UNIT I

GENERAL PHARMACOLOGY

Subtopics
Introduction to pharmacology
Historical landmark and Scopes of pharmacology
Nature and source of drugs
Routes of drug administration
 PHARMACOLOGY
Introduction

Definition: Pharmacology is a branch of science that deals with the study of drugs and their
actions on living systems.

Pharmacology is a branch of science which deals in the pharmacokinetic and pharmacodynamic

profile of drug.

The word pharmacology is derived from Greek word pharmakon meaning drug/poison and logy
means study of/ knowledge of.

Pharmacology is subdivided in two branches:

1. Pharmacodynamics: It is defined as how the body reacts to the drugs.

2. Pharmacokinetics: It is the study of the bodily absorption, distribution,
metabolism, and excretion of drugs by the body.

History of Pharmacology

Hippocrates (460-370 BC)

1. Hippocrates was known as the Father of Medicine. He founded a school of medicine
which treats the causes of disease rather than its symptoms.
2. His authored a book named Aphorisms and Prognostics.

Theophrastus (371-287 BC)

1. Theophrastus was a student of Aristotle.
2. Theophrastus is known as the Father of Botany.
3. Theophrastus wrote Historia Plantarium. It was the first attempt to organize and classify
plants.

Dioscorides (40-90 AD)

1. Dioscorides was the author of De materia medica.

2. De materia medica was the first extensive pharmacopeia.
3. De materia medica includes information about thousands of natural products.

Galen (129-216 AD)

1. Galen was a philosopher, physician, and pharmacist.

 2. Galen is known as father of Pharmacy.
3. He wrote on the structure of organs, but not their uses.
4. Galen wrote books such as On Theriac to Piso, On Theriac to Pamphilius, and On
Antidotes.
5. Galen identified a sixty-four-ingredient compound which was able to cure any known
illness
6. His medicine was based on the regulation of the four humors (blood, phlegm, black bile,
and yellow bile) and their properties (wet, dry, hot, and cold)

Rudolf Bucheim (1820-1879)

1. Rudolf Bucheim is considered to be "Father of Pharmacology".

2. Buchheim is remembered for his pioneer work in experimental pharmacology. He
introduced the bioassay to pharmacology.
3. A bioassay is an analytical method to determine the concentration or potency of a
substance by its effect on living animals.

Louis Pasteur (1822-1895)

1. Louis Pasteur was a French chemist and microbiologist

2. He discovered vaccination, microbial fermentation, and pasteurization.
3. He is known as "father of bacteriology"
4. Pasteur discovered germ theory of diseases
5. Pasteur is also regarded as one of the fathers of germ theory of diseases

Oswald Schmiedeberg (1838-1921)

1. Oswald Schmiedeberg is considered to be the "founder of modern pharmacology".
2. Estimation of Chloroform in blood.
3. Study of Chloralhydrate.
4. His work is related with chemicals poisonous to the heart, emetics (causing vomiting) and
diuretics (causing passing urine), hypnotics (induce sleep), venoms and metals.

Robert Koch (1843-1910)

1. Robert Koch was a German physician and microbiologist.

2. He discovered pathogens of diseases like tuberculosis, cholera and anthrax,
3. He is the father of modern bacteriology.

John Jacob (1857-1938)

1. Isolation of Histamine from pituitary gland.

 2. Preparation of pure crystalline Insulin.

Paul Ehrlich (1854-1915)

1. Father of Chemotherapy.
2. Used Arsenicals in the treatment of Syphilis.

Henry Dale (1875-1968)

1. Isolated the neurotransmitter Acetylcholine.
2. Identify Histamine in Animal tissue.
3. Role of histamine in Hypersensitivity.
4. Alpha blockers reduce blood pressure.

Alexander Flemming (1881-1955)

1. He discovered the benzyl penicillin (or penicillin G) from the mould Penicillium rubens
2. He also discovered the enzyme lysozyme from his nasal discharge.

Alfred Joseph (1885-1941)

General mechanism related with drug receptor interaction.

Sir Ram Nath Chopra (1882-1973)

1. Sir Ram Nath Chopra is considered the "Father of Indian Pharmacology”.

Mahadeva Lal Schroff (1902-1971)

1. Mahadeva Lal Schroff is considered as the father of Indian Pharmacy

2. He was the one who introduced 3 year course in Pharmacy in Banaras Hindu University
for the first time.

James Black (1924-2010)

1. Discovered beta blockers.

2. Beta blockers reduce blood pressure.
 Scope of Pharmacology

1. To study and understand pathogenesis of disease.

2. To study and understand pharmacodynamic profile of drug.

a. It is defined as how the body reacts to the drugs.
b. Drug may show both desired (Diagnosis, Prevention, Treatment) and undesired
effects (side effects and adverse effects).

3. To study and understand Pharmacokinetic profile of drug.

a. Pharmacokinetics is the study of the bodily absorption, distribution, metabolism,
and excretion of drugs by the body:

i. Absorption - the process of the drug moving into the bloodstream

ii. Distribution - the reversed transmission of the drug from one location to the
other in the human body
iii. Metabolism - the process of how the drug is metabolized in the liver of the
human body
iv. Excretion - the process of how the drug expels, happens in the liver and
kidneys.
4. In clinical pharmacology and therapeutics.
a. It is the study of efficacy, toxicity, pharmacodynamic and pharmacokinetic profile
of drugs in man.
b. The aim of clinical pharmacology is to evaluate safety and efficacy of drugs.

5. In Toxicology.
a. Toxicology is the study of the adverse effects of drugs on living systems and the
means to prevent such effects.

6. In forensic science.
a. The study of pharmacodynamic and pharmacokinetic profile of poison, fatal drug
drug interactions, fatal food drug interactions, environmental exposure to
chemicals, are extensively required to solve various medico-legal issues.

7. In Pharmacovigilence.
a. Pharmacovigilance involves the collection, analysis, monitoring and prevention of
adverse effects associated with drugs and therapies.

8. In Preclinical studies.
a. Drug toxicological studies are conducted on animals.
b. Preliminary information related to efficacy, toxicity, pharmacodynamic and
pharmacokinetic profile of test drug is collected through in-vitro (test tube or cell
culture) and in-vivo (animal) experiments.

9. During Clinical trials.

a. Clinical trials are experiments or observations done in clinical research.
b. Clinical trials are performed on human subjects.
c. Clinical trials generate data on dosage, safety and efficacy.
Que . What are the different sources of drugs?

Ans .Drugs obtained from plant sources:

Drug Plant source Therapeutic use

Digoxin Leaves of Foxgloves plant known as It is a cardiotonic glycoside
Digitalis purpurea Treat heart failure
Digitoxin Leaves of Foxgloves plant known as It is a cardiotonic glycoside
Digitalis purpurea Treat heart failure
Salicin Bark of willow tree. Analgesic, anti-clotting
Curcumin Curcuma longa Anti-inflammatory
Lycopene Pigment found in tomatoes, Anti-inflammatory
watermelons, red oranges, etc
Shatavarin IV It is the major saponin found in the Anti-cancer activity
roots of Asparagus racemosus.
Vinblastine Alkaloids derived from the periwinkle Anti-cancer activity
and vincristine plant Catharanthus roseus.
Nimbolide Leaves of Azadirachta indica Anti-cancer activity, Anti-bacterial
Papain It is a proteolytic enzyme extracted Wound healing, indigestion,
from the raw fruit of the papaya plant. diarrhoea
Morphine It is derived from the opium poppy, Narcotic analgesic
Papaver somniferum.
Narceine It is derived from the opium poppy, Narcotic analgesic
Papaver somniferum.
Caffeine coffee beans, tea leaves CNS Stimulant
Cocaine Leaves of Erythroxylum coca CNS Stimulant

Drugs obtained from mineral sources:

Drug Mineral source Therapeutic use
Zinc Whole grains and milk products Promote spermatogenesis
Cobalt Fish, meat, leafy vegetables Promote Erythropoeisis, part of Vit.B12
Iodine Fish, meat, leafy vegetables Synthesis of thyroid hormones.
Shilajit The rocks of the Himalayas An anti-inflammatory, an energy booster,
and a diuretic.
Borax Seasonal lakes Antiseptic
Selenium Brazil nuts, seafoods, and organ meats Use to prepare anti-dandruff shampoo.
Calcium Milk products Maintain bone strength
Iron Fish, meat, leafy vegetables make hemoglobin
Chlorine Green vegetables, melon, NaCl Disinfectant
Fluorine Minerals fluorite in earth’s crust Disinfectant
Silver Trace amounts of silver in whole grains, an Immunity booster
fish, mushrooms, and milk from
humans, cows and goats.
Drugs obtained from Animal sources:
Drug Animal source Therapeutic use
Lard fatty tissue of a pig Used as a cooking fat
Honey Honey is a sweet, viscous food substance Used as an antioxidant, anti-
made by honey bees (Apis mellifera). inflammatory, anti-bacterial
Honey is primarily fructose (38%), glucose agent and wound healing
(31%), water (17%) and maltose (7%)
Bovine Insulin, Bovine Pancreas Administered to humans
or beef insulin to control diabetes. Animal
insulin is derived from cows and
pigs.
Cod liver oil Liver of cod fish Rich source of Vit.A
Omega-3 Sea food Improve circulation (blood flow
around the body) prevent blood
clots.
Enexatide Saliva of the Gila monster Treatment of Diabetes milletus

Drugs obtained from Microbial sources:

Antibiotic Microbial sourse Treatment of
Cephalosporin Cephalosporium Respiratory tract infections, skin infections
acremonium and urinary tract infections.
Erythromycin Streptomyces erythreus, Typhoid, Common Pneumonia and Diphtheria,
Streptomyces aureofaciens Whooping Cough, etc.
Penicillin Penicillium chrysogenum, Tonsilitis, Sore Throat, Gnonorrhea,
Penicillium notatum Rheumatic Fever, some Pneumonia types.
Streptomycin Streptomyces griseus Meningitis, Pneumonia, Tuberculosis, Local
Infection.
Griseofulvin Penicillium griseofulvum Antifungal, especially for Ringworm.
Nystatin Streptomyces noursei Antifungal for Candidiasis and overgrowth of
Intestinal Fungi during excessive antibiotic
treatment.
Hamycin Streptomyces pimprei Antifungal for Thrush
Fumagillin Aspergillus fumigatus Broad spectrum antibacterial especially against
Salmonella and Shigella.
Bacitracin Bacillus licheniformis, Syphilis, Lymphonema or Reticulosis.
Bacillus subtilis
Polymixin Bacillus polymyxa Antifungal
Gentamycin Micromonosopora Effective against Gram (+) bacteria
purpurea
Chloramphenicol Streptomyces venezuelae Typhoid, Typhus, Whooping cough, A typical
Pneumonia, Bacterial Urinary Infections.
Ques. Explain different routes of administration.

Ans .

Routes of Drug administration:

Most of the drugs can be administered by different routes.
Drug- and patient-related factors determine the selection of routes for drug
administration. The factors are:
a. Characteristics of the drug.
b. Emergency/routine use.
c. Site of action of the drug—local or systemic.
d. Condition of the patient (unconscious, vomiting, diarrhoea).
e. Age of the patient.
f. Effect of gastric pH, digestive enzymes and first-pass metabolism.

a) Local/Topical Route of Drug Administration: In this route the drug is

applied on the skin and mucous membrane for the local action. E.g.
a. Clobetasol propionate is a medicine that's used on the skin to treat
swelling, itching and irritation. It can help with skin problems such as:
eczema, including contact dermatitis, psoriasis.
 b. Soframycin is used to treat bacterial infection of the eye or ear.
Soframycin is an antibiotic of the aminoglycoside class.
c. Lignocaine ointments, gels and creams for topical anaesthesia.
d. Terbinafine comes as a cream, gel or spray for treating athlete's foot,
ringworm.

b) Systemic Routes: drugs administered by this route enter blood and produce
systemic effects. They are divided in Enteral and parental routes.

I. Enteral route: It includes oral, sublingual and rectal routes. In this route the
drug is placed in the Gastrointestinal Tract and then it absorbs to the blood. This
route is further classified into three classes:

a. Oral route: It is the most common and acceptable route for drug
administration. Dosage forms are tablet, capsule, syrup, mixture, etc.,
e.g., paracetamol tablet for fever, omeprazole capsule for peptic ulcer
are given orally.

First-pass effect: This effect occurs with oral route of administration.

The first-pass effect is the term used for the hepatic metabolism of a
drug when it is absorbed from the gut and delivered to the liver via the
portal circulation. The greater the first-pass effect, the less the agent
will reach the systemic circulation (blood).

Drugs which undergo First Pass Effect: Imipramine, Propranolol,

Lidocaine. buprenorphine, diazepam, midazolam, pethidine,
tetrahydrocannabinol (THC), ethanol (drinking alcohol), cimetidine,
lidocaine, chlorpromazine, and nitroglycerin (NTG).

b. Sublingual route: The preparation is kept under the tongue. The drug
is absorbed through the buccal mucous membrane and enters the
systemic circulation directly, e.g. nitroglycerin (vasodilator) for acute
anginal attack and buprenorphine (opoid analgesic) for myocardial
infarction.
 c. Rectal routes: Suppositories containing phenylephrine are used to
temporarily relieve swelling, burning, pain, and itching caused by
hemorrhoids. It works by temporarily narrowing the blood vessels and
thus decreases swelling.

II. Parental route: In this route of administration the drug does not pass through
the gastrointestinal tract. It directly reaches to the blood. It can further be
classified into two classes:-
a. With injections: In this class the drugs are administered with the use of
injections e.g. Intravascular, Intramuscular, Subcutaneous.

1. Intravascular route: In this route of administration the drug

is directly taken into the blood with the help of injection. A
volume of 20 mL can be given at a time.
In Intravenous (i.v.) route drugs are injected directly into
the blood stream through a vein. Drugs are administered
as:
 Bolus: Single, large dose of a drug injected
rapidly or slowly as a single unit into a vein.
For example, i.v. ranitidine in bleeding peptic
ulcer.
 Slow intravenous injection: For example, i.v.
morphine in myocardial infarction.
 Intravenous infusion: For example, dopamine
infusion in cardiogenic shock; mannitol
infusion in cerebral oedema; fluids infused
intravenously in dehydration.

Advantages:
 Precise, accurate and almost immediate onset of
action
 Large quantities can be given, fairly pain free
 Can be given to unconscious patients.
 Quick action
 Drugs having unpleasant taste can be given.
 Disadvantages:
 Pain at the site of injection.
 Greater risk of adverse effects
 High concentration attained rapidly
 Risk of embolism

2. Intramuscular: In this route of administration the drug is

given into the muscles with the help of injection. Drug once
reaches to the muscles, absorbs into the blood.

Depot preparations (oily solutions, aqueous suspensions)

can be injected.

Drugs are injected into large muscles such as deltoid,

triceps, rectus femoris and gluteus maximus e.g.
paracetamol, diclofenac, etc.

A volume of 5 mL can be given at a time.

Advantages:
 Very rapid absorption of drugs in aqueous solution
 Depot and slow release preparations

Disadvantages:
 Pain at injection sites for certain drugs

3. Intrathecal route: Drug is injected into the subarachnoid

space (spinal anaesthetics, e.g. lignocaine; antibiotics, e.g.
amphotericin B, etc.). Subarachnoid space is the space
between arachnoid membrane and the pia mater.

4. Intra-articular route: Drug is injected directly into the

joint space, e.g. hydrocortisone injection for rheumatoid
 arthritis. Strict aseptic precautions should be taken. Repeated
administration may cause damage to the articular cartilage.

5. Subcutaneous route: The drug is injected into the

subcutaneous tissues of the thigh, abdomen and arm, e.g.
adrenaline, insulin, etc. A volume of 1.5 mL can be given at
a time.

6. Intradermal route: The drug is injected into the layers of

the skin, e.g. Bacillus Calmette–Guérin (BCG) vaccination
and drug sensitivity tests. It is painful and only a small
amount of the drug can be administered. The standard dose
for BCG vaccination is 0.1 g (powder) in 1 mL. The BCG
vaccine storage temperature is 2 – 8 °C and has a shelf life
of 24 months.

7. Transdermal route: The drug is administered in the form

of a patch or ointment that delivers the drug into the
circulation for systemic effect. For example, scopolamine
patch for sialorrhoea and motion sickness, nitroglycerin
patch/ointment for angina, oestrogen patch for hormone
replacement therapy (HRT).
 b. Without injections: - in this class the drugs are administered without use
of injections. e.g. Inhalations.

Onset of action of different routes is as follows:

 Intravenous: 30-60 seconds

 Intraosseous: 30-60 seconds
 Inhalation: 2-3 minutes
 Sublingual: 3-5 minutes
 Intramuscular: 10-20 minutes
 Subcutaneous: 15-30 minutes
 Rectal: 5-30 minutes
 Oral: 30-90 minutes
 Subject: Pharmacology I

Unit I

Topic: Pharmacokinetics

Subtopics:
Absorbtion
Distribution
Metabolism
Excretion

Presented by: Mr Rishabh Singh

 A. ABSORPTION OF DRUGS:

1. Absorption is defined as the process of entry of drug from its site of administration to
systemic circulation.

Bioavailability:

1. Bioavailability is the rate and extent to which drug from its dosage reaches systemic
circulation. Bioavailability is 100% for intravenously administered drug. i.v.>i.m.>s.c.
2. Bioavailability fraction: It is the fraction of unchanged drug that reaches systemic
circulation from site of administration.

Absolute bioavailability:

1. It is defined as the ratio of bioavailability of a drug from an oral dosage form to the
bioavailability of same drug after intravenous administration.
2. Absolute bioavailability= bioavailability of a drug from an oral dosage form/
bioavailability of same drug after intravenous administration
3. Absolute bioavailability= AUC (oral)/AUC (i.v.)

Relative bioavailability:

1. It is defined as the ratio of bioavailability of a test drug from an oral dosage form to
the bioavailability of the standard drug. The value of relative bioavailability ranges
from 0 to 1.
2. Relative bioavailability= bioavailability of a test drug / bioavailability of the standard
drug
3. Relative bioavailability= AUC (test)/ AUC (standard)
4. Bioequivalent: When the bioavailability of a drug from two or more dosage forms are
similar.

Measurement of Bioavailability:

The plasma concentration of a drug after administration of two or more formulations of same
drug plotted against time.

1. Peak plasma concentration (Cmax): It indicates the intensity of response. It should be

within therapeutic video.
2. Time for peak plasma concentration (Tmax): It indicates the rate of absorption of a
drug from its dosage form into systemic circulation. Rapid absorption gives higher peak
in shorter time.
3. Area under curve (AUC): AUC indicates extent of absorption of a drug. AUC indicates
the amount of drug absorbed into the blood in a specified period. Unit: µg-hr/ml.
4. Methods of determination of AUC:
a. Planimeter: The area of plane figures is measured mechanically by an instrument
called planimeter.
b. Cut and weight method: The area under the curve on a rectilinear graph paper is
cut and weighted using an analytical balance.
c. Trapezoidal method: It is a mathematical method used for determination of AUC.
d. Geometrical method: AUC= Peak height (H) × Width of peak at half peak
point(s/2) or AUC= h × s/2

Factors affecting Absorption and bioavailability of drug:

Physical state of drug Liquid forms of drugs are absorbed better than their
solid forms.
Solubility of drug Lipid soluble drugs are absorbed more rapidly than
water soluble drugs.
Disintegration It is the conversion of solid dosage form to fine
particles before their absorption in systemic
circulation.

It is the rate limiting step in the absorption of lipid

soluble drug.
Dissolution Fine drug particles dissolve in cavity fluids to form
drug solution.

The dissolution rate determines the rate at which

drug goes into solution.
Particle size Dissolution of drug increases with increase in
surface area of particles.

Particle size reduction increase surface area.

Crystal form Dissolution rate of amorphous form of drug is faster
than crystalline form.
Salt form Dissolution rate of salt form of drugs is much faster.
Water of hydration Hydrates possess less bioavailability than anhydrous
forms because Hydrates have poor dissolution rates.
Degree of ionization Absorption of unionized and lipid soluble drug is
faster than ionized, hydrophilic drugs.
Recipients Wetting agents enhance penetration of solvent into
drug particles thus enhancing their dissolution and
absorption rate.
 B. DISTRIBUTION OF DRUGS

Drug distribution refers to the movement of a drug to and from the blood and various tissues of
the body (for example, fat, muscle, and brain tissue).

Factors affecting Drug distribution:

1. Lipid solubility
2. Extent of plasma protein binding.
3. Blood flow variations.
4. Ionization at physiological pH.

Distribution pattern of drug:

Nature Examples Distribution
Small and water soluble Alcohol, Phenytoin, Total body water.
Diazepam
Large and water soluble Digoxin, Emetine Extracellular
space/Intracellular space.
Very large and Strongly Heparin Plasma
bound with protein
Highly lipid soluble Thiopentone Adipose tissue

Physiological barriers Nature of drug Examples

Blood Brain Barrier Glial cells constitute the Amphetamine, Diazepam,
(BBB) BBB Ephedrine, Levodopa,
Morphine, Thiopental,
Only lipid soluble and Propranolol.
unionized drugs can pass.
Blood –CSF Barrier It is present in Choroid Penicilline is a poor lipid
plexus of the Brain. soluble drug. It does not
cross BBB.
Only lipid soluble and
unionized drugs can pass. However, if given through
intrathecal route, it
crosses CSF-Brain barrier
and reach brain cells.
Placental barrier Only lipid soluble and Alcohol, hypnotics,
unionized drugs can pass. narcotics, General
anaesthetics
 Plasma- Protein binding

 Drug reaches systemic circulation.

 Drug remain in plasma (in bound/free forms)
 Bound drugs are bound with proteins like Albumin, α1 acid glycoproteins,(α,β,)
globulins.
 Unbound/ free drugs show pharmacological action.
 Metabolism and elimination of free drug occur.
 After the elimination of free drugs: Drug-protein complex in plasma dissociates and free
drug levels increases in plasma.
 Therefore, drugs which extensively bound with plasma proteins have prolonged action.
 Binding proteins
Albumin α1 acid glycoproteins (α,β,) globulins

There are two binding α1 acid glycoproteins Thyroxine bind with α

sites: levels increases in blood globulins
plasma during stress, Antigens bind with 
Site 1: Less specific myocardial infarction, globulins
towards drugs. A number inflammation.
of structurally unrelated
drugs bind here. Lipophilic drugs bind to
this protein.
E.g. Warfarin, phenytoin,
valproic acid, bilirubin Mostly basic drugs bind
to this protein.
Site2: Mostly acidic drugs
and BZD bind here. E.g. Chlorpromazine,
Propranolol, lidocaine,
E.g. Ibuprofen, imipramine
indomethacin, valproic
acid, Salisylic acid,
tryptophan.
 Volume of Distribution (Vd):

1. The apparent volume of distribution is the ratio of total amount of drug in the body to the
concentration of drug in plasma.

Vd= Total amount of drug in the body/Plasma drug concentration

2. Unit of volume of distribution= liter/kg

3. Drugs with low Vd (restricted to vascular compartments):

a. Highly protein bound drugs (Warfarin)
b. High molecular weight (Heparin)
c. Ionised drugs (Gentamicin)

Vd of Heparin= 5L/kg

4. Drugs with high Vd (Easily cross cell membrane)

a. Lipid soluble (Chloroquine)
b. Non-ionised (Chloroquine)

Vd of Chloroquine =13000L /kg

Factors influencing Vd
1.Lipid-water coefficient of Lipid soluble and unionized drugs easily cross
drug cell membrane therefore possess high Vd.
Drugs with high Lipid-water coefficient possess
high Vd.
2. Degree of plasma protein Increased drug-plasma protein binding leads to
drug binding low Vd
3. Affinity for different tissues Drugs with high affinity for tissues have high Vd
4. Disease Disease may influence BMR, cell membrane
permeability, plasma proten binding therefore
may alter Vd
 C. METABOLISM OF DRUGS

1. Drug metabolism is also called biotransformation.

2. Biotransformation involves the change of one chemical entity to another inside human
body by specific enzyme.
3. After undergoing biotransformation, parent drug is changed into metabolites.
4. Metabolites may have decreased, increased or similar pharmacological activity in
comparison to its parent drug.
5. Biotransformation facilitates the excretion of formed metabolites.
6. Thus lipophilic and non-polar parent drugs are biotransformed into hydrophilic and polar
metabolites.
7. Hydrophilic and polar metabolites are easily excreted through urine.
8. Drug metabolism is regarded as detoxification system.

Enterohepatic circulation

 Drugs taken by oral route.

 Drug disintegrates in stomach.
 Drug particles dissolve in cavity fluids and form drugs solution.
 Drug particles enter systemic circulation.
 Free drug particles undergo biotransformation in liver (First pass metabolism).
 Metabolites are distributed to body tissues or excreted through urine.
 Unchanged drug particles are released by Liver in small intestine through bile.
 Unchanged drugs particles which are released in small intestine through bile are
reabsorbed into systemic circulation. This cycle continues till all parent drug is either
metabolized or excreted through urine.
Significance:

1. Enterohepatic circulation help to conserve essential substances like vitamin B12, D3,
steroid hormones, bile salts, folic acids etc.
2. It prolongs the half life of drugs like oral contraceptives (upto 12 hrs), cardiac glycosides,
chlorpromazine, indomethacin.

Demerit:

1. Large doses of drugs are orally administered because drug undergo first pass metabolism.
2. First pass metabolism give rise to unpredictability in drug response.

Phase 1 reactions: Enhance water solubility and polarity of drugs by introducing certain
functional groups

Oxidation  Oxidation is defined as removal of electron.

Reactions  Oxidation involve the addition of polar functional groups (-OH)
which increase their hydrophilicity and thus facilitating their
secretion through kidney.

Two types:
1. Microsomal Oxidation: Cytochrome P 450 catalyzes oxidation
reaction.
2. Non-Microsomal Oxidation: This reaction is catalyzed by non-
microsomal enzymes (monoamine oxidase, esterase, amidase,
transferase) which are located in cytoplasm of hepatocytes. E.g.
Metabolism of catecholamines, alcohol, histamine, etc.

Reduction reactions  Reduction is defined as addition of H2 or an electron.

 Compounds contain nitro, azo, carboxyl functional groups undergo
reduction to give polar functional groups such as hydroxyl, amino
etc.
 Reduction of compounds containing nitro and azo functional
groups to primary aromatic amines is catalyzed by CYP 450 enzyme.

E.g. Metabolism of Chloramphenicol, halothane, disulfiram, protonsil,

sulfasalazine.

Hydrolysis  Hydrolysis of esters and amides is catalyzed by carboxylesterases

present in kidney.
 Metabolites are polar and easily excreted.
 E.g. Hydrolysis of Pethidine, procaine, Ach, atropine, neostigmine,
phenytoin

Phase 2 reactions/ Conjugation reactions

1. In conjugation reaction drugs or metabolites combine with certain conjugating agents to

form polar, water soluble.
2. Enzymes involved in conjugation reactions are called transferases.
3. Conjugation reactions are essential for elimination of lipophilic drugs.
4. Phase 1 metabolites become water soluble and excretable after undergoing conjugation
reactions.

Types:
Glucuronidation  It is the addition of glucuronic acid moiety into a compound.
reaction  Catalysing enzyme: UDP glucuronosyl transferase.
 UDP glucuronosyl transferase is present in Liver, intestinal cells,
other tissues.

E.g.
O-glucuronidation: Morphine, Benzoic acid
N-glucuronidation: Desipramine
S-glucuronidation: Thiophenol
C-glucuronidation: Phenylbutazone

Sulfation reaction  Sulfation is the process of addition of sulfate group to

compounds.
 Catalysing enzyme: Sulfotransferase
 Sulfotransferase is found in golgi bodies of various cells.

Methylation reaction  Methylation is a process of addition of methyl group into a

compound.
 Catalysing enzyme: Methyltransferase
 Methylation increases the pharmacological activity of metabolite.

E.g.
O-methylation: Morphine
N-methylation: Norephedrine
 S-methylation: 6-Mercaptopurine

Amino acid  It is the process of addition of amino acid to compound.

conjugation  Conjugates have decreased toxicity.

E.g. Phenyl acetic acid

Glutathione  It is the process of addition of a glutathione moiety into a

conjugation compound.
 Catalysing enzyme: Glutathione-s-transferase

E.g. Ethacrynic acid, Azathioprine

Acetylation reaction  It is the process of addition of acetyl group to the compound to

form amides.
 Catalysing enzyme: N-acetyltransferase
 It mainly occurs in Liver.
 Conjugates do not lose their pharmacological activity.

E.g. Para-amino salisylic acid.

 D. EXCRETION OF DRUGS

1. The excretion of unchanged drug or its metabolites from the body through Bile, Sweat,
Milk, Saliva and Gases.
2. Polar and water soluble drugs are easily excreted from the body.
3. Non-polar and lipid soluble drugs undergo biotransformation to become polar and water
soluble before their excretion.

Routes of Excretion:

a) Renal excretion:
1. Kidneys are most important organs for excreting unchanged drugs and their metabolites.
2. Polar and water soluble drugs are usually excreted unchanged.
3. Lipid soluble drugs are excreted as metabolites.
4. Drugs excreted in an unchanged form: Digoxin, Furosemide, Gentamycin, d-
tubocurarine.
5. Drugs excreted in metabolite form: Sulfonamide, Penicilline, Nalidixic acid,
Nitrofurantoin, Barbiturates, aspirin.
6. Three important processes during renal excretion:

Glomerular Molecular size:

filtration  Drugs with smaller molecular size easily pass through
(passive process): Glomerulus.
 Drugs with high molecular weight like heparin, insulin,
dextran, growth factors cannot pass through Glomerulus.

Plasma protein binding:

 Only unbound or free drugs are filtered through Glomerulus.
 Protein bound drugs do not pass through Glomerulus.
E.g. 98% of warfarin is protein bound. Hence only 2% pass through
glomerulus.

Renal blood flow:

 Increased renal blood flow enhances removal of drugs from
plasma.

Ionised drugs:
 Poorly soluble (ionized) drugs and Soluble (unionized) drugs
both pass through glomerulus. However, Soluble (unionized)
drugs are reabsorbed into tubules.
 Tubular secretion 1. Tubular secretion of weak acids (anion), weak bases (cation).
(Carrier mediated, 2. Carrier transporters: Organic anion transporter (OAT),
active transport Organic cation transporter (OCT), p-glycoproteins.
process): 3. Drugs secreted into lumen through same active transporter
may compete for tubular secretion. Therefore drug-drug
interaction may occur.

E.g.
 Probenecid inhibits tubular secretion of penicillin and hence
increases its half life.
 Salicylates increase the excretion of probenecid.
 Tubular secretion of methotrexate is decreased by salicylates.

Tubular  Drugs diffuse across tubules according to their concentration

reabsorption gradient (from tubules to peritubular capillaries).
(passive,  It depends on lipid solubility, pH.
bidirectional  In acidic urine, tubular resorption of basic drugs decreases.
process)  In basic urine, tubular resorption of acidic drugs decreases.

E.g.

Alkalisation of urine in barbiturate and salisylate poisoning

(weak acids) result in their rapid excretion.

b) Biliary excretion:

 Drugs/ metabolites and endogenous substance like bilirubin are transported from
plasma to bile.
 Drugs/metabolites are released in intestine through bile and then excreted through
faeces.

E.g., Ampicillin, Colchicine, Chlorpromazine, Corticosteroids, Erythromycin,

Quinine, Vinblastun, d-tubocurarine.

 p glycoprotein transporters in enterocytes actively secrete drugs and metabolites in

intestine and then excreted through faeces.
c) Alveolar excretion
 Gases, volatile liquids like general anaesthetics, nitrous oxide, ether, paraldehyde,
and alcohol are eliminated by lungs.
d) Milk
 If pH of plasma becomes alkaline then basic drugs are excreted through milk. E.g.,
Antihistaminics, bromocriptine, chloramphenicol, diazepam, immunosuppressant,
morphine, oral contraceptive, progesterone, ethanol, urea, tetracycline.
 Elimination kinetics

It is useful in designing dosage regimen.

First order kinetics:

 Rate of elimination of drug is proportional to plasma drug concentration.

 A constant fraction of drug is excreted from body in a unit time.
 Half life of drug following first order kinetics: t1/2=0.693/k
 k is the elimination rate constant which gives fractional changes per unit time:
k=0.693/ t1/2
 Half life (t1/2) is the time during which plasma drug concentration becomes half of
its original value. t1/2= 0.693×Vd/ Cl

Zero order kinetic:

 Rate of elimination is independent of plasma drug concentration.

 Increase in plasma drug concentration will not increase rate of drug excretion.
 Drug concentration in plasma falls at constant rate but remain unaffected by
plasma drug levels.
 E.g. Alcohol, propranolol, probenecid, salicylate, theophylline, tolbutamide,
warfarin.

Mixed order kinetics/ Michaelis-menten reaction

 Smaller dose of drug follow first order kinetics.

 Larger dose of same drug follow zero order kinetics.
 Mix-order kinetics is dose dependant.
 E.g. Aspirin, digoxin, phenytoin.

Difference
Parameters First order kinetics Zero order kinetic
Plasma drug Rate of elimination of drug is Rate of elimination is independent of
concentration proportional to plasma drug plasma drug concentration
concentration.

Rate of Rate of elimination increase when Rate of elimination remain constant

elimination plasma drug concentration is even if plasma drug concentration is
increased. increased.
Nature of Linear kinetics Constant rate
process
Units min-1, hour-1 mg/min
Half life t1/2=0.693/k t1/2=0.5Co/ko
Half life Half life is independent of plasma Half life is dependent on initial plasma
nature drug concentration. drug concentration (Co).
Slope -k/2.303 -ko

Clearance (Cl):

1) Clearance (Cl) is defined as the volume of plasma from which the drug has been completely
removed in a unit time.
2) Clearance (Cl) = Rate of drug elimination/Plasma drug concentration
3) Clearance (Cl) = Dose of drug/AUC
4) Unit of Clearance (Cl): ml/min or liters/hr
5) Clearance of drugs from various organs:
 Hepatic clearance (Cl H)= Rate of drug elimination through liver/Plasma drug
concentration
 Renal clearance (Cl R)= Rate of drug elimination through kidneys /Plasma drug
concentration
 Clearance from other organs (Cl O) = Rate of drug elimination through other organs
/Plasma drug concentration

Total clearance (ClT)= Cl H + Cl R + Cl O

 ENZYME INDUCTION

Enzyme induction is a process by which the activity of a drug metabolizing enzyme is

increased.

Enzyme inducer Drug whose metabolism is increased

Cigarette (benzopyrene) Benzodiazepines, Paracetamol, Theophylline
Ethanol Barbiturates, Phenytoin, Warfarin, Tolbutamide.
Barbiturates Phenytoin, Warfarin, Corticosteroids, Phenothiazine, Doxycycline,
(phenobarbitone) Digitoxin, Calcium channel blockers, beta blockers
Carbamazepine Corticosteroids, Doxycycline, Haloperidol
Phenytoin Digitoxin, Quinidine, Hydrocortisone, beta blockers, Methadone,
Theophylline
Rifampicin Oral contraceptives, Corticosteroids, Quinidine, Theophylline,
Warfarin, Tolbutamide.
Griseofulvin Warfarin

ENZYME INHIBITION

Drugs can inhibit metabolizing enzyme activity.

Enzymes Enzyme Drugs whose metabolism is inhibited

inhibitors
Hepatic Cimetidine Diazepam, Chlordiazepoxide, Phenytoin, Anti-
microsomal Depressants, Thepphylline, Lidocaine, Testosterone,
Warfarin
Erythromycin Theophylline, Warfarine, Cyclosporine.
Sodium valproate Phenytoin, Phenobarbital
Quinolones Theophylline
Chloramphenicol Phenytoin, Warfarin, Tolbutamide
Verapamil Theophylline
Diltiazem Carbamazepine

Xanthine oxidase Allopurinol 6- Mercaptopurine, Azathioprine

Monoamino MAO inhibitors Tri cyclic antidepressants
oxidase
Aldehyde Disulfiram, Alcohal, Phenytoin, Warfarin
dehydrogenase Metronidazole
Angiotensin Captopril, Angiotensin 1, Bradykinin.
converting enzyme Enalapril
 Questions/Answers (UNIT 1). Pharmacology 2, IV Semester.

Que1. Define Bioavailability.

Ans1. Bioavailability is the rate and extent to which drug from its dosage reaches systemic circulation.
Bioavailability is 100% for intravenously administered drug. i.v.>i.m.>s.c.

Que2. Write difference between Absolute and Relative bioavailability.

Ans 2.

Absolute bioavailability Relative bioavailability

It is defined as the ratio of bioavailability of a It is defined as the ratio of bioavailability of a
drug from an oral dosage form to the test drug from an oral dosage form to the
bioavailability of same drug after intravenous bioavailability of the standard drug. The value
administration. of relative bioavailability ranges from 0 to 1.

Absolute bioavailability= bioavailability of a Relative bioavailability= bioavailability of a

drug from an oral dosage form/ bioavailability test drug / bioavailability of the standard drug
of same drug after intravenous administration

Absolute bioavailability= AUC (oral)/AUC Relative bioavailability= AUC (test)/ AUC

(i.v.) (standard)

Que3. What is bioequivalence?

Ans.3 Bioequivalence is the property in which bioavailability of a drug from two or more dosage forms are
similar.

Que.4 Define drug absorption.

Ans.4 Absorption is defined as the process of entry of drug from its site of administration to systemic
circulation.

Que5. What are the different pharmacokinetic parameters used to determine

bioavailability?
Ans.5 Bioavailability can be assessed by using following pharmacokinetic parameters:

Pharmacokinetic parameters

a) AUC (Area Under the Curve)

 AUC indicates extent of absorption of a drug.
 AUC indicates the amount of drug absorbed into the blood in a specified period.
 AUC indicates extent of absorption of a drug.
  AUC is a measurement of the extent of drug bioavailability.
 The AUC reflects the total amount of active drug that reaches the systemic circulation.
 AUC is expressed in mcg-hr/ml.

b) Cmax (Peak plasma drug concentration)

 It is the maximum plasma drug concentration obtained after oral administration of drug;
 The point of maximum concentration of drug in plasma is known as the peak and
 The concentration of drug at peak is known as peak plasma concentration.
 Cmax is expressed in mcg/ml.

c) Tmax (Time of peak plasma drug concentration)

 It is the time required to reach maximum drug concentration in plasma after oral drug administration.
 It is useful in estimating the rate of absorption.
 It is expressed in hours.

Que6. What are the different pharmacodynamic parameters used to determine

bioavailability?

Ans6.
Pharmacodynamic parameters

a) Minimum Effective Concentration (MEC) / Minimum Inhibitory Concentration (MIC)

 MEC/MIC is the minimum concentration of drug in plasma required to produce the therapeutic
effect. The concentration of drug below MEC is said to be in the sub‐therapeutic level.

b) Maximum Safe Concentration (MSC) / Maximum Safe Dose (MSD)

 MSC/MSD is the concentration of drug in plasma above which adverse or unwanted effects are
expected to happen.
 Concentration of drug above MSC is said to be in the toxic level.

c) Duration of action
 The time period for which the plasma concentration of drug remains above the MEC level is known
as duration of (drug) action.

d) Onset of action
 When plasma drug concentration just exceeds the required MEC, the pharmacological response
starts and this is called as onset of action.

e) Onset time
 It is the time required by the drug to start producing pharmacological response.

f) Intensity of action (Peak response)

 It is the maximum pharmacological response produced by the peak plasma concentration of drug.
 g) Therapeutic Range (Therapeutic window)
 The concentration of drug between minimum effective concentration and maximum safe
concentration is known as therapeutic range.

Que7. What are the different methods used to determine AUC?

Ans.7 Methods of determination of AUC:

a. Planimeter: The area of plane figures is measured mechanically by an instrument called

planimeter.
b. Cut and weight method: The area under the curve on a rectilinear graph paper is cut and
weighted using an analytical balance.
c. Trapezoidal method: It is a mathematical method used for determination of AUC.
d. Geometrical method: AUC= Peak height (H) × Width of peak at half peak point(s/2) or
Que8. What are the factors which affect absorption and bioavailability of drug?

Ans.8.

Factors Explaination
Physical state of drug Liquid forms of drugs are absorbed better than their solid
forms.
Solubility of drug Lipid soluble drugs are absorbed more rapidly than water
soluble drugs.
Disintegration It is the conversion of solid dosage form to fine particles
before their absorption in systemic circulation.

It is the rate limiting step in the absorption of lipid soluble

drug.
Dissolution Fine drug particles dissolve in cavity fluids to form drug
solution.

The dissolution rate determines the rate at which drug goes

into solution.
Particle size Dissolution of drug increases with increase in surface area of
particles.

Particle size reduction increase surface area.

Crystal form Dissolution rate of amorphous form of drug is faster than
crystalline form.
Salt form Dissolution rate of salt form of drugs is much faster.
Water of hydration Hydrates possess less bioavailability than anhydrous forms
because Hydrates have poor dissolution rates.
Degree of ionization Absorption of unionized and lipid soluble drug is faster than
ionized, hydrophilic drugs.
Recipients Wetting agents enhance penetration of solvent into drug
particles thus enhancing their dissolution and absorption rate.

Que 9. What is drug distribution?

Ans.9 Drug distribution refers to the movement of a drug to and from the blood and various tissues of the body
(for example, fat, muscle, and brain tissue).
Que 10. What are the factors which affect drug distribution?

Ans. 10 Factors affecting Drug distribution:

1. Lipid solubility
2. Extent of plasma protein binding.
3. Blood flow variations.
4. Ionization at physiological pH.

Que. 11 Write a short note on different physiological barriers in our human body.
Ans. 11
Physiological barriers Nature of drug Examples
Blood Brain Barrier (BBB) Glial cells constitute the BBB Amphetamine, Diazepam,
Ephedrine, Levodopa,
Only lipid soluble and Morphine, Thiopental,
unionized drugs can pass. Propranolol.
Blood –CSF Barrier It is present in Choroid plexus Penicilline is a poor lipid
of the Brain. soluble drug. It does not cross
BBB.
Only lipid soluble and
unionized drugs can pass. However, if given through
intrathecal route, it crosses
CSF-Brain barrier and reach
brain cells.
Placental barrier Only lipid soluble and Alcohol, hypnotics, narcotics,
unionized drugs can pass. General anaesthetics

Que. 12 Write a short note on Drug-protein binding.

Ans.12

 Drug reaches systemic circulation.

 Drug remain in plasma (in bound/free forms)
 Bound drugs are bound with proteins like Albumin, α1 acid glycoproteins,(α,β,) globulins.
 Unbound/ free drugs show pharmacological action.
 Metabolism and elimination of free drug occur.
 After the elimination of free drugs: Drug-protein complex in plasma dissociates and free drug levels
increases in plasma.
 Therefore, drugs which extensively bound with plasma proteins have prolonged action.
 Binding proteins
Albumin α1 acid glycoproteins (α,β,) globulins

There are two binding sites: α1 acid glycoproteins levels Thyroxine bind with α
increases in blood plasma globulins
Site 1: Less specific towards during stress, myocardial Antigens bind with  globulins
drugs. A number of infarction, inflammation.
structurally unrelated drugs
bind here. Lipophilic drugs bind to this
protein.
E.g. Warfarin, phenytoin,
valproic acid, bilirubin Mostly basic drugs bind to this
protein.
Site2: Mostly acidic drugs and
BZD bind here. E.g. Chlorpromazine,
Propranolol, lidocaine,
E.g. Ibuprofen, indomethacin, imipramine
valproic acid, Salisylic acid,
tryptophan.

Que.13 What is apparent volume of distribution (Vd)?

Ans. 13
1. The apparent volume of distribution is the ratio of total amount of drug in the body to the concentration
of drug in plasma.
Vd= Total amount of drug in the body/Plasma drug concentration

2. Unit of volume of distribution= liter/kg

3. Drugs with low Vd (restricted to vascular compartments):

a. Highly protein bound drugs (Warfarin)
 b. High molecular weight (Heparin)
c. Ionised drugs (Gentamicin)

Vd of Heparin= 5L/kg

4. Drugs with high Vd (Easily cross cell membrane)

a. Lipid soluble (Chloroquine)
b. Non-ionised (Chloroquine)

Vd of Chloroquine =13000L /kg

Que.14 What are the factors which affect apparent volume of distribution (Vd)?
Ans. 14

Factors influencing Vd
1.Lipid-water coefficient of drug Lipid soluble and unionized drugs easily cross cell
membrane therefore possess high Vd.
2. Degree of plasma protein drug Increased drug-plasma protein binding leads to low Vd
binding
3. Affinity for different tissues Drugs with high affinity for tissues have high V d
4. Disease Disease may influence BMR, cell membrane
permeability, plasma proten binding therefore may alter
Vd

Que. 15 Write a short note on drug metabolism.

Ans. 15
1. Drug metabolism is also called biotransformation.
2. Biotransformation involves the change of one chemical entity to another inside human body by specific
enzyme.
3. After undergoing biotransformation, parent drug is changed into metabolites.
4. Metabolites may have decreased, increased or similar pharmacological activity in comparison to its
parent drug.
5. Biotransformation facilitates the excretion of formed metabolites.
6. Thus lipophilic and non-polar parent drugs are biotransformed into hydrophilic and polar metabolites.
7. Hydrophilic and polar metabolites are easily excreted through urine.
8. Drug metabolism is regarded as detoxification system.
Que. 16 Write a short note on Enterohepatic blood circulation with its merits and
demerits.
Ans.16 Enterohepatic circulation

 Drugs taken by oral route.

 Drug disintegrates in stomach.
 Drug particles dissolve in cavity fluids and form drugs solution.
 Drug particles enter systemic circulation.
 Free drug particles undergo biotransformation in liver (First pass metabolism).
 Metabolites are distributed to body tissues or excreted through urine.
 Unchanged drug particles are released by Liver in small intestine through bile.
 Unchanged drugs particles which are released in small intestine through bile are reabsorbed into
systemic circulation. This cycle continues till all parent drug is either metabolized or excreted through
urine.

Merits:

1. Enterohepatic circulation help to conserve essential substances like vitamin B12, D3, steroid hormones,
bile salts, folic acids etc.
2. It prolongs the half life of drugs like oral contraceptives (upto 12 hrs), cardiac glycosides,
chlorpromazine, indomethacin.

Demerits:

1. Large doses of drugs are orally administered because drug undergo first pass metabolism.
2. First pass metabolism give rise to unpredictability in drug response.

Que. 17 Write a short note on phase 1 reactions during drug metabolism with examples.
Ans. 17
Phase 1 reactions: Enhance water solubility and polarity of drugs by introducing certain functional groups

Oxidation Reactions  Oxidation is defined as removal of electron.

 Oxidation involve the addition of polar functional groups (-OH) which
increase hydrophilicity and thus drug excrete through urine.

Two types:
1. Microsomal Oxidation: Cytochrome P450 catalyzes oxidation reaction.
2. Non-Microsomal Oxidation: This reaction is catalyzed by non-microsomal
enzymes (monoamine oxidase, esterase, amidase, transferase) which are
located in cytoplasm of hepatocytes. E.g. Metabolism of catecholamines,
alcohol, histamine, etc.

Reduction reactions  Reduction is defined as addition of H2 or an electron.

 Compounds contain nitro, azo, carboxyl functional groups undergo reduction
 to give polar functional groups such as hydroxyl, amino etc.

E.g. Metabolism of Chloramphenicol, halothane, disulfiram, protonsil, sulfasalazine.

Hydrolysis  Hydrolysis of esters and amides is catalyzed by carboxylesterases present in

kidney.
 Metabolites are polar and easily excreted.

E.g. Hydrolysis of Pethidine, procaine, Ach, atropine, neostigmine, phenytoin

Que. 18 Write a short note on phase II reactions during drug metabolism with examples.
Ans. 18
Phase 2 reactions/ Conjugation reactions

1. In conjugation reaction drugs or metabolites combine with certain conjugating agents to form polar,
water soluble.
2. Enzymes involved in conjugation reactions are called transferases.
3. Conjugation reactions are essential for elimination of lipophilic drugs.
4. Phase 1 metabolites become water soluble and excretable after undergoing conjugation reactions.

Types:
Glucuronidation reaction  It is the addition of glucuronic acid moiety into a compound.
 Catalysing enzyme: UDP glucuronosyl transferase.
 UDP glucuronosyl transferase is present in Liver, intestinal cells, other
tissues.

E.g.
O-glucuronidation: Morphine, Benzoic acid
N-glucuronidation: Desipramine
S-glucuronidation: Thiophenol
C-glucuronidation: Phenylbutazone

Sulfation reaction  Sulfation is the process of addition of sulfate group to compounds.

 Catalysing enzyme: Sulfotransferase
 Sulfotransferase is found in golgi bodies of various cells.

Methylation reaction  Methylation is a process of addition of methyl group into a compound.

 Catalysing enzyme: Methyltransferase
 Methylation increases the pharmacological activity of metabolite.

E.g.
O-methylation: Morphine
 N-methylation: Norephedrine
S-methylation: 6-Mercaptopurine

Amino acid conjugation  It is the process of addition of amino acid to compound.

 Conjugates have decreased toxicity.

E.g. Phenyl acetic acid

Glutathione conjugation  It is the process of addition of a glutathione moiety into a compound.

 Catalysing enzyme: Glutathione-s-transferase

E.g. Ethacrynic acid, Azathioprine

Acetylation reaction  It is the process of addition of acetyl group to the compound to form
amides.
 Catalysing enzyme: N-acetyltransferase
 It mainly occurs in Liver.
 Conjugates do not lose their pharmacological activity.

E.g. Para-amino salisylic acid.

Que. 19 Explain different routes of drug excretion.

a) Renal excretion:
1. Kidneys are most important organs for excreting unchanged drugs and their metabolites.
2. Polar and water soluble drugs are usually excreted unchanged.
3. Lipid soluble drugs are excreted as metabolites.
4. Drugs excreted in an unchanged form: Digoxin, Furosemide, Gentamycin, d-tubocurarine.
Drugs excreted in metabolite form: Sulfonamide, Penicilline, Nalidixic acid, Nitrofurantoin,
Barbiturates, aspirin.

b) Biliary excretion:
1. Drugs/ metabolites and endogenous substance like bilirubin are transported from plasma to bile.
2. Drugs/metabolites are released in intestine through bile and then excreted through faeces.
E.g., Ampicillin, Colchicine, Chlorpromazine, Corticosteroids, Erythromycin, Quinine, Vinblastun, d-
tubocurarine.

c) Alveolar excretion
Gases, volatile liquids like general anaesthetics, nitrous oxide, ether, paraldehyde, and alcohol are
eliminated by lungs.

d) Milk
 If pH of plasma becomes alkaline then basic drugs are excreted through milk. E.g., Antihistaminics,
bromocriptine, chloramphenicol, diazepam, immunosuppressant, morphine, oral contraceptive,
progesterone, ethanol, urea, tetracycline.

Que. 20 Explain Elimination kinetics associated with drug excretion.

Ans. 20
Elimination kinetics is useful in designing dosage regimen.

First order kinetics:

1. Rate of elimination of drug is proportional to plasma drug concentration.
2. A constant fraction of drug is excreted from body in a unit time.
3. Half life of drug following first order kinetics: t1/2=0.693/k
4. k is the elimination rate constant which gives fractional changes per unit time: k=0.693/ t1/2
5. Half life (t1/2) is the time during which plasma drug concentration becomes half of its original value. t1/2=
0.693×Vd/ Cl

Zero order kinetic:

1. Rate of elimination is independent of plasma drug concentration.
2. Increase in plasma drug concentration will not increase rate of drug excretion.
3. Drug concentration in plasma falls at constant rate but remain unaffected by plasma drug levels.
4. E.g. Alcohol, propranolol, probenecid, salicylate, theophylline, tolbutamide, warfarin.

Mixed order kinetics/ Michaelis-menten reaction

1. Smaller dose of drug follow first order kinetics.

2. Larger dose of same drug follow zero order kinetics.
3. Mix-order kinetics is dose dependant.
4. E.g. Aspirin, digoxin, phenytoin.

Que. 21 Write difference between First order and Zero order kinetics.
Ans.21
Difference
Parameters First order kinetics Zero order kinetic
Plasma drug Rate of elimination of drug is proportional Rate of elimination is independent of plasma
concentration to plasma drug concentration. drug concentration

Rate of Rate of elimination increase when plasma Rate of elimination remain constant even if
elimination drug concentration is increased. plasma drug concentration is increased.
Nature of Linear kinetics Constant rate
process
Units min-1, hour-1 mg/min
Half life t1/2=0.693/k t1/2=0.5Co/ko
Half life nature Half life is independent of plasma drug Half life is dependent on initial plasma drug
 concentration. concentration (Co).
Slope -k/2.303 -ko

Que. 21 What do you mean by drug clearance through various organs?

Ans.21
1) Clearance (Cl) is defined as the volume of plasma from which the drug has been completely removed in a
unit time.
2) Clearance (Cl) = Rate of drug elimination/Plasma drug concentration
3) Clearance (Cl) = Dose of drug/AUC
4) Unit of Clearance (Cl): ml/min or liters/hr
5) Clearance of drugs from various organs:
 Hepatic clearance (Cl H)= Rate of drug elimination through liver/Plasma drug concentration
 Renal clearance (Cl R)= Rate of drug elimination through kidneys /Plasma drug concentration
 Clearance from other organs (Cl O) = Rate of drug elimination through other organs /Plasma drug
concentration

Total clearance (ClT)= Cl H + Cl R + Cl O

Que. 22 Explain enzyme induction with examples?

Ans.22
Enzyme induction is a process by which the activity of a drug metabolizing enzyme is increased.
Enzyme inducer Drug whose metabolism is increased
Cigarette (benzopyrene) Benzodiazepines, Paracetamol, Theophylline
Ethanol Barbiturates, Phenytoin, Warfarin, Tolbutamide.
Barbiturates (phenobarbitone) Phenytoin, Warfarin, Corticosteroids, Phenothiazine, Doxycycline, Digitoxin,
Calcium channel blockers, beta blockers
Carbamazepine Corticosteroids, Doxycycline, Haloperidol
Phenytoin Digitoxin, Quinidine, Hydrocortisone, beta blockers, Methadone,
Theophylline
Rifampicin Oral contraceptives, Corticosteroids, Quinidine, Theophylline, Warfarin,
Tolbutamide.
Griseofulvin Warfarin

Que. 23 Explain enzyme inhibitors with examples?

Ans.23
Drugs can inhibit metabolizing enzyme activity.
Enzymes Enzyme inhibitors Drugs whose metabolism is inhibited
Hepatic microsomal Cimetidine Diazepam, Chlordiazepoxide, Phenytoin, Anti-Depressants,
Thepphylline, Lidocaine, Testosterone, Warfarin
Erythromycin Theophylline, Warfarine, Cyclosporine.
 Sodium valproate Phenytoin, Phenobarbital
Quinolones Theophylline
Chloramphenicol Phenytoin, Warfarin, Tolbutamide
Verapamil Theophylline
Diltiazem Carbamazepine

Xanthine oxidase Allopurinol 6- Mercaptopurine, Azathioprine

Monoamino oxidase MAO inhibitors Tri cyclic antidepressants
Aldehyde Disulfiram, Alcohal, Phenytoin, Warfarin
dehydrogenase Metronidazole
Angiotensin Captopril, Enalapril Angiotensin 1, Bradykinin.
converting enzyme
Que 24. Write a note on Clinical trials

Ans.
1. Clinical trials are experiments or observations done in clinical research.
2. Clinical trials generate data on dosage, safety and efficacy.
3. They are conducted only after ethics committee approval in the country.
4. Clinical trials involving new drugs are commonly classified into five phases.

Phase Aim Notes

Pharmacodynamics and
Phase 0 pharmacokinetic s studies Subtherapeutic doses of study drug are given to a small
in humans group (10 to 15) of subjects to gather pharmacodynamics
and pharmacokinetics data.

Phase I Screening for safety Small group of people (typically 20–80) are involved.
Evaluation of safety parameters.
Observation of any side effects.

Data of Treatment group

is compared with Therapeutic dose range is established.
Phase II Placebo control group. Therapeutic efficacy of drug is established.

Phase III Final confirmation of Testing with large groups of people (typically 1,000–3,000)
safety and efficacy to confirm its efficacy, evaluate its effectiveness, and side
effects.
Phase IV Safety studies during Postmarketing studies define risks, benefits, and
sales optimal use in a large population of peoples.
Que 25. What is the difference between side effect and adverse effect?
Ans .

Side effects Adverse effects

A side effect is an effect of a drug, An adverse effect is always a harmful,
which occurs in addition to undesirable effect which occurs from
its pharmacological effect. incorrect dose of medicine.

For example,

Metformin, which is used to treat type 2

diabetes, can cause side effects such as muscle
aches or pains, dizziness, confusion, increased
hunger, etc.

Side Effects can be both therapeutic and Adverse Effects are generally harmfuland
harmful. undesirable.

Side Effects are mild Adverse Effects are more severe and life
Threatening.
Side Effects do not obstruct the Adverse Effects obstruct the
pharmacological action of drug. pharmacological action of drug.

Side Effects are known to doctor Adverse Effects are not known to doctor
Que 26 . What is the difference between Adverse Drug Reaction (ADR) and
Adverse Drug Event (ADE)?
Ans .
Adverse Drug Reaction (ADR) Adverse Drug Event (ADE)
1. An adverse drug reaction (ADR) is defined 1. An adverse drug event (ADE) is when
as an unwanted, undesirable effect of a someone is harmed by a medicine.
medication which occurs during usual
clinical use. 2. An adverse drug event (ADE) occurs due to
medication error (miscalculation,
2. Adverse drug reactions are more serious misadministration, difficulty in interpreting
than side effects. handwritten prescription, misunderstanding
of verbal orders, and name confusion of
drugs). E.g.,

Nephrotoxic drugs:

Cyclosporine, aminoglycoside antibiotics,

cisplatin, amphotericin B, beta-lactam
antibiotics and indomethacin.

Hepatotoxic drugs:

Antibiotic: Amoxicilline/ Clavulanate,

Que27 . Give a few examples of ADRs.

Ans .
Que 28 . What do you mean by iatrogenic diseases?
Ans .
1. Iatrogenic diseases are also called Physician induced diseases.
2. Drugs used in the treatment of a specific disease may initiate any other disease
pathogenesis.
E.g.
Peptic ulcers by Salicylates and Corticosteroids.
Parkinsonism by Phenothiazines and other Anti-psychotics.
Hepatitis by Isoniazids.

Que 29 . What do you mean by Photosensitivity?

Ans .
Photosensitivity is a cutaneous reaction resulting from drug induced skin sensitization to UV
radiation. Photosensitivity reactions are of 2 types:

Phototoxic:
1. Drug or its metabolite accumulate in skin, absorb light and induce a photobiological
reaction which damage local tissue
2. It cause Sun burn, Erythema, Edema, Hyperpigmentation,etc.
3. Shorter wavelengths (290-230nm) are responsible.
4. Phototoxic drugs: Tetracyclines, Nalidixic acid, Sulfonamide, Thiazides,
Fluoroquonolones

Photoallergic:
1. Drug or its metabolite induces a cell mediated immune response.
2. It occurs due to exposure of longer wavelength (320-400 nm).
3. It may cause Contact dermatitis, papule, and eczema on skin.
4. Photoallergy causing drugs: Griseofulvins, Chloroquine, Sulfonamide, Chlorpromazine.

Que 30 . What do you mean by Drug dependence?

Ans .
Psycological dependence occurs when the individual believes that optimal state of well being is
achieved only through action of drugs.

Physical dependence occurs when repeated administration of a specific drug disturbs the body
homeostasis and its repeated administration is required to maintain body homeostasis.
Discontinuation of drug causes withdrawal syndromes.
Que 31 . What is teratogenicity?
Ans .
Teratogenicity is the capacity of drug to cause fetal abnormalities when administered by pregnant woman.
Teratogenic drugs may cross placental barrier.
Teratogenic drugs can affect the fetus at 3 stages:
1. Fertilization and implantation (17 days)
2. Organogenesis (18-55 days of gestation)
3. Growth and development (56 days onwards)
Que 32 . What is Idiosyncrasy?
Ans.
1. Idiosyncrasy is an abnormal physical reaction by an individual to a food or drug.
2. Idiosyncrasy is an abnormal behavior or symptom shown by an individual towards any food or drug.
3. Idiosyncrasy usually occur due to any genetic abnormality.

SYNDROME DRUG FEATURE

Stevens-Johnson syndrome and toxic Phenytoin Sulfonamides Allopurinol Epidermal necrosis and detachment
epidermal necrolysis NSAIDs
Beta-lactams

Serum sickness-like reaction Cefaclor Cefprozil Fever, Rash Arthralgias (joint

stiffness)

Drug-induced hepatitis Azathioprine Antiretrovirals Statins liver failure

NSAIDs
Phenytoin Imipramine Amiodarone

Que 33 . What do you mean by drug tolerance?

Ans .
Tolerance is the requirement of higher dose of drug to produce a given response.
Requirement of higher dose of drug to obtain same therapeutic response.
E.g., Before 500 mg= Response X
After tolerance 800mg= Response X Types of tolerances:

Natural Tolerance: A species or an individual is less sensitive to given drug.

E.g. Rabbits are tolerant to Atropine.

Aquired tolerance: Repeated administration of a specific drug may cause its tolerance and reduce its therapeutic
efficacy.
E.g. Sulfonyl urea in Diabetes milletus, β2 agonist in Asthama, β blockers in hypertension.

Cross tolerance: Simultaneous administration of two pharmacologically related drugs may create tolerance for each
other. Development of tolerance to pharmacological related drug.
E.g. A person who frequently drinks Alcohol is tolerant to Barbiturate.
Que 34 . What do you mean by tachyphylaxis?
Ans .
1. Tachyphylaxis is the rapid development of tolerance when a drug is administered repeatedly within short
interval of time.
2. It is also known as Acute Tolerance.
3. In Tachyphylaxis, desired effect of drug cannot be achieved even after its dose is increased.
E.g. Amphetamine, Ephedrine, Tyramine.

Que 35 . What do you mean by combined drug effect?

Ans .
Synergism: In synergism, the action of one drug is facilitated by other drug. Both drugs are said to be Synergistic.
Synergism can be:
Additive: The effect of the two drugs in the same direction:
Additive drug Use
Aspirin+Paracetamol Analgesic/Anti-pyretic
Nitrous oxide + Halothane General Anaesthetic
Amlodipine+ Atenolol Anti-hypertensive
Glibenclamide + Metformin Hypoglycemic
Ephedrine+ theophylline bronchodilator

Supra-additive drug: The effect of combination is greater than the individual effects of
components.
Effect of A+B > Effect of A/ Effect of B
Que 36. Define receptor and different terms related with drug-receptor interaction.
Ans.
Receptors are proteins on the surface of cell membrane which bind with ligands (drugs) and produce intracellular
responses.

An agonist (ligand) is a chemical that binds to a receptor and activates the receptor to produce a biological response.
Partial agonists are drugs that bind with a receptor, but have only partial efficacy at the receptor comparative to a
full agonist.

An inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response
opposite to that of the agonist.

An antagonist blocks the action of the agonist.

Que 37. What is Receptor Occupation Theory?
Ans.
1. Receptor occupation theory was founded by Clark in 1973.
2. It is based on occupation of receptors by drugs.
3. The interaction between drug (D) and receptor (R) is guided by Law of mass action.
4. The pharmacological effect (E) is the direct function of Drug-Receptor Complex (DR).

5.
6. Occupation of receptor is essential but a drug/ligand must also induce conformational changes or activate the
receptor to show pharmacological action.
7. The ability of drug to bind with receptor is called affinity.
8. The capacity of drug to induce a functional change in the receptor is called intrinsic activity (IA) or efficacy.
9. Competitive antagonist occupies the receptor but do not activate it.
10. Partial agonist occupies the receptor but partially/submaximally activate the receptor.
11. A theoretical quantity (S) denotes strength of stimulus passed to cell.

12. Depending on the agonist, DR could generate a stronger or weaker S.

13. S is probably the function of conformational changes brought about by agonist in Receptor.
14. Agonists have both affinity and maximal intrinsic activity (IA=1), E.g., Adrenaline, Histamine, Morphine.
15. Competitive Antagonist have affinity but no intrinsic activity (IA=0), E.g., propanolol, Atropine, naloxone.
16. Partial agonists have affinity and submaximal intrinsisc activity (IA=0-1), E.g., pentazocine on µ opoid
receptor.
17. Inverse agonist have affinity but intrinsic activity with a minus sigh (IA=0 to -1), E.g., DMCM on
benzodiazepine receptors.
18. Full agonists may produce maximal response even if they occupy less than 1% receptors on cell membrane.
19. Spare receptors are receptors that exist in excess of those required to produce a full effect.
Que 38. What do you mean by spare receptors?

Ans.Spare receptors are receptors that exist in excess of those required to produce a full effect.

Que 39. What do you mean by silent receptors?

Ans. Silent receptors are the sites where specific drug binds but no pharmacological action is observed. They are
also called site of loss.

Que 40. What do you mean by essential drugs?

Ans. According to WHO, “essential drugs are those drugs which satisfy the priority healthcare needs of the
population. Essential drugs are selected with due regard to public health relevance, evidence on safety and efficacy
and cost effectiveness”.

Que 41. What do you mean by orphan drugs?

Ans. Orphan drugs are the drugs used for diagnosis/treatment/ prevention of a rare disease or condition.
They are non-profitable thus rarely manufactured by pharmaceutical companies.
For example, haem-arginate is used to treat acute intermittent porphyria.
 UNIT 2

PHARMACODYNAMICS

Subtopics
Introduction of pharmacodynamics
Principle and mechanism of drug action
Regulation of receptors
Drug –receptor interaction
Drug antagonism
Combined effects of drugs
Factors modifying drug actions
Drug interactions
Adverse drug reactions
 PHARMACODYNAMICS
1. Pharmacodynamics is defined as how the body reacts to the drugs.
2. Pharmacodynamics involves the physiological and biochemical effects of drugs on cellular
levels. E.g., Role of Adrenaline in promoting glycogenolysis (breaking Glycogen in glucose
molecules).

E.g., Role of Adrenaline in promoting glycogenolysis (breaking Glycogen in glucose

molecules):

Adrenaline binds to B adrenergic receptor on cell membrane of hepatocyte cells.

G-protein (3 subunits) activates after binding with B adrenergic receptor and Adrenaline
complex.

Activated G-protein subunit containing GDP detach

GDP is replaced by GTP.

G-protein subunit containing GTP activates Adenylyl cyclase

Activated Adenylyl cyclase synthesize cyclic adenosine monophosphate (cyclic AMP)

from adenosine triphosphate (ATP)

Cyclic AMP activates Protein kinase A.

Activated Protein kinase A activates Phosphorylase.

Activated Phosphorylase converts Glycogen in Glucose 6 phosphate.

Glucose 6 phosphate breaks to give Glucose.

Principle and mechanism of drug action:

An ideal drug binds with receptor to show its therapeutic effect.

An ideal drug show maximum therapeutic effect, minimum side effects and no toxicity.

Mechanism of drug action:

1. G-Protein Coupled Receptor or Metabotropic receptor

2. Receptors with intrinsic ion channel
3. Enzyme linked receptors
 1. G-protein coupled receptors (GPCR)

1. G-protein-coupled receptors (GPCRs) are present in eukaryotes.

2. GPCR has 7 α-helical membranes spanning of hydrobhobic amino acids.
3. There are three extracellular loops and three intracellular loops.
4. Extracellular domain is linked with NH2 group
5. Intracellular domain is linked with COOH group.
6. Intracellular domain is exposed to Cytosol and it contain 3 subunits of G
protein(α,β,)
7. G protein is attached with Intracellular domain.
8. When agonist/ligand will bind on extracellular domain then trimeric Gαβ will break
into: Monomeric Gα and Dimeric Gβ and GDP of Gα is replaced by GTP.
a) Adenylyl cyclase: cAMP pathway

Activated Gα (with GTP) will activate Adenylyl cyclase.

Adenylyl cyclase will convert ATP to cAMP
cAMP will activate Protein kinase A (PKA)
PKA wll phosphorylate other proteins.
PKA will also phosphorylate transcription factor (CREB) inside nucleus and promote
synthesis of proteins.

E.g. Glycogenolysis
b) Phospholipase C: IP3- DAG pathway

Activated Gα (with GTP) will activate phospholipace C.

Phospholipace C enzyme is attached with membrane.
Activated Phospholipase C will break membrane phosphatidyl inositol 4, 5 biphosphate
(PIP2) to give sec. messengers Inositol 1, 4, 5-triphosphate (IP3) and diacylglycerol
(DAG).
Inositol 1,4,5 triphosphate (IP3) cause release of Ca++ from Endoplasmic reticulum.
Ca++ bind with DAG (membrane bound) and activate Protein kinase C
Protein kinase C phosphorylate and activate other proteins.

Sec. messengers are: IP3, DAG

Third messenger is: Ca++
 c) Channel regulation
1) The activated G-proteins can open or close ionic channels without
intervention of anysec. messengers like IP3 and DAG.
2) Intracellular domain of GPCR is attached with trimeric Gαβ.
 When ligand bind on extracellular domain of GPCR then trimeric
Gαβ will break into: Monomeric Gα and Dimeric Gβ
4) GDP of Monomeric Gα is replaced by GTP.
5) Activated Monomeric Gα will open Ca++ channel and promote Ca++
influx.
Activated Dimeric Gβ may open or close k+ channel.

Type of G Action
protein
GS Open Ca++ channels in myocardium and skeletal
muscles
GO Open k+ channels in myocardium and smooth muscles

Type of G protein Actions on effector proteins

Gs Adenylyl cyclase Ca++ Channel
Gi Adenylyl cyclase k+ Channel
Go Ca++ Channel
Gq Phospholipase C
 2. Receptors with intrinsic ion channel

1. These receptors are present on the surface of membrane.

2. They are also called ligand gated ion channel.
3. These ligand gated ion channel enclose ion selective channels (Na +, Cl-, k+,
Ca++).
4. NMDA, GABAA, 5HT3 receptors also fall in this category.
5. Agonist directly opens or closes these receptors.

K+ channel opener Nicorandil, Diazoxide, Pinacidil

Na+ channel blocker Phenytoin , Carbamazepine, Oxcarbamazepine, Lidocaine,
Lamotrigine, Fosphenytoin
Ca++ channel blocker Amlodipine, Nifidipine, Felodipine, Verapamil
GABAA mediated Cl- Benzodiazipines, Barbiturates
channel opening

3. Enzyme linked receptors

These receptors contain a subunit which binds with JAK (Janus kinase) enzyme.

After binding with JAK receptor become activated.

Agonist bind with catalytic site present on outer and inner face of plasma
membrane.

Two domains are connected through a peptide chain.

They are of two types:

a) Intrinsic enzyme receptor

b) JAK-STAT binding receptor
a) Intrinsic enzyme receptor

1) They have intrinsic enzyme activity.

2) Intracellular domain is either protein kinase or guanyl cyclase.
3) When peptide hormone bind with extracellular domain then monomeric
receptors move towards each other and form a dimer.
4) Dimerisation activates Tyrosine protein kinase (t-Pr-k).
5) Activated Tyrosine protein kinase (t-Pr-k) phosphorylate Tyrosine (t)
residues on each other.
6) Activated Tyrosine protein kinase (t-Pr-k) also phosphorylate Substrate
proteins (SH2-Pr).
7) Phosphorylated substrate protein (Pr-P) perform downstream signaling.
8) cGMP levels increases in Cytosol.
9) cGMP activate cGMP –dependent protein kinases which modulate cellular
functions
b) JAK-STAT binding receptor

1) These receptors do not have any intrinsic protein kinase activity.

2) Cytokine/Hormone bind with extracellular binding site then two domains
comes closer to each other, dimerisation occurs.
3) Dimerisation activate the intracellular domain which bind with freely
moving Janus Kinase enzyme.
4) Activated JAK (Janus Kinase) phosphorylate tyrosine residues on receptor.
5) Tyrosine residue then binds with STAT (Signal transducer and activator of
transcription)
6) Activated JAK (Janus Kinase) also phosphorylate tyrosine residues on
STAT.
7) Phoshorylated STAT dimerise, dissociate from receptor and move to nucleus
to regulate transcription of target genes.
Regulation of Receptors (Receptor occupation theory)
1. Receptor occupation theory was founded by Clark in 1973.
2. It is based on occupation of receptors by drugs.
3. The interaction between drug (D) and receptor (R) is guided by Law
of mass action.
4. The pharmacological effect (E) is the direct function of Drug-
Receptor Complex (DR).
5. Occupation of receptor is essential but a drug/ligand must also induce
conformational changes or activate the receptor to show
pharmacological action.
6. The ability of drug to bind with receptor is called affinity.
7. The capacity of drug to induce a functional change in the receptor is
called intrinsic activity (IA) or efficacy.
8. Competitive antagonist occupies the receptor but do not activate it.
9. Partial agonist occupies the receptor but partially/submaximally
activate the receptor.
10. A theoretical quantity (S) denotes strength of stimulus passed to cell.
11. Depending on the agonist, DR could generate a stronger or weaker S.
12. S is probably the function of conformational changes brought about
by agonist in Receptor.
13. Agonists have both affinity and maximal intrinsic activity (IA=1),
E.g., Adrenaline, Histamine, Morphine.
14. Competitive Antagonist have affinity but no intrinsic activity (IA=0),
E.g., propanolol, Atropine, naloxone.
15. Partial agonists have affinity and submaximal intrinsisc activity
(IA=0-1), E.g., pentazocine on µ opoid receptor.
16. Inverse agonist have affinity but intrinsic activity with a minus sigh
(IA=0 to -1), E.g., DMCM on benzodiazepine receptors.
17. Full agonists may produce maximal response even if they occupy less
than 1% receptors on cell membrane.
18. Spare receptors are receptors that exist in excess of those required to
produce a full effect.
 Drug receptor interaction
1. Receptors are proteins on the surface of cell membrane which bind with
ligands (drugs) and produce intracellular responses.

2. An agonist (ligand) is a chemical that binds to a receptor and activates the

receptor to produce a biological response.
3. Partial agonists are drugs that bind with a receptor, but have only partial
efficacy at the receptor comparative to a full agonist.
4. An inverse agonist is a drug that binds to the same receptor as an agonist
but induces a pharmacological response opposite to that of the agonist.
5. An antagonist blocks the action of the agonist.
 Drug Antagonism
Antagonism: In antagonism, one drug decrease or stop the action of other
drug.

a. Physical Antagonism: In alkaloid poisoning, Charcoal is given.

Charcoals absorb alkaloid and prevent their absorption.
b. Chemical antagonism: In chemical antagonism two drugs react to
form an inactive product.

Poisoning Antidote MOA

Fe2+ poisoning Deferoxamine Form inactive chelate
Heparin overdose Protamine Sulfate Form inactive chelate
Acidity Sodium bi carbonate Neutralize acidity
Arsenic poisoning BAL (British anti- Form inactive chelate
Lewisite/Dimercaprol)
Mercury poisoning BAL Form inactive chelate
Lead poisoning BAL Form inactive chelate
Cadmium poisoning Calcium disodium EDTA. Form inactive chelate

c. Functional Antagonism: Two drugs act of different receptors but

have opposite effect on the same physiological function.

Drugs Opposite pharmacological actions

Histamine and Histamine cause
Adrenaline Bronchoconstriction
Adrenaline cause Bronchodilation
Glucagon and Glucagon promotes Glycogenolysis.
Insulin Insulin promotes Glycogenesis.

d. Receptor antagonism: One drug (antagonist) blocks the receptor

action of other drug (agonist).

Drugs Antagonism
Anti-cholinergic Anti-cholinergic will stop the
drugs and contraction of smooth muscles by
Cholinergic drugs antagonizing effect of Cholinergic
drugs.
Difference between Completive and non Competitive antagonism

1. Competitive antagonism:

1. The antagonist is chemically similar to Agonist.

2. Antagonist binds with the similar site of agonist.
3. Antagonist has affinity but no intrinsic activity.
4. No response is produced.

2. Non Competitive antagonism

1. The antagonist is chemically unrelated to Agonist.

2. Antagonist binds with different allosteric site thus
altering conformation of receptor.
3. Receptor is unable to bind with agonist.
 Combined Effect of Drugs
1. Synergism: In synergism, the action of one drug is facilitated by other drug.
Both drugs are said to be Synergistic. Synergism can be:
2. Additive: The effect of the two drugs in the same direction:

Additive drug Use

Aspirin+Paracetamol Analgesic/Anti-pyretic
Nitrous oxide + Halothane General Anaesthetic
Amlodipine+ Atenolol Anti-hypertensive
Glibenclamide + Metformin Hypoglycemic
Ephedrine+ theophylline bronchodilator

3. Supraadditive drug: The effect of combination is greater than the

individual effects of components.

Effect of A+B > Effect of A/ Effect of B

 Factors modifying drug actions
Age, body weight, Surface Age:
area 1) Neonates, Infant, Children

 Young’s formula (for children upto 12 years):

Child dose= Age in years/Age + 12× adult dose

 Dilling’s formula (age of child)= Age in

years/20 × adult dose

 Clark’s formula (weight of child relative to

adult) = Weight of child (kg)/70 × adult dose

 Based on body surface= body surface area m2

/18 × adult dose

2) Geriatrics
Sex In females purgatives and uterine stimulants must not
be given during menstruation.
Pregnancy and Lactation Morphine may cross placental barrier and cause
respiratory depression in foetus.

Plasma protein α acidic glycoprotein increases during

pregnancy, α acidic glycoprotein bind with basic
drugs. Basic drugs may get excreted in milk and cause
toxicity in baby.
Genetic factor Deficiency of glucose-6-phosphate dehydrogenase
(G6PD) in individuals may lead to haemolysis during
therepy with primaquine (anti-malaria), nitrofurantoin
(antibiotic to treat UTI)
Psychological state Higher dose of general anaesthetic is required in
nervous patient than in normal.
Food Tyramine containing food (milk, cheese, beer,
banana, yoghurt) when administered withMAO
inhibitors: May cause hypertensive crisis.

Tetracycline form chelate with milk.

Presence of food delays absorbtion of ampicilline.
Route of administration Magnisium sulfate (Oral): Purgative
Magnisium sulfate (i.v.): Sedative
Castor oil (topically): Soothing effect
Castor oil (oral): Purgative
Dosage form Rate of absorption

Solution>Suspention>Capsule>Tablet
Metabolic disturbances It is dealkylated by CYP450 enzyme in Liver and
excreted through Urine.

Lithium blocks sodium ion channels. Na+ levels

increases in blood. Edema: Na+ levels increases in
blood which can cause water retention and edema
mayoccur.

Chlorpromazine increase Prolactin release

(Hyperprolactemia may cause Gynaecomastia in
males).
Presence of disease Orally administered drugs are ineffective in diarrhea.
Combined effect of drugs
 Drug interactions
Drug interactions with TCAs
1. TCA potentiate effect of directly acting (bind on receptors)
Sympathomimetics: IncreaseBP.
2. Anti-cholinergic exacerbate toxicity of TCAs.
3. Phenytoin, Chlorpromazine, Aspirin displace TCAs from their protein
binding sites.Hence, they increase effect of TCAs.
4. MAO inhibitors have synergistic action with TCAs causing Hypertension,
Seizures.

Drug interactions with MAO inhibitors

1. Tyramine containing food (milk, cheese, beer, banana, yoghurt) when
administered withMAO inhibitors: May cause hypertensive crisis.
2. MAO inhibitors have synergistic action with TCAs causing Hypertension,
Seizures.
3. MAO inhibitors retard metabolism of Morphine: May cause
severe respiratorydepression.
4. MAO inhibitors retard metabolism of Sulfonyl ureas: May cause severe
hypoglycemia.
5. MAO inhibitors retard metabolism of Dopamine: May cause severe
hypertension.

Drug interactions with SSRIs

SSRIs with MAO inhibitors: 5HT levels increases causing Serotonin syndrome:
Hyperthermia,
Muscle rigidity, Tremors, Altered mental status, CVS collapse.

Anti-psychotic action of Chlorpromazine is blocked by those drugs which increase

dopamine levels like Levodopa. Those drugs which mimic action of dopamine like
Bromocriptine.
 Adverse drug reactions
According to WHO, Adverse drug reaction is any response to drug that is noxious
and unintended.

Adverse drug reaction may occur at doses used in man for prophylaxis, diagnosis,
or therapy of disease.

Types of Adverse drug reaction:

A. Type A (Predictable): Side effects, Toxic effects, Intolerance, Drug

withdrawal effects
B. Type B (Unpredictable): Idiosyncrasy, Photosensitivity
C. Miscellaneous: Carcinogenicity, Drug induced disease, Teratogenicity.

A. ADR Type A:
1. Side effects:
1. A side effect is an effect of a drug, which is in addition to
its intended pharmacological effect.
2. Side Effects can be both therapeutic and harmful.
3. Side Effects do not hinder the pharmacological action of drug.
4. Side Effects are known to doctor (Predictable)

Drug Therapeutic action Side effect

Estrogen Anti-ovulatory Nausea
Sulfonamides Anti-bacterial Hypoglycemia

2. Toxic effects:

Drugs Overdose
Barbiturate Coma
Digoxin A.V. block
Heparin Bleeding
Morphine Respiratory failure, Pin point pupil
Paracetamol Hepatic necrosis
Atropine Delirium
Cyclosporine, aminoglycoside Nephrotoxicity
antibiotics, cisplatin,
amphotericin B, beta-lactam
antibiotics and indomethacin.

Antibiotic: Amoxicilline/ Hepatotoxicity

Clavulanate,
Trimethoprim/Sulfamethoxazole,
Fluroquinolones, Macrolides,
Nitrofurantoin, Minocycline.

Antiepileptic: Phenytoin,
Carbamazepine, Lamotrigine,
Valproate

Anaesthetic agents: Halothane,

Chloroform, Isoflurane,
Desflurane, Nitrous oxide.

Anti-rheumatic drug:
Sulphasalazine, Azathioprine,
Mathotrexate

3. Intolerance (Sensitivity towards drug):

Sensitivity towards drug is measured using Gaussian frequency distribution curve.

Drug Symptoms due to high sensitivity

One tab of Vomiting and abdominal pain
Chloroquine
Few doses of Ataxia (Ataxia is a term for a group of disorders that affect co-
Carbamazepine ordination, balance and speech.)
 B. ADR Type B:

1. Idiosyncrasy:
1) Abnormal responses are shown upon administration of a drug because of
genetic responses.
2) Their responses are bizarre and do not occur in every patient.
3) The studies of idiosyncrasies are called pharmacogenetics.

SYNDROME DRUG FEATURE

Stevens-Johnson Phenytoin Epidermal necrosis and
syndrome and toxic Sulfonamides detachment
epidermal necrolysis Allopurinol Mucous membrane
NSAIDs erosions
Beta-lactams "Target" lesions

Serum sickness-like Cefaclor Fevers

reaction Cefprozil Rash
Arthralgias
Eosinophilia

Drug-induced lupus Procainamide Pleuritis

Hydralazine Musculoskeletal
Chlorpromazine complaints, eg. arthralgias
Isoniazid Fever
Methyldopa Weight loss
Penicillamine
Minocycline

Drug-induced hepatitis Azathioprine liver failure

Antiretrovirals
Statins
NSAIDs
Phenytoin
Imipramine
Amiodarone

Aplastic anaemia, Chloramphenicol Can be selective (eg.

agranulocytosis Dapsone neutropenia) or affecting
Clozapine multiple cell lineages
 Carbimazole

4. Photosensitivity:

Photosensitivity is a cutaneous reaction resulting from drug induced skin

sensitization to UV radiation. Photosensitivity reactions are of 2 types:
Phototoxic:
1. Drug or its metabolite accumulate in skin, absorb light and induce a
photobiological reaction which damage local tissue
2. It cause Sun burn, Erythema, Edema, Hyperpigmentation,etc.
3. Shorter wavelengths (290-230nm) are responsible.
4. Phototoxic drugs: Tetracyclines, Nalidixic acid, Sulfonamide, Thiazides,
Fluoroquonolones.
Photoallergic:
1. Drug or its metabolite induces a cell mediated immune response.
2. It occurs due to exposure of longer wavelength (320-400 nm).
3. It may cause Contact dermatitis, papule, and eczema on skin.
4. Photoallergy causing drugs: Griseofulvins, Chloroquine, Sulfonamide,
Chlorpromazine.

C. ADR Type C:

1. Drug induced disease:

Iatrogenic diseases are also called Physician induced diseases. Drugs used in
the treatment of a specific disease may initiate any other disease pathogenesis.
E.g.
1. Peptic ulcers by Salicylates and Corticosteroids.
2. Parkinsonism by Phenothiazines and other Anti-psychotics.
Hepatitis by Isoniazids.
 2. Teratogenicity

Teratogenicity is the capacity of drug to cause fetal abnormalities when

administered by pregnant woman.
Teratogenic drugs may cross placental barrier.
Teratogenic drugs can affect the fetus at 3 stages:
1. Fertilization and implantation (17 days)
2. Organogenesis (18-55 days of gestation)
3. Growth and development (56 days onwards)