight around 22000. In man GH has 191
aminoacid residues and a single chain containing two disulphide cross links

Actions

*The main action stimulate growth

*Other actions of GH: 1-increase protein synthesis (anabolic action) 2-Promote amino
acids uptake and favours a positive nitrogen balance (growth promoters in cattle acts as
GH) 3-GH elevate glucose levels in the blood 4-GH increase plasma free fatty acids 5-
GH stimulate synthesis of the growth factors by liver and kidneys called somatomedins
A 6-It stimulate other somatomedins DNA synthesis

Mode of action of GH

Growth hormone acts in part indirectly in that it stimulates the synthesis of agents
called somatomedins by the liver and kidneys. These growth hormone dependent factors
are of unknown chemical structure. Somatomedin A, also known as sulphation factor,
is involved in the sulphation of chondroition and is an important anabolic agent in
cartilaginous growth. Other somatomedins stimulate DNA synthesis, glucose and
amino acid transport into cells, and may be responsible for the continued effect of pulse
released GH.

Therapeutic uses of GH

1-Treatment of pituitary dwarfism

2-As meat growth factor in animals but its side effect is diabetogenic

2-Prolactin *See reproductive system

3-Melanocyte stimulating hormone (MSH) or intermedin

Chemical structure

α MSH…is a 13 amino acid residue poly peptide chain

161
β MSH…contain 18 residues

Source

These hormones are found in the anterior and posterior pituitary extracts

Action

*Their function is stimulation of melanin synthesis in melanocytes. Both a releaser

(MSH-RH) and a release inhibitor (MSH-RIH), a tripeptide in cattle) exist. The
darkening of skin color in lower animals is achieved by MSH activity. Melatonin, a
hormone released by the pineal gland, causes skin lightening by aggregation of
melanophores i.e. by opposing the melanophore dispersing action of MSH. Melatonin
has been used in attempt to treat acanthosis nigricans in the dog at a dose of 2 mg
subcutaneously at 2-day intervals for 8 days then 2 mg for two weeks.

4-Thyrotrophic hormone (TSH)

Thyrotrophic hormone (TSH) is a glycoprotein with a molecular weight of about

30000. It stimulate the thyroid gland to secrete thyroid hormones.

Mode of action

It acts at the membrane of thyroid cells, probably via adenylate cyclase. It

increases the metabolic activity of the cells, including the synthesis and release of
thyroid hormones. Both hypertrophy and hyperplasia follow lengthy exposure of the
gland to TSH.

Control of secretion

The adenohypophysis secretes TSH in response to a hypothalamic releasing

hormone (T-RH). While this is influenced in a feed-back mechanism by thyroid
hormones overall regulation, as with other trophic hormones is more complex and
allows of other inputs such as temperature T-RH output is increased in response to low
temperature via a neuronal input at the T-RH secretory cells. This response can be
reproduced with noradrenaline or dopamine and inhibited by 5-HT. T-RH is a
tripeptide, active by mouth or intravenously and also causes the release of prolactin.
The physiological significance of this finding is obscure, because prolactin and TSH.
Concentrations do not normally increase in phase because GH-RIH (Somatostatin) can
inhibit the release of TSH by T-RH it is possible for T-RH to bring about the release of
prolactin alone.

Therapeutic uses of TSH

1-As test for thyroid function 2-Treatment of hypothyroidism

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 5-Follicle stimulating hormone (FSH) and Luteinizing hormone (LH)

*See reproductive system

6-Corticotrophin (ACTH)

*It is 39 amino acid containing poly peptide hormone with interspecies variation.

Actions and mode of action

ACTH stimulate the middle and inner zones of the adrenal cortex to synthesize
glucocorticoids. Primarily cortisol and corticosterone. Aldosterone production by the
outer layer is little influenced by the pituitary. ACTH action causes a rise in intracellular
cyclic AMP concentration, this is followed by a number of changes, including the
increased synthesis of enzymes active in steroid biosynthesis and the provision of co-
factors. In this way ACTH increases the mitochondrial conversion of free cholesterol to
pregnenolone, the rate limiting first step in steroid biosynthesis. This reaction also
requires ascorbic acid, Ca++, oxygen and NADPH. The cholesterol is derived from
storage esters, again under the influence of ACTH which is able to increase the
gucocorticoid content of adrenal vein blood in minutes. This rapid response is
compatible with the absence of a glucocorticoid storage mechanism and the dependence
of steroid plasma concentrations on direct negative feed-back regulation.
Adenohypophyseal ACTH output is stimulated by a hypophyseal corticotrophin
releasing factor, C-RH, a 41 amino acid in sheep is itself is released in response to
hypoglycemia and stress of all kinds. Thus the CNS enables the adrenal cortex to fulfill
its function of increasing the ability of the body to withstand stress and also produces
the circadian rhythm in plasma glucocorticoid concentrations.

Synthetic preparation

(Tetracosactrin) consists of 24 amino acid sequence, can be used without antigenic

hazard. Natural ACTH is prepared by extraction of pituitary glands. Its half-life is about
15 minutes and so to obtain extended action depot preparations (in gelatin) are available
for intramuscular injection.

Uses

1-ACTH used in Addison's disease in dogs

2-Measuring plasma cortisol level at 30, 60 and 90 minutes after ACTH administration

3-A primary pituitary deficiency is detectable by plasma ACTH assay alone by assay
following the insulin induced hypoglycemia

Adrenal gland

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 The adrenal (supra-renal) glands secrete a group of hormones essential for life and
can be classified into :

1-Cortical hormones :

*secreted from adrenal cortex and include 2 main groups :-

a-Mineralocorticoids

-Are responsible for regulating electrolyte balance

-e.g…aldosterone…its secretion is regulated by rennin angiotensin system

b-Glucocorticoids

-Principally act on carbohydrate metabolism

-e.g…cortisol…regulated by ACTH from anterior pituitary

-it is powerful glucogenic and anti-inflammatory

-hyperactivity of adrenal cortex produce cushing syndrome while hypofunction causes

disease

2-Adrenal medulla is the site of synthesis, storage and release of adrenaline which is
fully discussed in autonomic nervous system

Effect of corticosteroids :

*Mineralocorticoids act on the kidney to increase reabsorption of sodium, chloride and

water and increase loss of potassium, phosphate and calcium *Mechanism of action
involves synthesis of protein in target cell may be the sodium carrier itself

*Overdose of glucocorticoids posses significant mineralocorticoid effect

*Physiological dose of glucocorticoids enhance water excretion by increasing

glomerular filtration and decrease water reabsorption

*Glucocorticoids increase gluconeogenesis (i.e. production of glucose from non

carbohydrate by deamination of amino acids and increase urinary nitrogen output)

*Glucocorticoids induced hyperglycemia accompanied by decrease uptake of glucose

and resistance to insulin

*Glucocorticoids favor lipolysis and thus provide glycerol for gluconeogenesis

*Long term administration of glucocorticoids causes muscle wasting and redistribution

of fat

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*Immunity of the body is decreased by glucocorticoids. Lympholytic response is a
reduction in size and activity of lymphoid tissues and a diminution of count

*Decrease antibody production and eosinophil count

*Depress acute inflammatory response, prostaglandins synthesis, cellular infiltration,

exudation, fibrosis and wound healing

Mode of action

1-Steroid hormones are bound partly to albumin mainly to a transport protein (in the
case of cortisol, a globulin called transcortin). This complex release the steroid at
appropriate cells where the steroid enters. Inside the cell the steroid reacts with a
specific receptor protein in the cytoplasm. This complex after a conformational changes
enters the nucleus. Within the nucleus the complex interacts with an acceptor and
becomes attached to a chromatin protein. In this position the synthesis of proteins is
influenced by an action which increases the transcription of mRNA leading in the liver
to the synthesis of enzymes involved in the gluconeogenesis and glycogenesis. In the
adrenal medulla, the synthesis of the enzyme convert adrenaline into adrenaline is
stimulated by corticosteroids. In other tissues such as skin, the glucocorticoids causes a
reduction in DNA synthesis and cell division.

2-Other mechanisms of action for steroids have also been proposed including the
involvement of cyclic amp production. The inhibition of prostaglandin synthesis is
believed to take place at the level of phospholipase, the enzyme which fees arachidonate
from membranes as the first step prostaglandin biosynthesis

Synthetic steroids

1-Hydrocortisone 2-Prednisone 3-Prednisolone 4-Methyl prednisolone

5-Flumethasone 6-Dexamethasone

Therapeutic uses of glucocorticoids

1-Treatment of bovine ketosis in dairy cattle and pregnancy toxemia in sheep

2-Stress, trauma and shock 3-Inflammation of eye, skin and joints

4-Hypersensitivity reactions 5-Lymphoma as they have lympholytic action

6-Induction of parturition

Contraindication

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1-Late pregnancy especially for C16 methylated corticosteroids except in pregnancy
toxemia
2-Deep corneal ulcer or other wounds after surgical operation as it retard healing

3-Cardiac insufficiency as they have depressive effect on circulatory system

Dosage

1-Prednisolone

-large animals….100-200 mg i.m daily

-small animals….2-20 mg i.m initially followed by oral therapy (dogs 0.5-1 mg/kg
b.wt. daily by moth while in cats 1 mg/kg b.wt. daily by mouth)

2-Dexamethasone

Parentral…-Horse, cattle: 10-30 mg., Foal, calf, sheep, goat and pigs: 2-5 mg.,

Dog: 0.5-2 mg., Cat: 0.25 -0.5 mg

Intra-articular…-Large animals: 2-10 mg

Peri-articular….-Small animals: 0.25-5 mg

Oral….-Small animals: 0.25-5 mg

These daily dosages should be divided. Initial doses may be maximum or near
maximum but once symptoms are controlled doses should be reduced to maintenance
levels quoted doses are guideline figures only and should in each case by adjusted
according to the circumstances

Steroid inhibitors

a-Hyperaldosteronism as a primary or secondary feature occurs in man. It can be treated

with a spironolactone a competitive antagonist of aldosterone

b-Dichlorodiphynyl dichloroethane (DDD) is a drug which can cause destruction of the

adrenal cortex in dogs or suppression of glucocorticoid production at lower dosage. It
is also known as mitotane, as it is closely related to DDT.

c-Amphenone B is a rather toxic drug which is able to block the β hydroxylation of

pregnenolone and so inhibits steroid biosynthesis.

Metyrapone prevents the 11 β-hydroxylation of the immediate precursor of

cortisol. It is used to suppress glucocorticoid output so as to induce the pituitary to

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release ACTH, in a test to distinguish between primary and secondary adrenal
hypofunction

Thyroid gland

It is an endocrine gland consists of two lobes lies on both sides of larynex joined by
isthmus anteriorly. The extract of thyroid gland contains thyroid hormones, thyroxine
(T4) and tri-iodothyronine (T3) which is more potent than thyroxine.

Thyroid hormones synthesis

The thyroid follicle cells contain vesicles of non iodinated thyroglobulin which
rupture release thyroglobulin (TG) into follicular lumen, the iodide diffuses down
concentration gradient and oxidized by thyroid peroxidase enzyme to iodine then
combines with tyrosine of thyroglobulins forming mono and di-iodotyrosine units and
tri-iodothyronine is formed by combination of one monoiodo tyrosine and one di-
iodotyrosine.

Secretion of thyroid hormones

(TSH) a glycoprotein hormone produced by anterior pituitary stimulate synthesis

and secretion of thyroid hormones in a feed-back manner to the hypothalamus and
pituitary (Figure 3).

Metabolism of thyroid hormones

1-Liver conjugates T4 to glucuronides and sulphate which are excreted in bile

2-De-iodination of thyroid hormones using de-iodinase enzyme (require selenium for

activity0 which is present in liver, kidney, muscle, thyroid, CNS, placenta and skin.

The iodine is recycled in thyroid hormones synthesis where the de-iodinated metabolic
products are of no thyromimetic activity

Physiological and pharmacological action of thyroid hormones

1-Thyroid hormones are anabolic in physiological level working in conjunction with

growth hormone, insulin and protein synthesis but it is catabolic in hyperthyroidism.

2-Increase heat production and oxygen consumption by stimulating Na,K-ATPase in all

tissues except brain, spleen and testis (i.e. increase BMR).

3-Essential for growth and maturation hence hypothyroidism cause dwarfism and
impaired mental development

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4-Increase glucogenolysis and gluconeogenesis i.e. insulin antagonistic activity, also
increase synthesis and degradation of cholesterol and stimulate lipolysis with releasing
of free fatty acids and glycerol

5-Necessary for normal hair skin turn over

6-On myocardium, causing direct positive inotropic effect, myocardial hypertrophy and
increase responsiveness to adrenergic stimulation

7-Stimulate the synthesis of many protein associated with normal nerve and activity,
thus hypothyroidism cause myopathies

8-Hypothyroidism decrease GIT motility

9-Essential for normal reproductive cycling. Hypothyroidism cause reproductive

disturbances, infertility, lack of libido, testicular atrophy and hypospermia

10-Hypothyroidism reduce phagocytosis of W.B.Cs

11-Increase erythropiosis and 2,3 diphosphoglycerate content of RBCs (increase O2

dissociation from Hb at the tissue)

12-Thyroid hormones influence normal secretion and metabolism of hormones.

Hypothyroidism cause glactorrhea due to increased prolactin secretion

Synthetic thyroid hormones

Thyroxine sodium (T4)

It is synthetic posses the same activity of thyroid extracts but 0.1 mg is

approximately equal in activity to 60 mg of the dried extract. After oral administration
of thyroxine, half the dose is absorbed and cause increase in metabolic rate, increase
carbohydrate metabolism causing depletion of liver glycogen. Also  catabolism of fat
and protein. It increase urinary salt, nitrogen and water. Increase sensitivity of
cardiovascular system to catecholamine

Liothyronine sodium (T3)

It has more rapid onset of action, shorter duration and more potent

Toxicity

*Overdose will cause symptoms of thyrotoxicosis include :

-increased pulse rate, cardiac irregularities, restlessness and sleepless, osteoperosis, loss
of weight and higher body temperature

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Therapeutic uses

1-hypothyroidism or thyroid deficiency including hairless calves, hairless piglet, big

neck, goiter and myxoedema

2-poor color of coat, obesity and edema

3-nymphomania in female cattle, loss of libido and depressed spermatogenesis in ram,

boar and bull

4-bilateral alopecia in dogs

Dosage

1-Acute foetal iodine or thyroid deficiencies is given sodium or potassium iodide 1

mg/kg b.wt. orally. Thyroid hormones 1-2 mg/kg b.wt. in all species

2-Adult hypothyroidism rarely to occur. given thyroxine 1-2 mg/kg b.wt.

Iodine deficiency

Deficiencies of thyroid hormones and iodine are inter-related and have been
shown to occur widely, causing considerable economic losses in herbivorous species,
carnivorous species and birds. Clinical manifestations take the form of goiter and are
most apparent in young animals. Animals may be born dead after prolonged gestation
or completely without hair or edematous and with enlarged thyroid glands. Canine
thyroid tumors and immune diseases that attack the thyroid gland usually result in
primary hypothyroidism because the thyroid tumor cells are destroyed. The thyroid can
not produce T4 and T3 regardless of how much it is stimulated by TSH. Goiter result in
hypothyroid condition caused by lack of iodine in the diet. Hairless calves and piglets
are perhaps the most common examples of hypothyroidism but sheep, goats, horses,
dogs, cats and birds may all be similarly affected.

Adults may be affected but the condition is then less spectacular and takes the
form of unthrift ness, loss of coat color and character and sometimes sterility (in male
and female), with loss of sex drive in the male. Goiter may be due directly to iodine
deficiency or may be associated with the goiterogenic effect of substances in the diet
thiocyanates, possibly from linseed or clover, substances in Kale and possible
goiterogens in other foods.

Mineral supplements usually contain about 0.03 % of potassium iodide or the

more stable iodate (especially suitable or tropical climates)

*Daily doses of such a supplement should be :

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-milk cattle (45-140 g), other adult cattle (60-180 g), calves (30-45 g), brood mares
(60-120 g), other horses (60-90 g), ewes (15-22.5 g), lambs (5-10 g), sows (60-120 g),
store and other pigs (30-60 g), laying hens (220-400 g per 100 birds), chicks (30-60 g
per 100 birds) and older chickens (90-160 g per 100 birds).

*Salt licks should contain about 0.05 % potassium iodide

Antithyroid drugs

*Drugs used to treat hyperthyroidism

Definition

-Hyperthyroidism is an increase in circulating concentrations of thyroid hormones. It is

common in cats and it is associated with a hormone secreting thyroid tumor

-Hyperthyroidism in cats is best treated by thyroidectomy or by injection of radioactive

iodine which destroy the tumorous thyroid tissues

-Radioactive iodine kills the tumor cells as appeared to methimazole which only
controls hormone production without destroying tumor itself

1-Goiterogenes of plant origin

These are chemical compounds in some plants that inhibit the thyroid peroxidase
enzyme (TPO)….e.g.

a-Plants of genus Brassica e.g rutabaga, cabbage and turnip

b-Broccoli and rape seed plants contain glucosinolates which are metabolized to
thiocyanate, inhibitors of thyroid iodide uptake and organification

c-Cassava, lima beans and sweet potatoen contain cyanogenic glucoside metabolized to
thiocyanate

2-Thioureylenes and thionamides

The thyroid organification and coupling steps are sensitive to inhibition by

antithyroids thioureylenes and thionamides which block thyroid hormone secretion also
they are actively concentrated in thyroid gland where they inhibit synthesis of thyroid
hormone in the following steps:

i-block incorporation of the iodine into the tyrosyl groups of thyroglobulin

ii-block the coupling ofiodotyrosyl group to for T3 or T4 direct interaction of with

thyroglobulin molecule 1 and 2 mediated through inhibition of (TPO).

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 Thioureylenes drugs commonly used in veterinary medicine are propylthiouracil
and methamizole after initiation of the treatment there is delays in formation of serum
thyroid hormones level until depletion of glandular store. Also block conversion of T4
to more active T3.

Side effects of propylthiouracil

1-Anorexia 2-Vomiting 3-Lethergy 4-Development of positive antinuclear antibody

titer 5-Development of autoimmune hemolytic anemia 6-Development of
immune mediated thrombocytopenia

Methimazole (Tabazole)

Is now the antithyroid drug of choice that has been used to control
hyperthyroidism in cats by blocking the thyroid tumor's ability to produce T3 and T4.
These drugs block the incorporation of the iodine into the thyroid hormone molecule.
But the drug can not destroy T3 and T4 molecules.

*It is given at dose of 5 gm TID…will return the serum T4 concentration to normal

within 2-3 weeks

*Serum half-life of 4-6 weeks

*Bioavailability 45-98 % and intra-thyroid residence time 20 hours

Side effects

-occur in 20 % of cats, vomiting, anorexia, lethargy, bleeding, hepatopathy,

thrombocytopenia, agranulocytosis, leucopenia, positive antinuclear antibodies

Carbimazole

It is carbthoxy derivative of methimazole, rapidly and completely metabolized to

the parent drug responsible for antithyroid activity. It is used in the treatment of feline
hyperthyroidism. Nonthioureylene antithyroid agent

I podate

It is a radiographic contrast used in treatment of feline hyperthyroidism at a dose

of 15 mg/kg b.wt. twice daily

Radioactive iodine (131I)

It is the most effective and appropriate treatment in bilateral toxic goiter in cats.
It has 8 days half-life

Calcitonin
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 This hormone originates mainly in parafollicular C-cells of the thyroid gland.
Procine calcitonin is a single-chain polypeptide of 32 residues which contains one
disulphide bridge. It is pre-formed and released in response to hypercalcemia and exerts
a hypocalcemic and hypophosphatemic effect. This is achieved by depressing the
resorption of bone, perhaps by opposing the action of PTH which increases cyclic AMP
concentration. The function of calcitonin seems to be the rapid control of
hypercalcemia. It is accompanied by hyperphosphaturia. However, the precise
contribution of calcitonin to the maintenance of normocalcemia has yet to be agreed up
on

Calcitonin is available for use in man, where it finds application in suppressing

the bone resorption of disease and in the treatment of hyperparathyroidism and vitamin
D poisoning.

Parathyroid gland - Parathyroid hormone (PTH)

Parathyroid hormone is water soluble parathyroid gland hormone for

subcutaneous or intramuscular administration. It contains not less than 100 parathyroid
units per ml., the unit being defined as 1/100 of the amount necessary to raise the
calcium content of 100 ml of the blood serum of normal dogs by 1 mg within 6-18 hours
after administration. A synthetic parathormone (PTH) analogue is now also available.

Action and uses

The parathyroids participate in calcium hemostasis by modulating the synthesis

and release of PTH in response to plasma Ca++ concentration. They respond to low
plasma Ca++ by secreting parathormone (PTH) which soon promotes active inorganic
phosphate and calcium absorption from the intestine, followed by their mobilization
from bone. PTH stimulates osteoclastic bone resorption and so elevates blood calcium
levels, while calcitonin inhibits bone resorption and so corrects hypercalcemia. In the
kidney, PTH acts rapidly via adenylcyclase activations to decrease phosphate resorption
in the proximal tubule, increase calcium resorption in the distal tubule and increase the
renal conversion of vitamin D to its active form (1,25-dihydroxy cholecalciferol). hours,
with a return and should reach a peak in about 18 hours, with a return to normal levels
approximately 24 hours after injection. In acute hypocalcemic tetany, calcium solutions
are requird because the delay before the onset of the effect of PTH unacceptable.

Lack of sufficient parathyroid activity causes the reverse of the above effects and
as the level of blood calcium falls, muscle and general nervous irritability increases until
the convulsive threshold is reached.

In hyperparathyroid states, the hormone causes a considerable increase in

calcium and phosphate excretion, low serum phosphate and continuous calcium

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mobilization. In chronic cases, decalcification of the bones calcium levels are
approximately doubled and the blood phosphate concentration also rises. Soft tissue
metastatic calcification occurs, with eventual death from renal failure. Treatment is
surgical.

Parathyroid extracts are unsuitable for oral administration, as digestive enzymes

destroy the majority of any dose. It is recommended to given via subcutaneous or
intravenous injections of 2-15 USP units for a dog. Owing to its effects on phosphate
and its side effects, use of PTH in therapy should be confined to hypoparathyroidism.
Even then, vitamin D, which appears to mediate the action of PTH, offers an acceptable
alternative when combined with a high calcium diet.

In the treatment of experimentally induced hypoparathyroidism, it has been found

that antibodies against parathyroid extracts develop and so the effect of a standard dose
progressively reduced.

The endocrine pancreas (Islets of langerhans)

The pancreas plays a role in both endocrine (hormone) and exocrine (digestive
enzyme) functions of the body

*There are three types of cells:

1-β cells secrete polypeptide hormone (insulin) blood glucose elevating hormone

2-α1 cells release somtostatin which inhibit the release of growth hormone from
hypothalamus

3-α2 cells secrete single chain polypeptide hormone (Glucagon) opposes the action of
insulin

Insulin

It is specific antidiabetogenic secreted from β cell of islets of langerhans. The

major effect of insulin is to move glucose from the blood into tissue cells. Insulin also
causes the liver to store glucose as glycogen and facilitates deposition of fat in adipose
tissue. The net effect of insulin is to decrease blood glucose concentrations by
enhancing distribution of glucose to body tissues. Lack of insulin results in diabetes
mellitus, a disease characterized by high blood glucose levels or hyperglycemia and
passage of glucose in the urine or glucosuria.

Insulin is standardized by bioassay to contain 20, 40 or 80 active units/ml. It is

rapidly absorbed from site of injection produce maximum effect within three hours.
More rapid effect achieved by I/V or I/M than by S/C. It is inactivated by
gastrointestinal enzymes when given orally.
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Types of insulin

A-Classified by their duration of activity as shown in table (1) into

1-Plain insulin….short duration, effective for 8 hours and should be given twice daily

2-Insulin zinc protamine or globin zinc insulin (40 or 80 unit/ml) -intermediate duration,
effective for 48 and 24 hours, respectively

3-Insulin lent with high amount of zinc, reduce the solubility of insulin -delay the onset
and duration of action between plain insulin and protein insulin complex reach 18-24
hour given once daily by s/c injection. long acting

B-Classified according to species from which insulin is derived

-beef, pork or genetically engineered human type insulin

-N.B…Table (1) show comparison of types of insulin for dog and cat.
Table (1): Comparison of types of insulin used for dog and cats

Insulin type Route of Onset of effect Duration of Duration of

administration effect (dog) effect (cat)

Regular IV Immediate 1-4 hr 1-4 hr

Crystalline IM 10-30 min 3-8 hr 3-8 hr

SC 10-30 min 4-10 hr 4-10 hr

NPH SC 0.5-2 hr 6-18 hr 4-12 hr

Lente SC 0.5-2 hr 8-20 hr 6-18 hr

Ultralente SC 0.5-8 hr 8-24 hr 6-24 hr

PZI SC 0.5-4 hr NA 6-20 hr

Adapted from Feldman EC, Nelson RW: Canine and feline endocrinology and reproduction, Philadelphia, 2004, WB saunders.

Action

*insulin binds firmly to receptors with anticyclic AMP effect, increase the rate of entry
of glucose, amino acids and potassium ions into most cells reverse hyperglycemia of
diabetes mellitus.

Therapeutic uses: 1-in diabetes mellitus in dog 2-acetonemia in cattle and pregnancy
toxemia in sheep besides the glucose therapy

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Dose: The optimum dose size depends on the severity of islet dysfunction. The glucose
is taken as reference adequate dose is that just eliminate or reduce glucosuria. The dose
interval varies according to the type of insulin for insulin lent 6-12 hour.

Orally active hypoglycemic drugs

These are drugs which reduce the blood glucose level when given orally by
stimulating insulin secretion so they have no effect in pancreatectomized animals.

Sulphonylurea (e.g. glipizide) which is

-sulphonamide with hypoglycemic effect even in normal animals.

-It may be short acting as Tolbutamide

-or long acting as Chloropropamide because it is not metabolized

-starting with 20-100 mg/kg b.wt. dosage is stabilized after 2-4 days at minimum level
which exclude glucose from urine

-stimulate additional insulin production by pancreatic beta cells, increase binding of

insulin to peripheral tissueinsulin receptors or enhance the cellular response to insulin

Glucagon

It is a plypeptide hormone secreted from α2 cells of islets of langerhans. Its action

on energy is opposite that of insulin. Glucagon release is enhanced by stress, starvation,
hypoglycemia and exercise producing glcogenolysis, glucon-eogenesis and lipolysis. It
is used therapeutically as glucagons hydrochloride for correction of insulin coma

Other drugs to control diabetes and drugs to avoid

Glucocorticoids as prednisone and dexamethasone

-mobilize glycogen stores, elevate blood glucose levels and interfere with insulin
receptors, inducing hyperglycemia in a diabetic animal.

Thiazide diuretics

Phenothiazine tranquilizers such as acepromazine

Progesterone Adrenaline

175
Pharmacology
Of
Integumentary
System
(Skin)

176
 Pharmacology of the skin
Function of the skin :
1-The skin is an organ of excretion and help in regulating the body temperature.
Excretion by the skin confined to the sweat glands. Water excreted in sweat aids in
regulating the body temperature. The sweat glands are excretory glands for water, salts
and to slight extent for nitrogenous products. Nervous control for the sweat gland by
sympathetic but cholinergic nerves with centers in the spinal cord. They respond to
drugs as if they possess parasympathetic nerve.
2-The cutaneous tissue, owing to their rich supply of sensory receptors are used in
therapeutics as a medium from which effects, mainly of a reflex type, can be produced
upon the CNS by means of counter irritations, baths and massage.
In small animals skin conditions make up a disproportionate section of the diseases
presented for treatments. The symptoms include dermatitis with irritation, eczyma.
Infection or allergy may induced from allergy to foetus, and parasitic mange due to
sarcoptic or demodectic mange mites, and dermatomycosis.

Drugs acting on the skin are classified as follows :

1-Diaphoretics or sudorifies
Definition : These are measures increasing the amount of perspiration, but those which
cause profuse sweating are sometimes called sudorifies. The horse is the only animal
will well developed sweat glands. Cattle and sheep do not possess them to any extent.
Dogs and cats have sweat glands only in the pads of their feet.

**Diaphoreses may be produced in the following ways :

A-By directly increasing the secretory activity of the sweat glands :
i-Stimulation of the sweat glands
a-directly by pilocarpine, arecholine and eserine.
b-indirectly as by emetics
ii-Stimulation of the sweat center in the spinal cord
a-directly as camphor and in poisoning with strychnine
b-indirectly, stimulation of the heat regulating center as by central antipyretic and
salicylates
c-reflexly in the afferent nerves of the mouth, throat and stomach can be used to
stimulate the sweat center reflexly as by hot drinks or by emetics
iii-Stimulation of the afferent thermine nerves in the skin as by hot weather

B-By action on the circulation in the skin:

i-locally, irritation of the sensory nerves of the skin as by counter irritation which
produce dilatation of the cutaneous blood vessels

ii-systemically:
a-indirectly, in case of rise of B.P (alcohol) dilates B.V.
b-directly: nitrites dilate the cutaneous B.Vs
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c-the vessels are dilated by paralysis of the constrictor mechanism
e.g….ergotoxin in large doses

**Therapeutic uses:
1-to reduce high body temperature in case of fever
2-to remove poisons
3-to relieve diseases of kidney

II-Anhydrotics
Definition: These are drugs which suppress profuse sweating. They are exactly opposite
to diaphoretics.
Mode of action:
They produce their action by:
i-inhibiting the secretion of the sweat glands directly as by astringents as lead salts and
vegetable astringents as tannic acid and plants containing it
ii-depressing or paralysis the secretory nerve ending in the sweat glands as by atropine,
hyoscyamine and hyoscine
iii-depressing the sweat center in the spinal cord as by bromides
iv-constricting the cutaneous B.Vs. as by cold water

III-Antibiotics and antibacterials

Antibiotic therapy is used in pyoderma. This may be local, topical treatment in
cases of limited scope. But in extent lesions requires systemic therapy
1-Forms of antibiotics locally includes creams containing neomycin, mupirocin or
fusidic acid
2-Forms of antibiotics for systemic therapy, activity against β–lactamase producing
staphylococci is important. Cephalexin, clavulanate-potentiated amoxicillin and
lincomycin have all been found to be effective. Treatment needs to be prolonged (in
most cases more than two weeks) and relapse is rather common

IV-Emollients (Skin softener)

Definition: Emollients are agents which soften, soothe, lubricate and protect a skin
surface and it is used as a base for more potent agents
a-Actions:
1-protective
2-soften the skin and make it more pliable
3-as drug vehicle
b-Formulary:
i-vegetable oils e.g…olive oil, cotton seed oil, corn oil, almond oil, pea nut oil and coca
butter
ii-animal fats e.g….lanolin (wool fat) contain 25-30 % H2O and lard
iii-hydrocarbons e.g…paraffin, petroleum, white petroleum (Vaseline) and mineral oil
iv-waxes…*white wax (bleached bees wax)
*yellow wax (bees wax)

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 V-Skin Astringents
These are drugs, applied to the skin to coagulate proteins and form a protective
scab under which healing can take place
Therapeutic uses:
1-in case of burns
2-wet eczyma
3-small bleeding
They are either:
1-metallic astringents as sliver nitrate, copper sulphate, zinc sulphate, alum…etc. at
concentration 0.5-5 % while at higher concentration it caused irritation
2-tannic acid astringents in the form of 1 %, 15 % tannic acid in glycerin or 20 % tannic
acid solution for the treatment of burns
N.B:- Formulary
1-metallic ions (silver, zinc, mercury, aluminium and bismuth)
2-iodine, alcohol, phenol
3-tannic acid (tannin, gallotannic acid):
a-toughens intact skin may be used to toughen the foot pads of working
dogs
b-tannic gel (tanisol) when applied to a braded skin it forms a film

VI-Local haemoststics or styptics

Definition: These are drugs or agents which are applied locally to stop bleeding from
superficial wounds in the skin and m.m
Mode of action:
1-Mechanical method such as:
a-ligature, clamping or pressure on the bleeding surface
b-application of cold water or ice
c-cautary
2-Drugs:
a-astringents such as tr. iodine, alcohol, alum and ferric chloride
b-vasoconstrictors as adrenaline
N.B:-
1-ferric chloride is sometimes used to stop bleeding after amputation of the tails, digits
and small warts on puppies or dogs. It is available as strong solution of ferric chloride
for the purpose of haemostasis
2-zinc oxide, zinc sulphate, zinc carbonate and calamine. They are used as mild
antiseptic-astringent, protective. They are applied in the form of dusting powders,
lotions, linaments, ointments and cream

3-ointments (zinc oxide, carbonate and calamine) used as bland protective dressings

VII-Skin disinfectants
These are drugs which used for removal or reduction in bacteria on the skin…..e.g.
benzol peroxide : it act by slowly release oxygen and this is bactericidal, especially
towards anaerobic or micro-aerobic bacteria. It is keratolytic and anti-seborrhoeic and
treatment of pyoderma. In veterinary use it is available in the form of gel fopr local

179
ap[placation or as shampoo containing 2 % or 50 % of benzoyl peroxide in pyoderma
in dogs.

VIII-Keratolytics
Definition: These are agents used to dissolve scales on the surface of the skin and
prevent their further formation. They are used in the form of lotion or ointment
e.g….salicylic acid, cool tar, resorcinol, benzoic acid and crysorbin
Keratolytics are indicated for treatments of cornified skin such as on elbows of
dogs lying on hard floors or granulation tissue forming at the surface of healing wounds.
These agents act to solubilize the intracellular cement which binds scales together in
the stratum corneum

IX-Corticosteroids
To reduce the problem of adrenal suppression, dosage orally with prednisolone on
alternate days in the early morning is often effective in reducing irritation and
inflammation. Whereas long acting steroid injections are given s/c result in thinning of
the skin above the injection site, with loss of hair and change in the color of the coat
(side effect). However, if used with suitable precautions, corticosteroids remains very
valuable in the treatment of skin conditions

X-Medicated shampoos
Bathing of animals in suitable shampoos is convenient in the treatment of
problems such as mange and also allows for non specific treatment of problems such as
pruritis (itching) or seborrhea 9excessive secretion of sebaceous glands) leading top
dandruff and oily skin.

XI-Caustics (Corrosives)
Caustics which are agents acting by causing the death of tissues when brought in
contact and usually produce severe action than pustulants
**This action may be due to:
a-inflammatory necrosis as occur by fire
b-direct chemical action as by sulphuric acid
c-precipitation of protein of the cell as by phenol and metallic salts or to forming
compounds with the cell protein as by strong alkalies and acids
**The most common caustics are:
1-hot iron
2-electricity
3-chemical agents such as
a-nitric acid for warts
b-trichloracetic acid for warts
c-phenol for infected tissue
d-silver nitrate, zinc chloride and copper sulphate for granulation tissue

These are three important points to remember when using caustics :

1-the material will not adhere to wet or greasy surfaces. It is therefore necessary, before
applying the collodion, to clip, clean and de-fat the horn bad area with ether or

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chloroform. Application is the best achieved by a short stiff bristled brush of the type
used for stencil painting
2-normal skin surrounding the horn bud should be protected by the application of a
protective greasy ointment such as zinc oxide ointment
3-disbuding to achieve the best results should be carried out within 48 h opf birth and
treatment should be thorough.

XII-Demulcents and Protectives

A-Demulcents
Are water soluble, high molecular weight agents act by alleviating irritation. They
have a soothing effect forming protective coating and protect underlying tissues and
used as drug vehicles
e.g…..gum, starch and mucilage
Formulary:
1-acacia 2-tragacanth 3-glycerin 4-propylene glycol 5-ployethylene glycol
B-Protective powder or dusting powders
It is inert fine powder used in cutaneous lesions and inflammatory conditions of
the skin to soothe and protect the underlying surface. Whereas the sedative powders are
local anesthetic used in case of irritation and pruritis
-e.g….Amethocaine, benzocaine
-protective powder: e.g….talk powder, starch, zinc oxide and zinc carbonate
N.B.
1-boric acid is antiseptic used with dusting powders
2-talk powder is a native hydrated magnesium silicate prepared as very fine, white,
odorless, tasteless powder insoluble in water. It is skin sedative, lubricant and protective
3-starch is used as dusting powder, sedatives and absorbent for fissured. Internally it is
used as mucilage of starch containing 2.5 % starch as demulcent

XIII-Antipruritis drugs
Definition: These agents which relieve itching and local irritation of the skin

Examples:
1-antihistaminics…can be used if pruritis is allergy
2-astringents…if there is exudation
3-local anesthetics…as napercaine
4-emollients…as oils, glycerin and Vaseline
IXV-Depilatories
Definition: These are agents used to remove hair from the surface of the body. They are
important in the treatment of chronic skin disease in different animal species as ring
worm
Examples
1-X-rays
2-Barium sulphide
3-Thalium acetate

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 XV-Counter irritants
Definition:
1-irritant drugs are agents which cause hyperaemia and inflammation when applied to
the intact skin.
2-counter irritant is an irritant applied for the relieve of inflammation of the tissues
under the skin
The reasoning which prompts their use is that, where a chronic inflammation
exists, a counter-irritant will cause an over-riding acute inflammation with a great
increase in vascularity and cause consequently, a greater concentration of the blood-
borne anti-disease factors such as leucocytes, increased nutrition and an improved
removal of waste products by the venous and lymphocytic systems
Counter irritants are therefore applied to the skin covering the area where chronic
inflammatory lesions exist just below the surface. These chronic inflammation may be
affect bone, ligaments, tendons or glandular tissues
Chronic arthritis (which frequently not true joint lesion but a strain and
ossification of ligamentous attachments, ruptured flexor tendons in the horse and
glandular infections such as strangles of the horse are commonly treated by counter
irritants.
They may be arranged according to the degree of their action or to their potency
or to their severity to one or more of the following three stages:

1-Rubefacient action (stage):

Where the irritant applied causes only mild irritation and a small increase in
congestion. Rubefacient often have pain-relieving or anodyne properties which may be
due to either to some pharmacological action of the drug or to the creation of
diversionary sensation
e.g…iodine, camphor, methylsalicylate, turpentine oil and ammonia
N.B….The redness is not clear in animals except in parts without pigmentation

2-Vesication (vesicant or blister stage):

Occurs when irritation is severe, this damages the capillary system and
results in serous exudes collecting in superficial skin layers to form blisters
e.g…mercuric iodine and cantharide ointments
Preparations:
i-biniodide of mercury used as 1:8 oint. in vaseline and lanoline or lard
ii-cantharides (Spanish flies) used as 10-30 % oint. in lard and wax

3-Pustulation stage (postulants or suppurants):

Where the irritation is so great that the deep layers of the skin are damaged and
the blisters become filled not with serous exudates but with the products of cellular
destruction-pus. At the deep layers of the skin are damaged, including the malpighian
layers, the ability of regeneration is lost and scar tissue is formed which when contracts
may limit the action of the joints or tendons and at best cause permanent blemishes. It
follows that no substances should normally be applied in a manner or form capable of
causing irritation beyond the stage of vesication
Examples:

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i-croton oil
ii-strong concentration of biniodide of Hg ointment
iii-firing to treat tendon injury in horse (hot metal) and kaolin poultice is the method of
applying heat, that kaolin being heated in boiling water then applied on bandage
N.B:---It should be noticed that the degree of counter irritation depends on :
1-the drug applied
2-its concentration
3-method and period of application
4-the base in which it is incorporated
e.g……bin iodide in a base of liquid paraffin 1:400 is rubefacient. Where
in Vaseline 1:8 and lard, it well be vesicant, where as 1:4 of biniodide in lard is
postulant. On the other hand when ammonia or volatile oils as turpentine when applied
with severe friction or prevented from evaporation by the use of bandage produce
vesicant effect
Therapeutic use:
Counter irritants are used to relieve chronic inflammation of parts in direct blood
supply with skin as pleura, joints, tendons and muscles as in case of pleurcy, arthritis,
sprain tendons and rheumatism. Also counter irritants cause reflex effect on CNS. S/C
injection of camphor irritates the sensory nerve in the skin and inhalation of ammonia
irritates the sensory nerve in the nose.

The most common counter irritants used in veterinary practice are :

i-Turpentine oil:
As rubefacient in the form of linaments relieve pain and stiffness of joints and
muscles as in case of chronic rheumatism, lumbago and pleurcy
ii-Camphor:
It is a volatile substance obtained from cinnamon camphorae or prepared
synthetically. It act as rubefacient drug used in the form of camphor linament

20 % in olive oil for muscular rheumatism, synovitis, lumbago, etc….S/C injection of

an oily solution of camphor produce reflex stimulant action on the medullary centers.
*Internally when taken by mouth, it causes mild GI irritation which causes:
a-reflex expectorant effect
b-reflex cardiac and respiratory stimulation
c-carminative and antispasmodic effect
Dose: 4-10 gm for horse and cattle and 0.1-0.6 for dog
iii-Methyl salicylate:
It is a colorless or pale yellow liquid with a characteristic odor. Used externally
as methyl salicylate linament 25 % or ointment 10 %. It is used in the same conditions
as camphor
iv-Iodine:
It is a bright-red heavy powder insoluble in water but soluble in pot. iodide
solution. At concentration 1:40 in Vaseline has a mild rubefacient. At 1:8 veasicant
especially used for large animals in case of chronic inflammation of joints and tendons.
If rubbed vigorously for 5-10 minutes it cause postulation. It is used as fungicide against
ring worm as 1:50 ointment

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v-Cantharides (Spanish fly):
It is dried bodies of this fly. It contains an irritant active principle canthridine. It
produce vesication in a very short time. The affected area should be clipped and
cantharides ointment should be rubbed for 5-10 minutes, depending on the degree of
action required. It may be used as combination with biniodide of mercury. Internally it
is known to be aphrodisiac because it cause engorgement of erectile tissue in male and
female during its excretion but without increasing sexual desire.

Precautions taken for application of counter irritants:

1-appicated area should be clipped or shaved
2-zinc oxide ointment or Vaseline should be smeared around the area of application
3-animals should be prevented from licking the blistered area
4-blisters should not be applied to the area where contamination of the m.m (like that
of urogenital system) can occur
5-The inner angles of the joints should be protected because misapplication may cause
severe damage

XVI-Parasiticide
These are drugs which are effective against parasites being on or in the skin. These
drugs are antifungal or antimycotic against ring worm. Insecticides against insects.

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Pharmacology
Of Eye

185
 Pharmacology Of Eye
A-Physiological principles:
1-Tears:
Tears are secreted by the lacrimal glands. They are an aqueous solution containing
salts, mucus and a bactericidal enzyme, a lysozyme. They are spread over the surface
of the eye ball. Their function is to moisten, clean, lubricate and protect the eye ball.
Tears leave via lacrimal ducts, lacrimal sac and nasolacrimal duct which carries tears to
the nasal cavity and to the mouth
2-Aqueous humor:
Aqueous humor is formed by the ciliary processes. Includes passive and active
transport which contains sodium pump and carbonic anhydrase/ bicarbonate systems. It
is similar to ultra filtrate of the plasma. It maintains a normal pressure in the different
animals between 10-30 mm Hg. Its function is to supply nutrients to, and remove wastes
from, the a vascular cornea and lens
B-Routes of administration of ophthalmic drugs:
1-Topical:
(solution, suspension and ointments)
topical preparations should be sterile, is osmotic and have pH of 6.8-7.4
2-Subconjuntival injections:
use no more than 1 ml per injection site
3-Retrobulbar injection:
used for regional anesthesia
4-Intraoccular injection:
5-Systemic use:
May be given oral or parentral. Penetration into tears or tissues of the eye from
blood depends upon the characteristics of each drug. Systemic antibiotics, for example
may yield rather high concentrations in the tears. On the other hand some drugs may
penetrate into aqueous humor.
C-Drug groups:

I-Mydriatics and Cycloplegics

1-Topically applied autonomic drugs may produce mydriasis (papillary dilatation) and
cycloplegic (paralysis of accommodation)
2-Adrenergic drugs (sympathomimetics "α stimulants") e.g…ephedrine, amphetamine,
cocaine
Mode of action:
They stimulate α receptors which present in radiating muscles of the iris indirect by
inhibiting MAO and prevent the catecholamines uptake, resulting in increasing the size
of the eye pupil (mydriasis)
3-Parasympatholytics: e.g……atropine 1 % and homatropine 1 %
Mode of action:

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 These drugs contract the radiating muscles, paralyzing the sphincter pupillae
results in mydriasis

Therapeutic uses of mydriatic drugs:

1-examination of the fundus and retina
2-treatment of iritis and keratitis
3-they are used alternatively with miotics to break the adhesion between the lens and
cornea
N.B….contraindicated in glaucoma

2-Drugs used for the treatment of glaucoma:

1-to maintain the proper intraocular pressure requires a proper balance between
formation (secretion) and outflow. When the secretion and removal of aqueous humor
are equal intraocular pressure will be normal. The different types of glaucoma are
characterized by an increase in intraocular pressure (Glaucoma)
2-drugs may be used to reduce an elevated intraocular pressure (Glaucoma) by
decreasing formation and/or increasing outflow or pulling water from the eye into blood
Examples for drugs used in glaucoma treatment:
a-cholinergic drugs (direct and indirect)
b-adrenergic (alpha agonist
c-beta adrenergic blockers
d-hyperosmotics
e-carbonic anhdrase inhibitors

II-Miotic drugs:
Miotic drugs are drugs which induce constriction of the eye pupil. They include
parasympathomimetic drugs such as carbachol 0.5 %, pilocarpione 2 % and
neostigmine
Therapeutic uses:
1-they are used in case of glaucoma
2-they are used to counteract mydriasis
3-they are used to break adhesion between lens and cornea
Mode of action:
The iris muscle supplied by circular muscles and radiating muscles. The
parasympathmimetic drugs stimulate the circular muscles that leads to contraction
results decreasing the size of the pupil (miosis)

Local anesthetics for the eye:

A-Local infiltration anaesthesia: e.g.
1-procaine…concentration used 1-4 %. Onset of action after 7-8 minutes. Duration of
action 30-45 minutes
2-lidocaine….concentration 1-2 %. Onset of action 4-6 minutes. Duration of action 40-
60 minutes
*local infiltration anesthesia are absorbed into systemic circulation. Excessive doses
when absorbed, could produce CNS toxicity

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B-Surface corneal anesthesia:
e.g.amethocaine and ophaine

Anti-allergic drugs and anti-inflammatory products

These are drugs which are used to relieve pain, excess granulation and
vascularization. They include:
1-adrenocorticosteroids
e.g.
a-hydrocortisone (acetate suspension, acetate oit., sol.)…conc. 2.5-0.2 %)
b-prednisolone (acetate suspension sod., phosphate sol., phosphate oint.)…con. 0.12-
0.25 %
c-fluomethasone
N.B.
Contraindicated in case of corneal ulcer, corneal opacity, bacterial infection and in
tendency to glaucoma
2-antihistaminics
e.g…..antazoline and privin
3-enzymes
e.g…..fibrinolysin
Drugs used for eye infection
I-Eye antiseptics
a-boric acid 4 % as eye lotion
b-NaHCO3…3 gm + borax 3 gm + NaCl + glycerol (10 ml) to 1 liter as eye lotion
c-heavy metal as zinc sulphate 1 %
II-Astringents and caustics
For corneal ulcer…zinc sulphate and silver nitrate
III-Antimicrobials
a-topical antibacterial products
e.g.
1-chloramphenicol oint. 10 mg/gm
" 5 % sol.
" oint. + prednisolone
2-gentamicin 0.3 % sol.
" 3 mg/gm oint.
" 0.3 % + betamethasone 0.9 % sol.
3-neomycin….sol., oint.
4-bacitracin….oint 500 units/gm
b-sulphonamides
-Na sulphacetamide eye drops 10 and 20 %
-Na sulphacetamide eye oint.
-Systemically sulphonamide…sulphadiazine and sodium sulphacetamide 30 %
c-Antimycotics
i-mycostatin oint…… in case of fungal infection
ii-amphotericin B in case of fungal infection as eye drops.

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