Basic Concepts

PHARMACOLOGY
SYLLABUS
Introduction to General Pharmacology (p. 179)
Explanation of terms
Pharmacology, drug pharmacokinetics, pharmacodynamics, therapeutics, chemotherapy, Pharmacy, clinical
pharmacology, orphan drug.
Terminology of allied branches, sources of information, drug nomenclature
Definition of terms
Alkaloid, glycoside, oil, tannin
Sources and Routes of Drug Administration (p. 180)
Sources and nature of drugs:
Common sources E.g. Synthetic and Natural (Plant, Animal)
Routes of drug administration
Common routes, advantages, disadvantages, new drug delivery systems
Pharmacokinetics (p. 184)
Absorption and bioavailability of a drug:
Methods of absorption, factors affecting drug absorption and bioavailability
Bioavailaility, Bioequivalence: (p. 184) I
Definition, Significance
Distribution of drugs: (p. 185)
Concept of apparent volume of distribution, protein binding of drugs (p. 185) and its clinical importance
Blood brain barrier, Placental barrier
Biotransformation: (p. 186)
Definition, Types of reactions, Consequences, factors affecting biotransformation, clinical significance
Excretion: (p. 188)
Routes, Factors affecting
Kinetics: (p. 189)
First order, Zero order, Biological half-life
Optimization of dosage regimen: (p. 189)
Loading dose, maintenance dose and steady state plasma concentration
Therapeutic drug monitoring: (p. 190)
Importance,
Methods of prolonging the duration of action of a drug (p. 190)

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Pharmacodynamics (p. 191)

Principles of drug action (p. 191), drug-receptor interactions
Dose response relationships (p. 192), types of DRC, different components like ED50, LD50
Therapeutic index (p. 193)
Factors affecting Drug response: (p. 194)
Drug factor, Factors related to patient (p. 195): Age, Body weight, sex, Pharmacokinetics, Tolerance (p.
196), Dependence
Drug antagonism, synergism, cumulation (p. 194)
Adverse Drug Reactions
Adverse drug reactions: (p. 196)
Definition, Types, Clinical significance
Drug-toxicity: Organ-toxicity, Hypersensitivity, Teratogenicity (p. 197), Carcinogenicity, dependence (p. 198)
Heavy metals: (p. 198)
Antagonists (brief), Chelators
Dimercaprol, dpenicillamine, EDTA
Essential drug concept and Rational Drug Therapy: (p. 199)
Essential Drug Concept: Principles, Importance, Model list preparation
Rational drug therapy: Concept, Example: p-drug concept

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PHARMACOLOGY
♦ Pharmacotherapeutics:
INTRODUCTION TO GENERAL
- Pharmacotherapeutics refers to the judicious
PHARMACOLOGY application of the pharmacological knowledge
Explanation of terms with the knowledge of the disease for its
prevention, control or treatment.
♦ Pharmacology: (Pharmacon-drugs, logos-
discourse) ♦ Chemotherapy:
- Chemotherapy refers to the treatment of
- Pharmacology is the science of drugs that deals
systemic infection of malignancy with specific
with the interaction of exogenously
drugs that possess selective toxicity for the
administrered chemical molecules other than
infective organism or malignant cell with
foods, with the body, either at the cell, tissue,
no/minimal side effects on the host cells.
organ or system level.
♦ Pharmacy:
♦ Drug:
- Pharmacy is the art and science of
- According to WHO (1996), compounding and dispensing drugs or
“ Drug is any substance or product that is used preparing suitable dosage forms for
or is intended to be used to modify or explore administration of drugs to man and animals.
physiological systems or pathological states for - It includes collection, identification,
the benefit of the recipient.” purification, isolation, synthesis,
♦ Pharmacokinetics: (Pharmacon-drug, kinesis- standardization and quality control of I
medicinal products.
movement)
♦ Clinical pharmacology:
- Pharmacokinetics refers to the quantitative
- This is the scientific study of drugs in individual
study of the movement of the drug into the
subjects for obtaining data for the optimum
body, alteration and processing within the
use of drugs
body and its elimination out from the body.
- It includes:
- Pharmacokinetics deals with the following
a. Pharmacokinetic & pharmacodynamic
major processes:
investigation
a. Absorption b. Evaluation of efficacy and safety
b. Distribution c. Study of usage patterns, adverse effects,
c. Metabolism etc.
d. Excretion [@ADME] ♦ Orphan drugs:
♦ Pharmacodynamics: (Pharmacon- drug, dynamis- - These are the drugs or products for the
power) diagnosis or treatment of a rare disease or
condition for which there is no reasonable
- Pharmacodynamics refers to the physiological
expectation that the cost of developing and
and biochemical effects of drugs and their
marketing the drug will be recovered from its
mechanism of action at organ-system or
sales.
subcellular or macromolecular level
E.g. Sodium nitrite, Femopizole, Rifabutin, etc.

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SOURCES AND ROUTES OF DRUG 2. Fixed oils (non-volatile):

ADMINISTRATION E.g. Ground nut oil, Coconut oil, Castor oil, etc.
Past Questions: 3. Mineral oil:
1. a. List drugs used by inhalation and give its - Mostly petroleum products
advantages. - Mainly used as vehicles for preparation of
b. Enumerate advantages of sublingual route of ointment
drug administration E.g. Liquid paraffin
c. List importance of enzyme induction [03] Gums:
2. Write short note on: These are the colloidal exudates of plants.
a. Sublingual route of drug administration - They either swell or dissolve or form adhesive
mucilage in water.
Source and nature of drugs:
- They are used as emulsifying or suspending
A. Natural Sources: agents.
1. From plants: E.g. Gum acacia, Gum tragacanth
Alkaloids: Tannins:
- These are the basic, nitrogenous, heterocyclic - Non-nitrogenous phenolic derivatives from
compounds of plant origin which are
plant source.
crystalline, bitter in taste and soluble in
alcohol. Their names usually end with ‘-ne” - Used as astringents
E.g. E.g. Tincture of catechu
• Atropine - obtained from Atropa belladonna Resins:
• Quinine - obtained from Cinchona bark - Polymers of volatile oil and insoluble in water
E.g. shellac (in enteric coating), tolu of balsam
I • Morphine - obtained from Papaver
somniferum (as expectorant)
• Reserpine -obtained from Rauwolfia 2. Animal sources:
serpentine leaves - Used for extracting hormones, vitamins,
Glycosides: vaccines, sera, etc.
- These are the plant products fromed by the E.g. Insulin, Vitamin B12, Thyroxine, etc.
condensation of a sugar moiety (a 3. Microbiological sources:
monosaccharide or monosaccharide residue) - Fungi - Penicillin, Cephalosporin, Griseofulvin
with another sugar or non-sugar moiety
- Bacteria - Polymyxin B, Aztreonam, Bacitracin,
through an ether linkage.
Colistin
- When the sugar moiety is glucose, it is called a
glucoside - Actinomycetes - Aminoglycosides, Macrolides,
- When the sugar moiety is an amino sugar, it is Tetracycline, Macrolides, Chloramphenicol
called an aminoglycoside 4. Mineral sources:
E.g. Digoxin - obtained from Digitalis purpura. E.g. Ferrous sulphate (iron supplementation in
Ouabain - Stropanthus gratus anemia)
Oils: - Magnesium sulphate (as a purgative)
1. Essential oils (volatile oils): - Aluminium hydroxide and sodium bicarbonate
- Obtained from leaves or flower petals (as antacid)
- Also used as flavoring agents - Radioactive iodine (I131) (for treatment of
E.g. Eucalyptus oil, Clove oil, Peppermint oil thyrotoxicosis)
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B. Synthetic sources: e. Nasal

- These are the drugs synthesized in the f. Inhalational
laboratory. g. Parenteral:
- Better quality control can be obtained. - Intravenous
E.g. Aspirin, Paracetamol, Phenytoin, - Intramuscular
Chlorpromazine, Amphetamine, etc. - Intradermal
C. Genetically engineered drugs: - Sub-cutaneous
- These are the drugs obtained through 1. Local Routes:
recombinant DNA technology through
♦ These allow the drug to exert its effects at the
manipulation of genes in variety of micro-
local site without exerting any adverse effect or
organisms such as yeast, bacteria, etc.
toxicity to the rest of the body.
E.g. Hep. B vaccine Recombinex, Insulin (Humulin)
a. Topical:
Routes of drug administration - External application of the drug on the
♦ Same drug can be administered to a patient surface (skin or mucous membrane) for
through a variety of routes. localized action.
♦ The route of administration is selected on the i. Skin: ointment, cream, lotion, paste,
basis of a number of drug-related as well as powder, dressing, spray, etc.
patient-related factors. ii. Mucous membranes:
A. Drug-related factors: • Mouth and pharynx: paints, lozenges,
- Physical and chemical properties of the drug. mouth-wash, gargles
E.g. State, Stability, Solubility, pH, etc. • Eyes, ears and nose: drops, ointments,
- Rate and extent of absorption from different irrigational fluids, nasal sprays.
from different routes. I
• GI tract: Mg(OH)2, Sucralfate
- Effect of digestive juices and first pass
Note:
metabolism on drugs.
These drugs don’t affect the physiology of digestion
B. Patient- related factors:
but only act locally on mucosa, hence the route is
- Site of the desired action - local or systemic topical.
- Rapidity of the response required
• Bronchi and lungs: inhalations, aerosols
- Accuracy of the dose required (Salbutamol)
- Condition of the patient
• Urethra: jellies (Lidocaine)
♦ The different routes of administration are:
• Vagina: pesseries, creams, powders
1. Local routes:
• Anal canal: ointments, suppositories
a. Topical
b. Deeper tissues:
b. Deeper tissues
- Administering a drug to deep areas using a
c. Arterial supply syringe and a needle but acting only locally
2. Systemic routes: without diffusing systemically.
a. Oral E.g.
b. Sublingual/buccal • Intra-articular injection- Hydrocortisone
c. Rectal acetate
d. Cutaneous • Infiltration around a nerve - Lidocaine

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c. Arterial supply: Advantages:

E.g. - Rapid absorption and effect (E.g. GTN in
- Intra-arterial injection of contrast media in angina)
angiography - Effect can be terminated after desired
- Intra-arterial infusion of anti-cancer drugs action by spitting the tablet
for limb malignancies - First pass metabolism is avoided.
2. Systemic routes: Disadvantages:
These allow the drug to be absorbed and diffused - Inconvenient for frequent use
into the systemic circulation and exert widespread - Larger doses can’t be given
effects.
- Mucosal irritation and excess salivation
a. Oral route:
c. Rectal route:
- Oldest and commonest route of
administration - The drugs are inserted into the rectum as
suppositories (solid forms) or retention enema
- The drug is administered in solid dosage
(drug in water solution) to be absorbed into
forms (E.g. powders, tablets, capsules,
the systemic circulation.
spansules, matrix tablets, etc.) or in
liquid dosage forms (E.g. syrups, elixirs, - Drugs given by this route: Diazepa,,
emulsions, mixtures) Indomethacin, Paraldehyde
Advantages: Advantages:
- Safe and non-invasive (painless) - Drugs irritant to stomach (e.g Indomethacin)
- Convenient as self-medication is can be given
possible. - Suitable in unconscious, uncooperative or
I - No need for sterilization of drugs vomiting patient
- Cheap - Useful in children or elderly who have difficulty
Disadvantages: swallowing
- Slow onset of action and not suitable in - About 50 % bypasses liver metabolism.
emergencies. Disadvantages:
- May exert irritant or unpleasant (E.g. - Absorption may be irregular and unreliable.
nausea, vomiting) effects. - Patient may feel embarrassed.
- Difficulty in administering to - Self-medication usually difficult.
unconscious, uncooperative or vomiting
- Rectal inflammation.
patient
- Some drugs may be destroyed by gastric Note:
juices (E.g. insulin) Nitroglycerin ointment for anal fissure is local
- Absorption can be variable or irregular, (topical) route. Diazepam given intra-rectally for
hence unreliability of drug action. febrile seizure is systemic (rectal) route.
b. Sub-lingual/buccal routes: [11, 03, 02] d. Cutaneous route:
- The drug containing tablet is placed under - The drug (should be highly lipid soluble) is
the tongue or crushed and spread over the applied over the skin for slow and
buccal mucosa. prolonged absorption.
- Drugs given by this route: GTN, - Absorption enhanced by rubbing, using an
Buprenorphine oily base or occlusive dressing.

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Advantages: Disadvantages:
- Easy application with better patient • Quick action is not achieved.
compliance. • Not useable in vasoconstricted patients
- First pass metabolism avoided. (E.g. haemodynamic shock)
Disadvantages: • Irritant drugs cause inflammation, pain
- Absorption not regular or reliable. and necrosis.
- Local erythema, swelling and irritation may ii. Intra-muscular (i.m.) injection:
occur. • Drug injected into large muscles like
e. Nasal route: deltoid, gluteus maximus, rectus
femoris, etc.
- The drug is applied as spray or nebulized
solution is absorbed from the nasal mucosa. Advantages:

- Drugs used by this route: GnRH agonists • Easier to administer as less painful.
(Nafarelin), Desmopressin • Absorption quicker, uniform and
predictable
f. Inhalational route:
• Depot preparations can be used.
- The drug in the form of volatile liquid or gas
Disadvantages:
is inhaled and absorbed into the blood
through alveoli. • Self-administration difficult - deep
penetration required.
- Drugs used by this route: General
• Insoluble drugs not absorbed
anaesthetics
• Defective technique may damage nerves
Advantages:
and vessels.
- Drugs as gases/aerosols can be rapidly
iii. Intra-venous (i.v.) route:
taken up/eliminated. I
• Drug injected either bolus or by slow
Disadvantages: infusion into one of the superficial veins.
- Special apparatus is required. Advantages:
- Irritant vapours can cause inflammation and • Rapid attainment of blood drug level and
increased secretion. quick action - useful in emergencies.
g. Parenteral routes (par-beyond, enteral- • First pass metabolism totally avoided.
intestinal) • No absorption process involved - blood
- Administration of a drug by injection levels uniform and accurately
directly into tissue fluid or blood without predictable.
having to cross the intestinal mucosa. • Suitable for unconscious, vomiting or
i. Sub-cutaneous (s.c.) route: uncooperative patients
• Drug deposited in the loose sub- • Least dose of the drug is effective.
cutaneous tissue • Large doses can be given as
Advantages: instantaneously diluted.
Disadvantages:
• Absorption is slow - useful when long
duration of action is needed. • Only aqueous solutions injectable.
• Painful and difficulty in self-
• Deep penetration is not needed - self-
administration
injection possible.

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• Defective and unsterile techniques may c. Liposomes:

lead to pain, inflammation and infection - Fatty droplets made artificially in the lab by
• Most risky route as vital organs (heart, addition of water solution to a phospholipid
brain) get directly exposed to high gel-mimic natural phospholipid membranes.
concentrations - Liposomes encapsulate the active drugs and
• Chances of allergic reactions, local enhance their delivery.
vanous thrombosis and hemolysis. - Often attached to molecules like
iv. Intra-dermal route: polyethylene glycol (PEG) that will prevent
• The drug is injected into the dermis of detection by immune system.
the skin, thus raising a bleb.
• This route is used for BCG vaccination,
PHARMACOKINETICS
allergen-sensitivity testing. Past Questions:
3. Newer drug delivery systems: 1. Briefly describe the clinical significance of:
a. Implants: (3×3=9) [10 Jan]
- The steroid drug implanted under the skin, a. Tolerance
from which the steroid is released slowly b. Volume of distribution
over a period of 1-5 years.
c. Elimination kinetics of drug
- May contain:
2. Write short notes on:
• Bio-degradable polymeric matrices, which
don’t need to be removed on expiry a. Biological half life [06 Dec, 02 Dec]
(Leuprolide acetate in prostate cancer) b. Method of prolonging the duration of action
• Non-biodegradable rubber membranes, [10 Jan]
which need to be removed on expiry c. Synthetic reactions [08 July]
(Norplant) d. Bioavailability [10 July, 07 July, 04 June]
I - Norplant: A set of 6 capsules (×36 mg=216 e. Plasma protein binding
mg) levonorgestrel used for subcutaneous
[09 July, 07July, 04 June]
implantation as a method of contraception
f. Volume of distribution [04 Dec]
- Progestasert: A progesterone containg
intra-uterine insert acting locally on the g. First pass metabolism [09 July, 06 Dec, 05 Dec]
endometrium. [04 Dec, 04 June, 03 June,]
b. Transdermal Drug Delivery System: h. Phases of drug metabolism and their
- Consists of adhesive patches that deliver significance [06 June]
the drug into the systemic circulation at a i. Fixed dose ratio combination in
pre-determined and controlled rate across pharmaceutical preparations [05 Dec]
the patient’s skin j. 1st order kinetics (2) [09 Jan]
- Drug held in a reservoir between an k. Drugs metabolized by acetylation [03 June]
occlusive backing film and a rate controlling
3. Define bioavailability. Explain factor affecting
micropore membrane.
bioavailability of drugs. (2 + 3 = 5) [05 June]
- Due to micropore membrane, the drug
delivered to skin surface is less than the Bio-Equivalence
slowest possible rate of absorption from the ♦ Two or more pharmaceutical products are said to
skin. Thus, drug delivery independent of be pharmacologically bio-equivalent if their bio-
skin variations. availabilities after administration in the same
- Provide smooth plasma concentrations, molar dose are similar to such a degree that their
minimize individual variations and side- biological effect on the recipient are expected to
effects. be almost the same.

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♦ Similar drugs may not always be bio-equivalent due to
the effect of additional components such as diluents,
stabilizing agents, binders, lubricants, etc.
Volume of distribution [04, 03]
♦ Definition: The (apparent) volume of distribution
is defined as the volume of fluid required to
accomodate the total amount of drug
homogeneously at the concentration found in the
blood plasma.
♦ If ‘Q’ is the total amount of the drug administered
and ‘Cp’ is the concentration of the drug in the
plasma, then, the hypothetical volume of
distribution will be given by:
Vd = Q/Cp
♦ Higher the tissue-binding of the durg, higher will
be the Vd because the Cp will be lower in such
cases.
- Lipid insoluble drugs do not enter the cells and
their Vd approximates the extracellular fluid
volume.
- Drugs extensively bound to plasma proteins
have low Vd .
- Drugs sequestered in other tissues have high Vd.
Factors governing volume of distribution:
- Lipid-water partition coefficient of the drug.
- pKa value of the drug
- Degree of plasma-protein binding
- Affinity for different tissues
- Fat: lean body mass ratio
- Diseases such as CHF, uremia, cirrhosis
Re-distribution
♦ Highly lipid-soluble drugs are initially distribted to
organs with higher blood-flow such as brain,
heart, kidney, etc while later, they enter less
vascular but more bulky tissues such as muscle &
fat. This phenomenom is called re-distribution.
♦ Greater the lipid-solubility of the drug, higher is
the re-distribution phenomenom.
♦ It is an important aspect of CNS drug-dosage (such
as nitrazepam, thiopentone sodium) because the
duration of action of an initial dose may depend
more upon the re-distribution than on the drug’s
half-life. With repeated doses, the low perfusion
high capacity sites are gradually filled up and the
drug becomes long-acting.
FAST TRACK
Basic Concepts
Plasma-protein binding [09, 07, 04]
♦ This is the physio-chemical affinity of the drugs to
certain proteins in the blood plasma.
♦ Generally, acidic drugs bind more to plasma
albumin
E.g. Barbiturates, Penicillins, Sulfonamides,
Tetracycline, NSAIDs, etc.
♦ Generally, basic drugs bind more to plasma α1-
glycoprotein
E.g. β-blockers, Quinidine, Verapamil, Lidocaine,
etc.
Clinical importance of plasma-protein
binding:
- Drugs with higher drgree of plasma-protein
binding have low volume of distribution
because protein-bound drugs don’t cross the
membranes easily.
- Only the free-form of the drug is available for
action. The bound form slowly dissociates to
remain in equilibrium with the free form which
is reduced due to elimination.
- Higher degree of protein-binding prolongs the
duration of action of the drug because the
bound form is unavailable for metabolism or I
excretion.
- The expressed plasma concentration of the
drug refers to the combination of both bound
and free-form of the drugs in the plasma.
- One drug can bind to many sites on the
albumin molecule. Conversely, many drugs can
bind to the same site.
- In hypoalbuminemia and uraemia, protein-
binding of drugs is reduced while in pregnancy
and inflammatory diseases, it is increased.
Blood-brain barrier
♦ It is a biological barrier between the blood vessels
in the brain and the brain tissue which prevents
numerous drugs from entering into the brain
tissue.
♦ It consists of the following two components:
a. Mechanical component:
- Tight junctions and lack of intercellular
pores between the endothelial cells
- Investing foot processes from the glial cells.
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b. Physiological component: • Mostly carried out in the liver by a group

- Efflux transporters such as P-gp and OATP of monooxygenase enzymes involving
that extrude the drug that enter the brain cytochrome P-450 haemo-protein,
- Enzymatic barrier consisting of MAO, NADPH, cytochrome P-450 reductase,
Cholinesterases, etc. which prevent entry of molecular oxygen.
catecholamines, serotonin, acetylcholine, E.g. of drugs metabolized by oxidation
etc from entering the brain are barbiturates, phenothiazines,
benzodiazepines, paracetamol, etc.
- The BBB is absent at the CTZ in the medulla
ii. Reduction:
oblongata and at certain periventricular
sites such as the anterior hypothalamus. • Converse of oxidation reaction and
involve the P-450 enzyme working in the
Biotransormation [08, 03] opposite direction.
♦ Definition: Bio-transformation is the chemical E.g. Chloramphenicol, Warfarin,
alteration of the drug in the body through which Chloralhydrate, etc.
non-polar (lipid-soluble) drugs are rendered polar iii. Hydrolysis:
(lipid-insoluble) so that they are not reabsorbed in • Cleavage of the drug molecule by
the renal tubules and are excreted. addition of a molecule of water.
♦ Bio-transformation can perform the following • Esters hydrolyzed by esterases, amides
actions on the drug: by amidases, peptides by peptidases,
i. Inactivation of the drug: E.g. Ibuprofen, etc.
Paracetamol. E.g. Choline esters, Lidocaine, Aspirin,
ii. Conversion of an active drug to its active Oxytocin, etc.
metabolite: iv. Cyclization:
I
E.g. Allopurinol → Alloxanthine, Codeine → • Formation of ring structure from a
Morphine straight chain compound.
iii. Conversion of inactive drug to active E.g. Proguanil.
metabolite: v. Decyclization:
E.g. Levo-dopa → Dopamine, Bacampicillin→ • Formation of straight chain structure
Ampicillin from ring-structure.
Phases of biotransformation: E.g. Barbiturates, Phenytoin.
a. Phase I/ Non-synthetic/ Functionalization b. Phase II/Synthetic/Conjugation reactions:
reactions:
- Involve conjugation of the drug or its phase
- A functional group is generated or exposed. I metabolite with an endogenous
- It may involve the following processes: compound to form a highly polar organic
i. Oxidation: acid, easily excretable into urine or bile.
• Involves the addition of oxygen / - Depending upon the compound added,
negatively charged radicle or removal of various conjugation reactions are:
hydrogen / positively charged radical. i. Glucuronide conjugation:
• May involve hydroxylation, oxygenation • Addition of glucuronide catalyzed by a
at C, N or S atoms, N or O-dealkylation, group of UDP- glucuronosyl transferases
oxidative deamination, etc. (UGTs)

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• Used by compounds containing hydroxyl
or carboxylic acid group. E.g.
chloramphenicol, aspirin, paracetamol.
• Undergo entero-hepatic circulation after
being hydrolyzed by the bacteria in the
gut.
ii. Acetylation: [03]
• Addition of acetyl group catalyzed by
acetyl CoA
• Used by drugs with amino or hydrazine
groups. E.g Sulfonamides, Isoniazid.
iii. Methylation:
• Addition of methyl groups with
methionine or cysteine acting as donors.
• Used by drugs with amine or phenol
groups. E.g. Adrenaline, Histamine,
Methyl-dopa.
Comparison between microsomal and non-microsomal enzymes
Microsomal Enzymes
Location Smooth endoplasmic reticulum, mostly in Cytoplasm and mitochondria, mostly in liver
the liver, but also in the kidney, intestinal but also other tissues and plasma
mucosa and lungs
Nature Inducible by drugs, diet and other agents
Reactions carried out Most oxidations, reductions, hydrolysis and Some oxidations and reductions, many
glucuronide conjugation
Examples Monooxygenases, cytochrome
glucuronyl transferase
Microsomal enzyme induction
[09, 05, 02, 03]
♦ Microsomal enzymes can be induced by the
administration of some drugs, insecticides and
carcinogens.
♦ Such induction may cause increased metabolism
of the same (inducing) drug or other drugs.
♦ Inducing drug may bind to the cytosolic receptors,
which may inturn bind to specific DNA sequences
that are associated with the production of certain
drug-metabolizing enzyme.
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Basic Concepts
iv. Sulfate conjugation:
• Addition of sulfate group catalyzed by
sulfotransferases.
• Used by phenolic compounds and steroids.
E.g Chloramphenicol, Methyl-dopa
v. Glycine conjugation:
• Used by salicyates and other drugs with
carboxylic acid groups.
vi. Glutathione conjugation:
• Formation of mercapturate used by
highly reactive quinine or epoxide
intermediates formed during the
metabolism of certain drugs. E.g
Paracetamol.
vii. Ribonucleoside/nucleotide synthesis:
• Used for activation of many purine and
pyrimidine antimetabolites used in
cancer chemotherapy.
Non-microsomal enzymes
Not inducible but may show genetic
I
polymorphism
hydrolysis reactions and all conjugations
except glucuronidation.
P-450, Flavoprotein oxidases, esterases, amidases
and conjugases
Examples of enzyme-inducing drugs:
- Phenobarbitone, rifampin, glucocorticoids
induce CYP3A enzymes
- Isoniazid induces CYP2E1 enzymes.
- Rifampin induces CYP2D6 enzymes.
Consequences of Microsomal Enzyme
induction:
1. Decreased intensity and/or duration of action of
drugs that are inactivated by metabolism.
E.g. Failure of contraception contraception with
OC.
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2. Increased intensity of drug action that are
activated by metabolism.
E.g. Acute paracetamol toxicity.
3. Tolerance - if the drug induces its own
metabolism.
E.g. Carbamazepine, Rifampin.
4. Faster metabolism of some endogenous
substrates.
E.g. Steroids, Billirubin.
5. Precipitation of acute intermittent porphyria: due
to increased porphyrin synthesis
6. Difficulty in adjustment of of dose of one drug due
to intermittent use of an inducer.
E.g. Oral anticoagulants, Antiepileptics.
Possible uses of microsomal enzyme
induction:
1. Congenital non-hemolytic jaundice - reabsorbed in acidic urine while weak acids
Phenobarbitone
2. Cushing’s syndrome - Phenytoin
3. Chronic poisonings
4. Liver diseases
First pass metabolism [09, 06, 05, 04, 03]
Definition:
I ♦ This is the metabolism of the drug during its
passage from the site of absorption into the
systemic circulation.E.g.
- Metabolism of orally administered drugs in the
instestinal wall and the liver
- Metabolism transdermally administered drugs
in the skin
- Metabolism of drugs reaching the venous
route in the lungs
♦ Attributes of drugs with high first pass
metabolism:
i. Oral dose is considerably higher than
sublingual or parenteral dose
ii. There is marked individual variation in the oral
dose due to differences in the extent of first
pass metabolism.
iii. Oral bioavilability is apparently increased in
patients with severe liver diseases.
iv. Oral bioavailability of a drug is increased if
another drug competing with it in first pass
metabolism is given concurrently.
E.g Chlorpromazine and Propranolol.
-188- FAST TRACK
Excretion of drugs
Routes of excretion:
A. Urine:
- Excretion of the drug through kidney is the
most important route.
- The amount of drug excreted is given by:
Net renal excretion = (Glomerural filtration +
Tubular secretion - Tubular reabsorption)
- Glomerural filtration depends upon the total
renal blood flow and the protein-binding of the
drug.
- Tubular reabsorption depends upon the lipid
solubility and ionization of the drug at the
urinary pH.
- Weak bases ionize more and are less
ionize more and are less reabsorbed in alkaline
urine.
- Tubular reabsorption is carried out by different
non-specific transporters such as OATP, OCT, P-
gp efflux transporters, MRP2, etc.
B. Faeces:
- Most of the drug in faeces comes from bile.
- The liver actively transports into bile organic
acids (by OATP and MRP2), organic bases (by
OCT), lipophilic drugs (by P-gp), etc.
- Certain drugs are excreted directly in colon.
E.g. Antracene purgatives, Heavy metals.
C. Exhaled air:
- Gases and volatile liquids (general
anaesthetics, paraldehyde, alcohol) are
eliminated by lungs.
D. Saliva and sweat:
- Lithium, potassium iodide, rifampin and heavy
metals are present in these secretions in
significant amounts.
E. Milk:
- More lipid soluble and less protein-bound
drugs enter the breast milk better.
- Amiloride, Cyclosporine, Indomethacin are
some drugs contraindicated in breast-feeding.
BASIC SCIENCE MBBS

Kinetics of elimination:
Clearance (CL):
- The clearance of a drug is the theoretical
volume of plasma from which the drug is
completely removed in unit time.
- It is calculated as:
CL = rate of elimination / plasma concentration
of the drug
First Order (Exponential) Kinetics: [09]
- A constant fraction of the drug is eliminated
per unit of time.
- For example, if 800 mg of a drug is
administered and its half-life is 1 hr, then the
amount of drug remaining in the blood after
each hour will be as follows:
800mg→ 400mg→ 200mg→ 100mg→ 50mg…
and so on
- Graphically, first order kinetics follows an
exponential decay curve (hyperbolic)
- Attributes of First Order Kinetics:
• Rate of drug elimination is directly
proportional to drug concentration
• CL remains constant
• T1/2 remains constant
Note:
- Rate of drug metabolism = Vmax [C]/Km+[C]
- Where, Vmax= maximum rate of drug elimination
Km= plasma concentration at which elimination
rate is half-maximal.
- When concentration of drug [C] is much less than
Km, then,
- Rate of drug elimination= Vmax [C]/Km
i.e. rate of elimination is directly proportional to [C]
- Thus, at low concentration of drug, the elimination
is always first order.
Zero Order (Linear) kinetics: [03]
- A constant amount of drug is eliminated per
unit time.
- There is no fixed half-life for the drug.
For example, if 500 mg of drug is administered
and 100 mg is eliminated every hour, the
amount of drug after each hour is:
500mg→ 400mg→ 300mg→ 200mg→ 100mg
FAST TRACK
Basic Concepts
- Graphically, zero order kinetics follows a linear
decay curve.
- Attributes of zero-order kinetics:
• The rate of elimination is constant
• CL increases with decrease in concentration
of the drug.
• T1/2 decrease with decrease in
concentration of the drug.
Note:
- When the concentration of the drug is much
higher than Km, then, Rate of elimination =
Vmax[C]/[C] =Vmax = constant
- Thus, at high drug concentrations, the elimination
is zero order.
- In case of some drugs, kinetics change from first
order to zero order at higher doses.E.g. Phenytoin,
Tolbutamide, Theophylline, Warfarin, etc.
Plasma Half-Life (T1/2) [06, 02]
Definition: The time taken for the plasma
concentration or the amount of drug in the body
to be reduced to half.
For drugs eliminated by:
- First order kinetics - T1/2 remains constant
- Zero order kinetics - T1/2 increases with dose
because CL progressively decrease with I
increase in dose.
Factors determining half-life of a drug:
- Route of administration of drugs
- Amount of drug administered
- Age of patients: during childhood and old age,
renal and hepatic elimination are relatively
weaker.
- Genetic factors: due to variations in enzymatic
actions
- Plasma-protein binding of the drugs
- Drug metabolism
- Elimination kinetics
Optimization of dosage regimen
Steady state plasma concentration:
- When a drug is repeated at relatively short
intervals, it accumulates in the body until the
elimination of the drug balances its input and
hence a steady state plasma concentration is
attained.
- This steady state concentration is given by:
Cpss = dose rate/CL [where, CL=clearance]
BASIC SCIENCE MBBS -189-
 Pharmacology

Target level strategy: Uses of therapeutic drug monitoring:

- For those drugs whose effects are not easily - Drugs with low safety margin - digoxin, anti-
quantifiable and safety margin is not big (E.g. convulsants, antiarrhythmics, aminoglycoside
Anticonvulsants, Antidepressants, Lithium, antibiotics, tricyclic antidepressants.
Antiarrhythmics, etc.), it is best to aim to - If individual variations are large -
achieve a certain steady state plasma
antidepressants, lithium
concentration which is defined to be in the
therapeutic range. - Potentially toxic drugs used in the presence of
renal failure - aminoglycoside antibiotics,
- It is achieved through the concept of loading
dose and maintenance dose. vancomycin.

Loading dose: - In case of poisoning.

- This is a single or a few quickly repeated doses - In case of failure of response without any
given in the beginning to attain the target apparent reason - Antimicrobials
concentration. - To check patient compliance-
- It takes into account only the total plasma psychopharmacological agents.
volume without considering the elimination of Methods of Prolongation of Drug
the drugs, i.e. dependent on ‘V’ and not on ‘CL’
Action [2010]
[V= volume of distribution, CL= clearance]
- It is given by: 1. By prolonging absorption from site of
Loading dose = target Cp ×V/F absorption:
[where, F= the fraction of drug reaching the Oral:
systemic circulation in active form after oral - Sustained release tablets, capsules, spansules.
administration].
I - Drugs coated with resins, plastic materials or
Maintenance dose: any substances which temporarily disperse
- This is the dose to be repeated at regular release of the active ingredient in the gut.
intervals of time after attainment of target Cpss
- Control release tablets which use a semi-
so as to maintain it.
permeable membrance to control the release
- From the equation of steady state plasma
of drug from dosage form.
concentration,
Dose rate = CL × Cpss/F Parenteral:
Hence, the maintenance dose is given by: - The s.c and i.m injection of drug in soluble form
Maintenance dose = target Cpss × CL/F (benzathine penicillin, lenti-insulin)

Therapeutic drug monitoring: [06] - As oily solution (depot progestin), pellets,

♦ The Cpss of the drug in a patient’s body is
dependent upon F, V and CL in that patient and
such parameters can vary widely among
individuals.
♦ Measurement of attained Cpss can give an estimate
of the pharmacokinetic properties of the
individual and adjust the dosage regimen.
♦ Revised dose rate= Previous dose rate × Target
Cpss / Measured Cpss
-190- FAST TRACK BASIC SCIENCE MBBS
implants, etc, that can provide absorption for
many days to years.
- Inclusion of vasoconstrictor with the drug
delays the absorption (E.g. Adrenaline with
local anaesthetics)
Transdermal:
- Adhesive patches, strips or as ointment applied
on skin.
 Basic Concepts

2. By increasing plasma protein binding: Principles of drug action

- Drugs highly bound to plasma protein are
slowly released in active form. E.g.
Sulfonamides
3. By retarding the rate of metabolism:
- Applying small chemical modifications to the
drug.
E.g. Addition of ethinyl group to estradiol
makes it longer acting and suitable fro use as
an oral contraceptive
- Inhibition of specific enzyme that metabolizes
the drug.
E.g. Allopurinol inhibits the degradation of 6-
mercaptopurine.
4. By retarding renal excretion:
♦ Suppression of renal tubular secretion by using a
competing substance
E.g. Probenecid prolongs duration of action of
penicillin and ampicillin.
♦ The different facets of drug action are as follows:
a. Stimulation:
- It refers to the selective enhancement of the
level of activity of specialized cells. E.g
Adrenaline stimulates the heart, Pilocarpine
stimulates the salivary glands.
b. Depression:
- It refers to the selective diminution of the
activity of specialized cells. E.g. Barbiturates
depress CNS, Quinidine depresses heart.
c. Irritation:
- It refers to a non-selective, often noxious effect
and is particularly applied to less specialized
cells (epithelium, connective tissue)
- Mild irritation can stimulate the function while
heavy irritation can cause inflammation,
corrosion or necrosis.
d. Replacement:

PHARMACODYNAMICS - It refers to the use of natural metabolites,

Past Questions:
1. Write short notes on:
a. Therapeutic index
b. Receptor regulation
c. Synthetic reactions
d. Synergism
e. Receptor antagonism
f. Antagonism
g. Competitive antagonism
h. Drug antagonism
i. Types of drug antagonism
j. Microsomal enzyme induction
[09 Jan, 05 June, 02 Dec]
k. Tolerance
l. Differences between agonist and antagonist,
give example
m. Significance of monitoring
concentration
hormones or their congeners in deficiency
states. E.g. Levo-dopa in parkinsonism, Insulin
in diabetes mellitus. I
[06 June, 04 June] e. Cytotoxic action:
[08 July] - Selective cytotoxic action for invading parasites or
[08 July] cancer cells with no or minimal effect to the host
(3) [11 July] cells. E.g. Anti-microbials, Anti-cancer drugs.
[07 July] Receptor
[04 June] ♦ A receptor is defined as a macromolecule or
[03 June] binding site located on the surface or inside the
effector cell that serves to recognize the signal
[02 Dec]
molecule/drug and initiate the response to it, but
[10 July] itself has no other function.
Drug-receptor interactions:
The following terms are used to describe the
[03 Jan, 04 Dec] various drug-receptor interactions:
- Agonist:
[06 Dec] • An agent which binds to a receptor to
drug plasma produce an effect similar to that of the
[06 June] physiological signal molecule

FAST TRACK BASIC SCIENCE MBBS -191-

 Pharmacology

- Inverse agonist: Receptor down-regulation Receptor up-regulation

• An agent which binds to a receptor to - Results due to prolonged - Results due to
produce an effect in the opposite direction use of agonist prolonged use of
to that of the agonist. antagonist
- Antagonist: - Decreased number and - Increased number
• An agent which prevents the action of an sensitivity of receptors and sensitivity of
agonist on a receptor or the subsequent receptors
response, but does not have any effects of - Decreased response to - Increased response
its own the action of drug to the action of drug
- Partial agonist: E.g. down-regulation of E.g. withdrawal
• An agent which binds to a receptor to β2 adrenergic receptors syndrome in
produce submaximal effect but antagonizes due to repeated use of β2 patients after
the action of a full agonist agonists in chronic stopping prolonged
bronchial asthma propanolol use,
- Ligand:
patients leading to
• Any molecule which attaches selectively to Refractorism and ‘on-off’ nervousness,
particular receptor or sites. (A collective effect seen in anxiety, palpitation,
term for agonists, antagonist, inverse or Parkinsonism patients tachycardia,
partial agonists) treated with levo-dopa increased BP, etc.
Different types of receptors: for prolonged time due to up-regulation
of β-adrenoceptors.
a. G-protein coupled receptors:
i. Acting through adenylyl cyclase pathway: Dose-response relationship
M2 muscarinic, β-adrenergic, D2-dopaminergic ♦ Dose refers to the amount of drug or medicinal
I preparation to be administered at required
ii. Acting through IP3-DAG pathway:
intervals for desired therapeutic action.
H1-histaminic, α1-adrenergic
♦ The pharmacological effect of a drug depends
iii. Acting through channel regulation: upon its concentration at the site of action, which
Opioid-κ, GABAB in turn depends upon the dose of the drug
b. Receptors with intrinsic ion-channels: administered.
Nicotinic receptors, GABAA ♦ Thus, dose-response relationship is a combined
concept which unites ‘dose-plasma concentration’
c. Enzyme-linked receptors:
relationship and ‘plasma concentration-response’
Insulin receptor, Growth-factor receptor relationship
d. Nuclear receptors: ♦ Dose-response curve is a rectangular hyperbola
Steroid receptors, Thyroid hormone receptor because drug-receptor interaction follow the laws
of mass action
Receptor regulation: [08, 07]
Response (E) = Emax × [D]/Kd + [D]
- Receptors exist in a dynamic state because
where,
their density and efficacy is regulated by the
E=observed effect (response)
level of ongoing activity, feedback from their
own signal output and other D=dose of drug
physiopathological influences. Emax=maximum response
- Receptors can either be up-regulated or down- Kd=dissociation constant=dose of the drug at
which half maximal response is produced
regulated.
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 Basic Concepts

Types of dose-response curve: Drug Efficacy:

Graded dose-response curve: - It refers to the maximal response that can be
- This curve when plotted on graph takes the achieved by the drug and is the upper limit of
form of rectangular hyperbola while log-dose the dose response curve. i.e. higher is the
response curve takes the form of a sigmoid maximal effect of a drug, the more efficacious
curve it is.
Quantal dose response curve: - Efficacy of a drug depends upon:
- Certain pharmacological effects which cannot • Mode of interactions of drugs with
be quantified but can only be said to be absent receptors
or present (all or none) are called as quantal • Characteristics of the receptor effector
response. system involved.
E.g. Drugs causing ovulation, Emetic drugs, etc.
1
A B
100%

70% 0.62
C

D
0.5
30%

0.31
Dose
Dose-response and log dose-response curve
I
Median Effective Dose (ED50): Drug (Log. concentration)

- It is the dose at which the desired therapeutic
effect is observed in half of the total test
subjects.
Median Lethal Dose (LD50):
- It is the dose at which the adverse effects or
toxicity of the drug is observed in half of the
total test subjects.
Drug potency and drug efficacy
Drug potency:
♦ It refers to the amount or concentration of the
drug required to produce the desired therapeutic
effect. i.e lower the dose required to produce the
effect, higher is the potency of the drug.
♦ Potency of a drug depends upon:
- Affinity of receptor for binding the drug
- Efficacy with which the drug-receptor
interaction is coupled to response.
FAST TRACK
Dose response curve showing drug potency
and drug efficacy
In the above figure,
♦ Potency of D > Potency of A > Potency of B>
Potency of C
♦ Efficacy of A = Efficacy of B > Efficacy of D =
Efficacy of C
Note:
Efficacy is a more important factor in the choice of drug.
E.g Morphine is more efficacious than Aspirin. This
implies that the analgesic effect produced by morphine
could not be attained by aspirin at any doses.
Therapeutic index [08, 06, 04]
♦ Therapeutic index is a measure of safety of a drug
which is graphically represented by the gap
between the ‘therapeutic effect dose-response’
curve and the ‘adverse effect dose-response’
curve.
BASIC SCIENCE MBBS -193-
 Pharmacology

♦ Mathematically, ii. Supra-additive: Effect of drugs A+B > Effect of

Therapeutic index = LD50/ED50 drug A + effect of drug B
where, LD50 = median lethal dose E.g. Acetylcholine + Physostigmine, Levodopa +
ED50 = median effective dose Carbidopa
♦ Significance of therapeutic index: b. Antagonism: [07, 04, 03, 02]
a. Its value is always greater than 1 - When one drug decrease or abolishes the
action of another, they are said to be
b. It gives a measure of the safety margin of the
antagonistic. i.e.
drug, i.e. the gap between therapeutic effect
Effect of drugs A+B < Effect of drug A + Effect
and adverse effect
of drug B
c. Higher the therapeutic index, safer the drug. - Depending upon the mechanism involved,
d. A drug may have many therapeutic indices, antagonism can be of different types:
depending upon its clinical use. E.g. margin of i. Physical antagonism:
safety of aspirin when used for headache is E.g. Charcoal is used in alkaloid poisoning due
more than when used in arthritis. to it alkaloid-adsorbing property.
Therapeutic window phenomenom [08] ii. Chemical antagonism:
E.g. Chelating agents (BAL) form complex with
♦ Some drugs exert an unusual feature where the
toxic metals (Hg)
optimal therapeutic effect of the drug is exerted
KMno4 Oxidises alkaloids-used for gastric
only over a narrow range of plasma drug
lavage in poisoning
concentration, and both above and below that
iii. Physiological/functional antagonism:
concentration, the therapeutic effects are sub-
E.g. Histamine and Adrenaline on bronchial
optimal. This is called therapeutic window
muscles and BP, Insulin and Glucagon on blood
phenomenom.
glucose level.
Examples:
iv. Receptor antagonism:
- Tricyclic antidepressants exert maximal
I • One drug blocks the action of another by
antidepressant effect at plasma concentration
between 50 and 150 ng/ml blocking the receptor where it acts.
E.g. β-blockers oppose the action of
- Clonidine lowers BP at plasma concentration
adrenaline by preventing Adr from acting on
between 0.2 and 2 ng/ml, higher dose may
the adrenergic receptors
raise BP
• Receptor antagonism can be of 2 types:
Combined effect of drugs Competitive (equilibrium Non-competitive
♦ When two or more drugs are administered type) antagonism antagonism
simultaneously, they may either be indifferent to
Antagonist binds with the Antagonist binds to
each other or may exhibit synergism or same receptor as agonist another receptor than the
antagonism. agonist
a. Synergism: [11]
Antagonist resembles Does not resemble
- When the action of one drug is facilitated by
chemically with the agonist
another, then they are said to be synergistic.
- Synergism can be either additive or supra- Same maximal effect can Increasing the agonist
additive: be attained by increasing doesn’t regain maximal
i. Additive: Effect of drugs A+B = Effect of drug A the agonist response
+ effect of drug B Parallel rightward shift of Flattening of agonist DRC
E.g. Aspirin+Paracetamol as Analgesic/ agonist DRC
Antipyretic E.g. Ach-Atropine, E.g. Diazepam-Bicuculine
Nitrous oxide + Halothane as general Morphine-Naloxone
Anaesthetic

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 Basic Concepts

Factors affecting drug-response iii. Sex:

A. Drug Factors: - Females usually require lower dose of the
i. Particle size, form of drug effective range because of smaller body
size.
ii. Solubility, stability, pH of the drug
- Many anti-hypertensive drugs (clonidine,
iii. Presence of additives, excipients, diluents,
methyl-dopa, diuretics, β-blockers) interfere
lubricants, etc.
with sexual function in males but not in
iv. Presence of synergistic or antagonistic agents.
females.
v. Cumulation of drug
- Ketoconazole causes gynaecomastia and
B. Patient Factors: loss of libido only in males.
i. Body size: - Pregnancy can affect the action of drugs
- The dose required fluctuates with the body due to various changes such as reduced GI
size motility, expansion of extracellular fluid
- Some formulae for estimating required volume, alteration in plasma albumin and
dose: acid glycoprotein levels, increased renal
Individual dose = BW(kg)/70 × average adult blood flow, microsomal enzyme induction,
dose etc.
Individual dose = BSA(m2)/1.7 × average iv. Genetics:
adult dose - The response of individual to the drug is
ii. Age: heavily vested upon his/her genetic make-
- Newborns, infants and children are up which controls all aspects of drug
physiologically immature. E.g. metabolism such as enzymes, receptors,
transporters, ion-channels, etc.
• Low GFR (glomerular filtration rate) and
[See chapter ‘Pharmacogenetics’ under I
immature tubular transport.
Pharmacology section of ‘Genetics’.]
• Inadequate hepatic metabolic enzymes
v. Route of administration:
• More permeable BBB
- Different routes have different speed and
• Lower gastric acidity and slow intestinal
intensity of drug-action.
transit
[For individual details, refer to ‘Routes of
• Underdeveloped immune function
Administration of Drugs’ section earlier.]
- Young’s formula: Child dose =
vi. Psychological factor:
(Age/Age+12)×adult dose
- Patient’s beliefs, attitudes, expectations and
- Dilling’s formula: Child dose = (Age/20) ×
confidence levels can alter the efficacy of
adult dose
drugs, mostly drugs acting on CNS.
- Elderly patients are sensitive because of:
Placebo:
• Progressive loss of renal function
- It is an inert substance which is given in the
• Reducation of hepatic microsomal garb of medicine and acts by altering the
enzymes psychological mindset of the individual
• Prone to developing cumulative toxicity without any pharmacological action.
• Lesser plasma protein-binding - Substances like lactose tablets/capsules,
• Reduced motility and blood-flow to the distilled water injection, etc. are commonly
intestines, etc. used.

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 Pharmacology
vii. Drug Tolerance: [04, 03]
- Drug tolerance is an adaptive phenomenon
due to which higher dose of a drug is
required to produce a given response than
normally expected.
- Drug tolerance can be of various types:
a. Natural: E.g. Rabbits are tolerant to
atropine, black races are tolerant to
mydriatics.
b. Acquired: This is due to repeated use of
the drug in an individual who was
initially responsive.
E.g. Tolerance to sedative action of
chlorpromazine, tolerance to analgesic
and euphoric action of morphine
• Cross Tolerance: Development of
tolerance to pharmacologically
related drugs.
E.g. Alcoholics are relatively tolerant
to barbiturates and general
anaesthetics.
• Tachyphylaxis: Rapid development of
tolerance when doses of a drug
I repeated in quick succession result in
marked reduction in response.
- Seen with indirectly acting drugs such as
ephedrine, nicotine, tyramine which act
by releasing catecholamines in the body
and the stores are rapidly depleted due
to repeated use.
viii. Drug dependence:
- Drug dependence is a state in which the use
of drugs for personal satisfaction is accorder
a higher priority than other basic needs,
often in the face of known health risks.
- Different forms of dependence are known:
a. Psychological dependence:
- The individual believes that optimal state
of well-being is achieved only through
the actions of drug.
- The intensity of psychological
dependence may vary from desire to
craving.
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- Drugs like opioids, cocaine can strong
reinforces, i.e. they have the ability to
produce effects that make the user wish
to take the drug repeatedly.
b. Physical dependence:
- Altered physiological state produced by
repeated administration of a drug which
necessitates the continued presence of
the drug to maintain physiological
equilibrium.
- Discontinuation causes withdrawal
syndromes.
E.g. Opioids, Barbiturates, Alcohol, etc.
ix. Cumulation:
- If the rate of administration of a drug is
more than the rate of elimination, then the
drug accumulates in the body.
- Slowly eliminated drugs can produce
cumulative toxicity. E.g. Chloroquine
cancasue retinal damage.
- Full loading dose of digoxin should not be
given if administered within past week.
ADVERSE DRUG REACTIONS
Past Questions:
1. Write short notes on:
a. Chelating agents [05 Dec]
b. Adverse drug reactions [10 July]
c. Teratogenicity, with examples [02 June]
Definition:
♦ Any noxious change which is suspected to be due
to a drug, occurs at doses normally used in man,
requires treatment or decrease in dose or
indicates caution in the future use of the same
drug.
Adverse drug reactions are broadly classified as:
a. Predictable (Type A or Augmented) reactions:
♦ Those based on the pharmacological properties of
the drug which are expected as a normal
response.
♦ Include side effects, toxic effects and
consequences of drug withdrawal.
BASIC SCIENCE MBBS

b. Unpredictable (Type B or Bizarre) reactions:
- Those based on the peculiarities of the
individual and not on the drug’s known actions.
- Include allergy and idiosyncrasy.
A. Toxicity:
- Toxicity is defined as the result of excessive
pharmacological action of the drug due to
overdose or prolonged use.
- The effects are predictable and dose-related.
- Toxicity may be either from extension of the
therapeutic effect itself (E.g. Coma due to
barbiturate used as sedative, bleeding due to
hepatin) or may be due to a different facet of
action (E.g. Respiratory failure due to
morphine used as anaesthetic, ototoxicity due
to streptomycin used as anti-TB drug).
B. Hypersensitivity:
- Hypersensitivity is defined as exaggerated
immune response to an external offending
agent which produces stereotype symptoms
which are unrelated to the pharmacodynamic
profile of the drug and can occur at even small
doses.
- The drug or its metabolite acts as an antigen or
a hapten which combines with an endogenous
protein and induces the production of
antibodies or sensitized lymphocytes.
- Hypersensitivity can occur through different
mechanisms:
i. Humoral:
a. Type-I (anaphylactic) reactions:
- Reaginic IgE are produced which get fixed to
the mast cells.
- On exposure to the drug, Ag:Ab reaction
takes place on the surface of mast cells
releasing mediators like histamine,
serotonin, leukotriene, prostaglandins, PAF,
etc.
- Urticaria, itching, angioedema,
broncchospasm, rhinitis or anaphylactic
shock are the manifestations.
FAST TRACK
Basic Concepts
b. Type-II (cytolytic) reactions:
- Drug + component of a specific tissue act as
AG.
- The antibodies (IgG, IgM) bind to the target
cells, activation of complement and
cytolysis occur.
- Thrombocytopenia, agranulocytosis,
aplastic anemia, SLE, etc. are the
manifestations.
c. Type-III (retarded, Arthus) reactions:
- Mediated by circulating antibodies whereby
Ag:Ab complexes bind complement and
precipitate on vascular epithelium causing
destructive inflammatory reactions.
- Rashes, serum sickness, polyarthritis
nodosa, Steven-Johnson’s syndrome are
some manifestations.
ii. Cell-mediated:
a. Type-IV (delayed hypersensitivity) reactions:
- Mediated by sensitized T-lymphocytes with
receptors for AG.
- On contact with the Ag, these T-cells
produce lymphokines which attract
granulocytes and generate an inflammatory I
response.
E.g. Contact dermatitis, Photosensitization,
etc.
C. Teratogenecity: [02]
- The capacity of a drug to cause fetal
abnormalities when administered to the
pregnant mother.
- Due to incomplete barrier nature of placenta,
many drugs can cross it to varying extents.
- Drugs may affect the fetus at 3 stages:
a. Fertilization and implantation: conception
to 17 days-failure of pregnancy which often
goes unnoticed.
b. Organogenesis: 18 to 55 days of gestation -
most vulnerable period, deformities are
produced.
c. Growth and development: 56 days onwards
-developmental and functional
abnormalitites can occur.
BASIC SCIENCE MBBS -197-
 Pharmacology
- Examples of teratogenic drugs are as follows:
• Thalidomide - phocomelia
• Indomethacin/aspirin - premature closure
of ductus arteriosus
• Valproate - spina bifida
• Phenytoin - cleft palate/lip
• Stilboestrol - vaginal carcinoma in female
offspring
D. Carcinogenecity:
- Capacity of the drug to cause genetic defects
and cancer.
- Some drugs produce reactive intermediates
which affect the genes and may cause
structural changes in the chromosome.
- Modified DNA sequences code for factors that
regulate cell proliferation (proto-oncogenes)
and uncontrolled proliferation of cells.
- Anti-cancer drugs, radio-isotopes, estrogens
are some carcinogenic drugs.
E. Dependence:
- See ‘Drug Dependence’ under ‘Factors
affecting drug response’.
I - Drug Abuse: Use of a drug by self-medication
in a manner and amount that deviates from
the approved medical and social patterns.
- Drug Addiction:
• Compulsive drug use characterized by
overwhelming involvement with the use of
the drug.
• Procuring and using the drug
precedence over other activities.
• Physical dependence is not an essential
feature.
• Examples of addictive drugs are
Amphetamines, Cocaine, Cannabis, LSD, etc.
- Drug Habituation:
• Less intensive involvement with the drug, so
that its withdrawal produces only mild
discomfort.
• Physical dependence is almost
present.
E.g. habituation to tea, coffee, tobacco.
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F. Drug Withdrawal reactions:
- The adverse clinical consequences produced
due to sudden interruption of therapy with
certain drugs. E.g.
• Acute adrenal insufficiency on cessation of
corticosteroid therapy
• Worsening of angina pectoris, precipitation
of MI due to stoppage of β-blockers.
Heavy metal antagonists (chelating
agents): [05]
♦ These are the drugs which complex with metallic
ions, forming ring structures within their
molecules.
♦ They form stable, non-toxic and easily excreted
complexes with the toxic metals and are used in
heavy metal poisoning.
♦ Heavy metals exert toxic effect by combining with
and inactivating functional groups of enzymes or
other biomolecules. Chelating agents prevent the
metals from such combination.
♦ Some important chelating agents are:
[01]
Dimercaprol (BAL), Calcium disodium EDTA,
Dimercaptosuccininc acid, Penicillamine, Disodium
edentate, Deferiprone.
Dimercaprol (British Anti-Lewisite, BAL):
- Oily, pungent, viscous liquid developed by
British during WWII as an antidote to the
arsenical war-gas lewisite
- The two SH groups of dimercaprol bind those
metals which produce their toxicity by
interacting with sulfhydryl containing enzymes
like As, Hg, Au, Bi, Ni, Sb, Cu.
takes
Uses:
- Poisoning by the above metals
- Adjuvant to Ca Na2 EDTA in lead poisoning.
- Adjuvant to penicillamine in Cu poisoning and
Wilson’s disease.
d-Penicillamine:
- Chemically, dimethyl cysteine obtained as
degradation product of penicillin.
- Strong Cu-chelating property, also Hg, Pb and
Zn.
never - Preferred over l-isomer which produces optic
neuritis and is more toxic.
BASIC SCIENCE MBBS

Uses:
- Wilson’s disease (hepato-lenticular degeneration)
- Cu/Hg/Pb poisoning
- Cystinuria and Cystine stones
- Scleroderma
Calcium Disodium EDTA:
- Chemically, calcium chelate of Na2EDTA
- High affinity for Pb, Zn, Cd, Mn, Cu and some
radioactive metals
- Not absorbed from g.i.t. due to ionic nature,
should be given parenterally.
Uses:
- Lead poisoning (first choice)
- Fe, Zn, Cu, Mn poisoning
ESSENTIAL DRUG CONCEPT AND
RATIONAL DRUG THERAPY
Past Questions:
1. Write short notes on:
a. Essential drugs concept [08 Jan, 03 Dec]
b. Essential drugs [10 Jan]
Essential drug concept [08, 03]
♦ The WHO has defined Essential Drugs as “those
that satisfy the priority health-care needs of the
population.
♦ The list of essential drugs is prepared with due
regard to public health relevance, evidence on
safety and efficacy, and comparative cost
effectiveness.
♦ Intended to be available at all times and at adequate
amounts, in appropriate dosage forms, with assured
quality and adequate information, and at a price the
individuals and community can afford.
Criteria laid down by the WHO to guide
selection of essential medicine:
- Adequate data on its efficacy and safety should
be available from clinical studies.
- It should be available in a form in which
quality, including bio-availability, and stability
on storage can be assured.
- Its choice should depend upon pattern of
prevalent diseases; availability of facilities and
trained personnel; financial resources; genetic,
demographic and environmental factors.
FAST TRACK
Basic Concepts
- In case of two or more similar medicines,
choice should be made on the basis of their
relative efficacy, safety, quality, price and
availability. Cost-benefit ratio should be a
major consideration.
- Choice may also be influenced by comparative
pharmacokinetic and local facilities for
manufacture and storage.
- Most essential medicines should be single
compound. Fixed-ratio combination products
should be included only when dosage of each
ingredients meets the requirements of a
defined populations group, and when the
combination has a proven advantage in
therapeutic effect, safety, adherence or in
decreasing the emergence of drug resistance.
- Selection of essential medicines should be a
continuous process which should take into
account the changing priorities for public
health action, epidemiological conditions as
well as availability of better
medicines/formulations and progress in
pharmacological knowledge.
- Recently, it has been emphasized to select
essential medicines based on rationally
developed treatment guidelines.
Rational drug therapy [ 02] I
♦ Rational drug therapy involves different steps in
the supply and use of drugs such as selection,
procurement, storage, prescribing, dispensing,
monitoring and feedback.
♦ Rational prescribing involves the following criteria:
- Appropriate indication: the reason to prescribe
the medicine is based on sound medical
considerations
- Appropriate drug in efficacy, tolerability,
safety, and suitability for the patient
- Appropriate dose, route and duration
according to specific features of the patient.
- Appropriate patient: no contraindications exist;
drug acceptable to the patient; likelihood of
adverse effect is minimal and less than the
expected benefit.
- Correct dispensing with appropriate
information/instruction to the patient.
- Adequate monitoring of the patient’s
adherence to medication, as well as of
anticipated beneficial and untoward effects of
the medication.
BASIC SCIENCE MBBS -199-
 Pharmacology

SPECIAL POINT FOR MCQs

1. Pharmacokinetics is the quantitative study of drug movement in, through and out of the body, i.e.
what the body does to the drug.
2. Pharmacodynamics is what a drug does to the body.
3. Pharmacogenetics is the study of genetic basis of variability in drug response.
4. Pharmacovigilance refers to the science and activities related to detection, assessment and
understanding and prevention of adverse effects of a drug or other drug-related problems.
5. Important terms:
a. Affinity: Ability of a drug to combine with a receptor.
b. Intrinsic activity (efficacy): Ability of a drug to activate receptor.
c. Agonist: Have affinity and maximal intrinsic activity.
d. Antagonist: Have affinity and no intrinsic activity.
e. Partial agonist: Have affinity and sub-maximal intrinsic activity
f. Inverse agonist: Have affinity and opposite efficacy.
6. Clearance is a measure of the body’s ability to eliminate drugs, which mathematically is defined
as the plasma volume from which the drug is completely eliminated in a unit time considering the
rest of the plasma to be maintaining constant concentration.
7. Volume of distribution is an indication of the extent to which the drug is distributed in the body
outside the vascular compartment.
I 8. Bioavailability is the fraction of the administered dose that reaches the systemic circulation.
9. Therapeutic index is the ratio of the median toxic dose to the median therapeutic dose, i.e.
LD50/ED50.
10. Half-life is the time that it takes for the plasma concentration or amount of drug in the body to
decline by 50%.
11. Drug potency refers to the amount of drug required to produce a certain response.
12. Drug efficacy is the maximum response given by a particular drug at highest dose possible.
13. Therapeutic window phenomenon: Optimum therapeutic response of the drug is exerted only
over a narrow range of plasma drug concentration, E.g. tri-cyclic anti-depressants, clonidine and
glipizide.
14. T1/2 can determine:
a. Elimination time
b. Steady state plasma concentration
c. Dosing rate
d. Maintenance dose
15. First pass metabolism is seen with oral route and rectal route.
16. Bio-availability by i.v. route is 100%.
17. Sub-lingual route bypasses first pass metabolism.

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 Basic Concepts

18. Phase I of drug metabolism includes oxidation, reduction, hydrolysis, cyclization and
decyclization.
19. Phase II of drug-metabolism includes conjugation with glucuronide, sulfate, acetylation,
methylation, glutathione, etc.
20. Drugs with high first pass metabolism are β-blockers (propranolol), lignocaine, salbutamol,
verapamil, nitroglycerine, testosterone, morphine, hydrocorstisone.
21. Drug monitoring is useful in drugs with low safety margin and low therapeutic index. E.g.
lithium, digoxin, anti-epileptics, theophylline, amino-glycosides.
22. Factors governing volume of distribution are:
a. Lipid-water partition coefficient
b. pka value of the drug
c. Degree of plasma-protein binding
d. Degree of blood-flow
e. Affinity for different tissues
f. Fat: lean body mass ratio
g. Diseases like uremia, CHF, cirrhosis
h. Pregnancy
23. Highly plasma protein-bound drugs are restricted mainly to vascular compartment and hence
have low volume of distribution.
24. Displacement of protein-bound drug increases the plasma level of drugs.
25. Drugs bound to albumin are: Barbiturates, Benzodiazepines, Phenytoin, Penicillins, I
Sulfonamides, tetracycline, Warfarin, etc.
26. Drugs bound to α-acid glycoprotein are: Prazosin, Lidocaine, Verapamil, Methadone,
Imipramide, Bupivacaine, Quinidine
27. Hit and run drugs are those drugs whose effects last much longer than the drug itself. E.g.
Reserpine, MAO inhibitors, Omeprazole
28. Attributes of First order kinetics:
• Rate of drug elimination is directly proportional to drug concentration
• CL remains constant
• T1/2 remains constant
29. Attributes of Zero-order kinetics:
• The rate of elimination is constant
• CL increases with decrease in concentration of the drug.
• T1/2 decrease with decrease in concentration of the drug
30. Acidic drugs ionize more at alkaline pH while alkaline drugs ionize more at acidic pH.
31. Unionized drugs are lipid soluble and diffusible while ionized drugs are lipid-insoluble and
indiffusible.
32. Ionized drugs are excreted mainly by kidney.

FAST TRACK BASIC SCIENCE MBBS -201-

 Pharmacology

33. Acidic drugs are absorbed mainly in stomach whereas basic drugs are mainly absorbed in
proximal intestine.
34. Ionized drugs poorly pass through placenta, blood-brain barrier and renal tubules
35. Microsomal enzyme inducers: Barbiturates, Carbamazepine, Clofibrate, DDT, ethanol, Phenytoin,
Phenobarbitone, Rifampin, Ritonavir
36. Microsomal enzyme inhibitors: Quinolones, Erythomycin, Quinidine, Cimetidine, Allopurinol,
Ketoconazole, Omeprazole, Sulfonamides, MAO inhibitors
37. Hepatotoxic drugs:
a. Causing hepatitis: halothane, MAO inhibitors, methyl-dopa, Rifampicin, ISoniazid,
Pyrazinamide
b. Causing intrahepatic holestasis: Phenothiazines, TCA, NSAIDs, Erythromycin, Sufonamides
c. Hepatotoxins: tetracycline, CCl4, Paracetamol, Methotrexate, Aflatoxin.
38. Cardiotoxic drugs: Doxarubicin, halothane, alcohol, Daunorubicin, Vincristine
39. Pulmonotoxic drugs: Bleomycin, Methotrexate, Nitrofurantoin, Sulfasalazine, Practolol,
Amiodarone
40. Drugs causing Osteoporosis: Glucocorticoids, Anti-convulsants, Cytotoxic drugs, cyclosporine,
Lithium, heparin, Aluminium
41. Drugs produced by recombinant DNA technology: human insulin, Growth hormone, Interferon,
Interleukins, Monoclonal antibodies, vaccines

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