GENERAL

PHARMACOLOGY
compiled by
ARNAB MAZUMDAR AVI (26th/16)

JALALABAD RAGIB-RABEYA MEDICAL COLLEGE,

SYLHET.

Contents
INTRODUCTION TO PHARMACOLOGY ..................................................................................... 2

SOURCES OF DRUGS & DOSASGE FORMULATION ......................................................... 14

ROUTES OF DRUG ADMINISTRATION .................................................................................... 24

ABSORPTION OR BIOTRANSPORT OF DRUGS .................................................................. 33

DISTRIBUTION OF DRUGS............................................................................................................ 47

BIOTRANSFORMATION OF DRUGS .......................................................................................... 57

EXCRETION OF DRUGS .................................................................................................................. 67

MECHANISM OF DRUG ACTION ................................................................................................. 74

ADVERSE DRUG EVENTS .............................................................................................................. 89

DOSE RESPONSE CURVE ............................................................................................................ 110

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 INTRODUCTION TO PHARMACOLOGY

The word PHARMACOLOGY is derived from two Greek words – ‘PHARMAKON’ and
‘LOGOS’. The Greek word 'PHARMAKON' means drugs and ‘LOGOS’ means knowledge or
study.
So, PHARMACOLOGY is the subject that deals with the knowledge or study about drugs.

Definition: It is the branch of medical science which deals with history, sources, physical
and chemical properties, dosage forms, routes of administration, absorption,
distribution, mechanism of action, physiological & biochemical changes produced by the
body i.e., pharmacological actions, biotransformation, excretion, therapeutic uses,
doses, adverse effects and contraindication of drugs.
Therapeutics (Medical pharmacology): Greek word 'Therapeia' means treatment. So
therapeutics means the treatment of disease or pathological condition. It is the branch
of medicine concerned with the application of remedies and treatment of diseases.
Important Branches of Pharmacology:

1. Pharmacokinetics
2. Pharmacodynamics
3. Pharmacy
 Pharmacognosy
 Pharmaceutical chemistry
 Bio pharmaceutics
4. Clinical Pharmacology
5. Toxicology
6. Biotechnology
7. Pharmacogenetics
8. Pharmacogenomics
9. Pharmacoechonomics
10. Pharmacoepidemiology
11. Experimental Pharmacology
th
[T 25 ] What do you mean by pharmacokinetics?

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Pharmacokinetics: It is the branch of pharmacology that deals with the absorption,
distribution, biotransformation and excretion of drugs. It answers the question ‘what
the body does to the drug’.
Pharmacodynamics: It is the branch of pharmacology that deals with mechanism of
action and pharmacological effects of drug. It answers the question ‘what does the drug
do to the body’.
Pharmacy: It is the branch of pharmacology which deals with the preparation, quality,
control and dispersion of drugs. It includes –

 Pharmacognosy: It is the branch which deals with botanical sources of drugs

along with identification, purification and isolation of drugs from plant
sources.
 Pharmaceutical chemistry: It deals with the synthesis of new drugs.
 Bio pharmaceutics: It deals with the formulation of drug.

Clinical Pharmacology: It is the branch of pharmacology which deals with the scientific
study of drugs in the patients and also in healthy persons for the safe and effective use
of drugs.

Toxicology: It deals with the adverse effects of drugs including their diagnosis and
management.

Biotechnology: It deals with production of drugs like antibiotics, hormones (like insulin)
etc. by biological means. Now a days it refers to the use of "Recombinant DNA
Technology".

Pharmacogenetics: It deals with genetically altered drug response. In G-6PD deficient

patient, primaquine causes hemolytic anemia.
Pharmacogenomics: It describes the use of genetic information to guide the choice of
drug therapy on an individual basis.
th th rd
*Nov ’19, TS 25 , T 24 , T 23 ] Define drug.

Drug: The word drug derived from the French word "drogue" which means dry herb.
According to the definition of World Health Organization (WHO), "A drug is any
substance or product that is used or intended to be used to modify or explore
physiological systems or pathological states for the benefit of the recipient".

Recipient means man or animal (Laboratory or other).

th
[T 24 ] What are the benefits of recipient?

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Benefit means purpose of drug used which consists of diagnosis, prevention, control
and cure (eliminating a disease).

Diagnosis:

 Barium sulphate which is a radiopaque substance used in X-ray for detection of

pathology of GIT.
 Histamine is used for the diagnosis of pernicious anemia.
Prevention:

 Chloroquine is used for the prevention of malaria.

 Contraceptive is used for the prevention of conception.
Control:

 Insulin is used for the control of diabetes mellitus.

Cure:

 Antimicrobial (ciprofloxacin) is used for the treatment of typhoid fever.

Drug information sources:

 Pharmacopoeia
 Formulary [A list of pharmaceutical drugs, along with the formulas used to make
them, their uses and how to prepare them]
 Compendia [A drug compendium (eg. QUIMP) is a book that lists all the different
pharmaceuticals, and a bunch of things that a medical professional might need to
know about them]
 Text books
 Biomedical journals
 Pharmaceutical company
 Drug information center
 Drug bulletins and news
 International database
Pharmacopoeia: It a book written by legally authorized body constituted by law which
describes drugs that are used commonly with their sources, identification, preparation,
standardization, purification, action, uses, doses, contraindication, toxicities.
Example:

Arnab Mazumdar Avi (26th/16) 4|Page

  British Pharmacopoeia (BP)
 United States Pharmacopoeia (USP)
 European Pharmacopoeia (EP)
*May’20+ Write difference between pharmacopoeia & formulary.

Difference between –

Pharmacopoeia Formulary
1. Published by authorized body 1. Published by drug administration
authority
2. Contains descriptions of all drugs 2. May contain all nationally licensed drugs
individually including structure, chemistry prescribed by the health professionals or
etc. lists of only preferred drugs.
3. Trade names are not included 3. Trade names are included
4. Can be followed by doctors of all over 4. Can't be followed by all doctors of the
the world as there is generic name world as there is trade name here. Used
only by doctors of the same country
5. Published less frequently (5 yearly or 5. More frequently (Yearly/Two yearly)
more)
6. Example: United states Pharmacopoeia, 6. Example: British National Formulary
British Pharmacopoeia (BNF), Bangladesh National Drug
Formulary (BDNF).
*May ’19, Nov ‘19+ Short note: BDNF.

BDNF (Bangladesh National Drug Formulary)

The Bangladesh National Formulary (BDNF) is a comprehensive list of the drugs available
in the local market that support the health care providers to offer the most effective
drug therapy with limited resources. It is published by Directorate General of Drug
Administration. Its fourth edition was published in 2015.
Characteristics of BDNF:
1. All the drugs (both locally manufactured and imported), which are registered
with the Directorate of Drug Administration and are in current use in Bangladesh,
are included in the BDNF. Each of them is described individually.
2. Drugs are first grouped into Chapters according to their pharmacological or
physiological or other medical category.
3. 4th edition of the BDNF has 17 Chapters.
4. Each Chapter is again sub-divided into Sections.
5. Each Section begins with a brief description of the subject matter, i.e., the drug or
its group. Description of the drug is followed by brief notes on its indications,

Arnab Mazumdar Avi (26th/16) 5|Page

 side-effects, cautions, contra-indications, warnings, drug interactions, doses,
names of the proprietary preparations containing the said drug, names of the
manufacturers, the available dosage forms of the drug and their strengths and
the price of the drug.
6. The opening Chapter of the BDNF includes a Guideline on Prescriptions, which
highlights various aspects of prescription writing, prescribing for children and the
elderly and prescribing in terminal illness. It also includes notes on the concept of
essential drugs and control of narcotics.
Role of BDNF in health care of Bangladesh:
1. It helps us to offer the safest, most effective and least costly health care ensuring
the rational use of medications.
2. BDNF is intended to provide sound and updated information about the use of
drugs with their properties such as presentation, dosage and administration, side
effects, cautions, indications, contraindications, proprietary preparations etc. to
physicians, pharmacists and other healthcare professionals.
3. BDNF helps physician to know the efficacy, price, risks and other information
about a drug before prescribing.
Types of Drugs:

Prescription drug: drugs are restricted to sale by prescription. Example –

antibiotics.

Non Prescription drug / over the counter drugs (OTC): Drugs are available
without prescription. Example – paracetamol, ORS, iron tablet, vitamin tablet,
antacid, omeprazole, ketoconazole.

Controlled drugs: These are the drugs which will produce addiction. Example –
hallucinogens (pethidine, heroine, LSD), narcotics.
Orphan drugs: Drugs for rare diseases.
Official drugs: Drugs that included in the Pharmacopoeia.

Essential drugs: WHO has defined essential drugs as "those that satisfy the health
care needs of the majority of the population and therefore should be available at
all times, in adequate amounts, in appropriate dosage forms and at a price the
individual and the community can afford."
In 1977 WHO introduced approximately 300 essential drugs. The list is updated
every few years.

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 According to Bangladesh Gazette, May 22, 2008, there is a list of 209 essential
drugs in Bangladesh.

Experimental drugs: The drugs which are in the stage of clinical trials. Example –
newer, better & safer drugs.
rd
*May ’19, T 23 ] List advantages & disadvantages of proprietary & non-proprietary name of drugs.

Drug Nomenclature: Nomenclature means systematic naming. Each drug has four
names-
1. Code name
It is the first name given to a drug by the pharmaceutical manufacturer. It
may be an abbreviation, a numerical or combination of both; example:
BAY-O-987. Here BAY comes from the famous pharmaceutical Company
"BAYER". The name used by laboratory personnel.
- It does not carry any pharmacological and chemical significance.

2. Chemical name
The name describes the chemical structure of a drug; example: 2-methyl-
5-nitroimidazole-1-ethanol is the chemical name of metronidazole. It is
adopted by International Union of Pure and Applied Chemistry (IUPAC).
Advantages are:
- It is helpful for discovery of new drugs
- Describes the chemical structure of drugs.
Disadvantages are:
- Quite long name
- Difficult to remember, spell and pronounce
- Not suitable for routine usage by medical professionals or common
people.

3. Generic Name/Nonproprietary Name /Pharmacological name

If the newly synthesized drug appears promising and the manufacturer
wishes to sell it in the market, then a nonproprietary name is given. This
drug is often referred to as generic name. It is the condensed form of
chemical name. For example – “Metronidazole” comes from its chemical
name. The word 'methyl nitro' is condensed to metro and ‘nidazole’
indicates the presence of imidazole group.
WHO has introduced some general principles for adopting nonproprietary
name:
- Name should preferably be free from any anatomical, physiological
pathological or therapeutic suggestion

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 - Name should be formed by syllables from the scientific chemical
names; example - "Aspirin". Here ‘A' from Acetyl.
- Name should not exceed more than 4 syllables.
- Name should be distinct in sound and spelling with no capital letter or
number at the end.
- Example: *‘ine’ for alkaloids (morphine, nicotine)+, *‘in’ for glycosides
(digoxin, digitoxin)+, *‘ol’ for alcohol (ethanol)+, *‘olol’ for β antagonists
(atenolol, propranolol)+, *‘dipine’ for dihydropyridine CCB (nifedipine,
amlodipine)+, *‘pril’ for ACEIs (captopril, ramipril)+
Advantage of Nonproprietary names:
- Short, easier to remember
- Medical professionals choose it for its simplicity
- Free of conflicts with other name
- It is cheaper than those sold under trade name
- The same name pronounced everywhere in the world
- The pharmacist can supply any brand of drug and can run his/her
business at a low cost investment
Disadvantages of Nonproprietary names:
- Drugs with low quality may be supplied to the patients
- Some Nonproprietary names are confusing; example –
Acetazolamide (carbonic Acetohexamide (oral
anhydrase inhibitor) hypoglycemic agent)
Piperazine (anthelmintic) Pirenzepine (antimuscarinic)

4. Trade name/proprietary/brand name

It is most frequently used. Trade name frequently appear with the sign (‘R’ ®
in a circle) in the upper right corner which indicates that the name is
registered and its production is restricted to that company as sole owner.
Trade name is registered for 50 years
Advantages of Proprietary Name:
- Shorter, easier & simpler to remember and write
- Most frequently used
- Drugs with high bioavailability can be prescribed
- Medical practitioners can prescribe the best one from the different
formulations.
Disadvantages of Proprietary name:
- Drugs in trade name are costly
- Does not provide the information about class of drugs
- Drugs in trade name sometimes confusing

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 - It differs from country to country; example - Losectil in Bangladesh and
Prilosec in U.S.A.
- Inconvenience to the pharmacist because he/she is obliged to supply
the prescribed drug under trade name
- Pharmacist cannot run his/her business at a low cost investment
- Trade name is registered and its use is restricted to that
pharmaceutical company as sole owner.
Example of drugs with 3 types of name:

Chemical name Generic name Trade name

Acetylsalicylic acid Aspirin Dispirin
Acetaminophen Paracetamol Napa

Medicine: A medicine is a chemical preparation, which contains one or more drugs and
usually other substances (excipients, stabilizers, solvents etc.) besides the active drug to
make them more convenient to use.
Placebo / dummy medicine: Placebo are inactive substances (having no
pharmacological effect) given to satisfy patients demand for medicine. Substances used
as placebo are – starch, glucose, sucrose, lactose, dextrose etc.

Purpose of using placebo:

- As a control in scientific evaluation of drugs.
- To please a patient psychologically.
- To prevent habituation & addiction.
Difference between –

DRUG MEDICINE
1. Drug is the active ingredient of medicine 1. Medicine = Drug + additional substances
(excipients, stabilizers, solvents, etc.)
2. Drugs may not be stable 2. Medicine is made more stable by adding
stabilizers
3. It has chemical and generic name 3. It has brand or trade name
4. All drugs are not medicine 4. All medicines are drugs
5. It does not have a suitable form and 5. It has suitable form and dose; Example -
dose Cap. Omeprazole 20 mg. Here capsule is
form and 20 mg is dose.
th th rd
*Nov ’18, May’17, May’18, TS 25 , T 25 , T 23 ] What is prodrug? Purpose of using prodrugs. Short note: Prodrug.

Prodrug:

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There are some chemical substances which do not produce pharmacological effects until
they are chemically altered within the body. Such chemical substances are called
prodrug.
Significance/purposes/ advantage/ clinical importance of prodrug:
1. To increase absorption -

 Talampicillin cause increased absorption than its active form ampicillin.

 Levodopa can cross BBB but its active form dopamine cannot cross BBB.
 Dipiverine HCl has 147 times more penetration than its active form adrenaline
due to its high lipid solubility when applied over the eye for treatment of
glaucoma.

2. To reduce unexpected tissue damage -

 The cytotoxic drug cyclophosphamide becomes active after it has been

metabolized in the liver & can be taken orally without causing injury to the GIT.
3. To modify route of administration –

 Fosphenytoin is a more soluble prodrug of phenytoin and is rapidly converted to

phenytoin in the blood. Phenytoin should never be given IM because it can cause
tissue damage and necrosis. Fosphenytoin is the drug of choice and standard of
care for IV and IM administration.

4. To increase bioavailability of drug at receptor sites -

 Carbidopa (prodrug) is used with levodopa to prevent its breakdown by inhibiting

peripheral dopa decarboxylase.
L-dopa Dopa-decarboxylase Dopamine
5. To prevent peripheral biotransformation, or to avoid first-pass metabolism -

 L-dopa Dopa-decarboxylase
Dopamine (In liver)
6. To reduce offensive odor of the drugs -

 Chloramphenicol palmitate prodrug is used because of the bitter taste of

chloramphenicol.
7. To increase the specificity of drug action at desired site –

 Zidovudine is used in the form of zidovudine triphosphate.

8. To modify duration of action.

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Disadvantage of prodrug administration:

 Requires activation before pharmaceutical action.

th th
*Nov ’18, TS 25 , T 25 ] Write 4 prodrugs with their active metabolite & use.

Prodrug with their active metabolite & uses:

Prodrug Active drug Use

Levodopa Dopamine

Talampicillin Ampicillin

Alpha methyldopa Alpha methyl nor

adrenaline

Prednisone Prednisolone

*May ‘20+ Rational use of drugs.

Rational use of drug / medicine (RUD / RUM):

Appropriate drug in appropriate indication with proper dosage regimen is called rational
use of medicine. According to WHO, rational use of medicines requires that "patients
receive medications appropriate to their clinical needs, in doses that meet their own
individual requirements, for an adequate period of time, and at the lowest cost to them
and their community".

Selection criteria of RUM / RUD:

 Safety profile
 Efficacy
 Suitability / individualization
 Affordability
 Need
 Cost
Objectives of RUM / RUD:

 To identify the magnitude and nature of inappropriate medicine utilization.

 To describe factors which influence the decision making processes.

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  To identify the factors which influence the behavior of the prescribers.
 To relate issues to specific medicine use problem.
 To assess which prescribers and patients' factors might be addressed in a
program to reduce irrational use of medicine.
Uses of RUM/RUD:

 Prescription
 Purchase/availability
 Intake

Guidelines for RUD / Educational intervention:

A. To fix the target of the drug:

1. Target may be the cure of the disease / infection

2. Target may be the control of the disease (controlling HTN, DM)
3. Prevention of disease (prophylactic drugs for TB, malaria)
4. Diagnosis of the disease

B. To select out the therapy:

1. No drug therapy:
2. Drug therapy:
a) Selection of the drug.
b) Selection of proper dosage regimen.
c) Monitoring drug therapy.
d) Programming patient education.
Rational prescribing:

Rational prescribing means prescribing the drugs by considering their therapeutic

efficacy suitability.

Criteria / steps / factors / principles of rational prescribing:

1. Appropriate diagnosis
2. Appropriate indication
3. Appropriate medicine
4. Appropriate patient
5. Appropriate dosage
6. Appropriate duration
7. Appropriate route of administration
8. Appropriate information to the patient

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 9. Appropriate monitoring must be done

Necessity of rational prescribing:

It is necessary –

 To improve treatment outcome.

 To decrease adverse drug reactions (ADRs).
 To decrease financial loss of patient.

*May ‘20+ Clinical study (Vaccine / Drug)

th
Answer – Blueprint 11 Edition, Page – 51.

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SOURCES OF DRUGS & DOSASGE FORMULATION
th rd
[T 24 , T 23 ] Name the sources of drug with example.

Sources of drugs:
1. Natural sources
 Plant
 Animal
 Mineral
 Micro-organism
2. Laboratory / synthetic sources
3. Semi-synthetic sources
4. Bio-technology & genetic engineering

1. NATURAL SOURCES
th rd
[TS 25 , TS 23 ] Name the plant sources of drug with example. Characteristics of alkaloids & glycosides.

Plant sources:
From some plants the active compounds are purified and used as drug. These active
compounds are classified according to their chemical structure. Such as-

- Alkaloid
- Glycoside
- Oil
- Gum
- Mucilage
- Carbohydrate
Alkaloid –
Alkaloids (alkali + oid) literally mean alkali like substance. Characteristics of alkaloid

 White crystalline substances

 Bitter in taste
 Soluble in alcohol, not in water
 It gives salt with acid
 Name of alkaloids usually ends in '-ine' eg – morphine, atropine except
adrenaline, pentamidine, procaine.
 Examples with sources:

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 Alkaloids Sources
Atropine, Scopolamine Atropa belladona
Quinine, Quinidine Cinchona
Morphine, Codeine Seed capsule of poppy plant
Caffeine Coffee plant

Glycoside –
Glycosides are condensation products of a sugar with various kinds of organic hydroxyl
compound such as phenol, alcohol, sterol, and glycerol.

 Glycoside consists of sugar and non-sugar part.

 Non sugar part is called ‘aglycone’ or ‘genin’.
 Aglycone part may be a phenol, alcohol, sterol, and glycerol.
 Sugar part is responsible for pharmacokinetic behavior.
 Combination of both parts is necessary for the transport of the drug through
biological membrane.
 The Glycosides are widely distributed in barks, seeds, and leaves of the plants.
 They can be recognized by identifying the suffix ‘-in' at the end of the name;
example - digoxin, digitoxin, quabain etc.
Oils –

Two types:

 Fixed oil
- Lighter than water
- Insoluble in water but soluble in fat solvent (ether, chloroform)
- Example: Olive oil (edible) and emollient (moisturizer) and castor oil (used as
laxative). It stimulates defecation.
 Volatile oil
- Evaporate when exposed to air & odorous
- Also called essential oil
- Example: Peppermint oil such as menthol used as solvent and flavor; Clove oil -
Active portion is eugenol used for toothache; Wintergreen oil – locally used for
joint pain.
Gum –
Gums are secretory hydrocarbon product of plant origin.

 Chemically it is polysaccharide which on hydrolysis produces sugar.

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  Easily dissolve in water.
 Example Agar and psyllium seeds used as laxatives.
Mucilage –
Mucilage is a viscous solution obtained from plant.

 They produce slimy mass when dissolved in water.

 Example: Tragacanth used as suspending agent for insoluble powder, emulsifying
agent for oil & resin and an adhesive.
Carbohydrate –

 They are used as demulcent, nutrient, food etc.

 Example: glucose, sucrose, fructose.
Animal Sources:

 Vitamin A - Obtained from liver of Cod fish.

 Insulin - Extracted from bovine and porcine pancreas.
 Immunoglobulin - Obtained from selected human donor.
 Heparin - Obtained from porcine intestine and bovine lung.
 HCG - Isolated and purified from urine of pregnant women.
Minerals:

 Iodine is used for goiter.

 Antacid (Aluminum hydroxide and magnesium trisilicate) used for peptic ulcer
diseases.
 Magnesium sulphate is used to relieve constipation.
 Iron is used for anemia.
Micro-organism:

 Fungus - penicillin, cephalosporin

 Actinomycetes - chloramphenicol, erythromycin
 Bacteria - bacitracin, polymixin B, streptomycin

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 2. LABORATORY / SYNTHETIC SOURCES:
Now a days most of the drugs are synthesized in laboratory by combing two or more
compounds or elements
Advantage of synthetic drugs:

 High quality, pure, less expensive, safe.

 Can be produced in large scale in short time.
 More effective than drugs of animal and plant sources.
Examples:

 Aspirin
 Paracetamol
 Antimalarial drugs
 Sulfonamides
3. SEMI-SYNTHETIC SOURCES

Examples:

 Ampicillin
 Tetracycline
 Pethidine
4. BIOTECHNOLOGY & GENETIC ENGINEERING
*May ‘19+ Explain with importance – Recombinant DNA technology.

Recombinant DNA technology:

 DNA recombination means sharing genetic information between chromosomes

 Drugs (proteins) can be synthesized by this means - called Biological drugs such as
insulin, heparin, vaccines, IGs, histamine etc.
 Here, nonpathogenic microorganisms are used
 Human genes are introduced in microorganism's genetic material.
 The microorganism will produce the product of gene during its protein synthesis
 Large amount and purified drug can be synthesized by this means.
Medically important human proteins produced by recombinant DNA technology:
- Human insulin
- Growth hormones
- Erythropoietin

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 - Interferon
- Factor VIII
- Hepatitis B vaccine
- Tissue plasminogen activator
- Calcitonin
*May ‘20+ Advantage & disadvantage of different formulations.

Dosage Formulation:
1. Solid preparation
 Tablet
 Capsule
 Pill
 Powder
 Granule
 Suppository
2. Semi-solid preparation
 Ointment
 Paste
 Cream
 Gel
3. Liquid preparation
 Oral liquid preparation
- Solution
- Suspension
- Emulsion
 Injection
 I/V infusion
 Drop / liquid spray (nasal / ear / eye)
 Shampoo
 Lotion
4. Gaseous preparation
 Aerosol
 Gas
 Volatile liquid
5. Liposome based formulations

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Tablet:
Tablet is a solid dosage form in which powder, crystalline, or granular form of drug is
compressed in a disk or molded with pharmacologically inert substances (excipients).
Composition of a tablet:
1. Active ingredients
2. Inert substance / Excipient
 Diluents: Form bulk of drug (shape, size); e.g. dextrose, lactose, starch,
sucrose etc.
 Binder: They bind several drug molecules to prevent auto breakdown. It is
known as shelf life. E.g. methyl cellulose.
 Disintegrating agent: To break the drug molecule before absorption, e.g.
Starch.
 Lubricant: To lubricate drug molecule, e.g. stearic acid.
 Coloring substances: To color drug for identification, attraction etc. e.g.
brilliant blue, caramel etc.
 Flavoring agent: Orange flavor, peppermint oil etc. are the flavoring
substances.
 Sweetening agent: To make a drug sweet in taste, e.g. saccharin, lactose,
mannitol.
Type of tablet:

1. Coated tablet
 Enteric coated tablet - Aspirin
 Flim coated tablet - Metronidazole
 Sugar coated tablet - Vitamin C tablet
 Implant - Norplant
 Modified released tablet - Diclofenac
 Pill - Oral contraceptive pill
2. Uncoated tablet
 Chewable tablet - Antacid tablet, vitamin c tablet
 Effervescent tablet - Aspirin, vitamin C tablet
 Lozenge - Nystatin
 Sublingual – Nitroglycerine
Another type:
1. Compressed type
 Single time compression

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  Multiple compression
2. Molded type
Characteristics of tablet:
1. Solid structures & sufficiently hard.
2. Shape is usually discoid. It also may be circular, ovoid, triangular, elliptical, flat or
any other suitable shape.
3. May have lines or breaking marks on the surface.
4. Usually onset is slow.
5. Needs disintegration after reaching in the GIT
6. Comparatively cheaper than parenteral routes
7. Not suitable for hospitalized/unconscious/non-cooperative patients including
children.
Capsule:
Capsule is a solid dosage form in which one or more active ingredients with or without
inert substances are enclosed within a small shell or container generally prepared from
gelatin.
Composition of a capsule:
1. Capsule shell - composed of gelatin or other materials.
2. Active ingredient
3. Diluent - Lactose
4. Lubricant - Magnesium stearate
5. Preservative - Soft gelatin shell may contain a preservative to prevent the growth
of fungi. Commonly used preservatives are methyl & propyl parabens, sorbic acid
Types of capsule:
1. Hard capsule - The active ingredient is usually in solid form (powder, granule). Eg,
antibiotic capsules.
2. Soft capsule - Liquid may be enclosed directly. Eg, high potency vitamin A capsule
(VAC-HP), vitamin E capsule.
3. Modified-release capsule - analgesics.
4. Coated capsule - eg, gastro-resistant capsules.
5. Implant capsule - eg, norplant.
Advantage of capsule:
1. Bypasses disintegration.
2. Provides stability of drugs.

Arnab Mazumdar Avi (26th/16) 20 | P a g e

 3. Avoids unwanted taste.
Powder:
It is a mixture of finely divided drugs and/or chemicals in dry form.
Types of powder:
1. Powder for external uses: They are applied to various parts of the body as
lubricant, protective absorbent, antiseptic, and antipruritic. Example – dusting
powder such as antiseptic powder.
2. Powder for internal uses: It is designed for oral or parenteral administration.
Example – antacid & laxative powder.

Granule:
It is the solid dosage form of drugs in which diameter is 0.5 to 2 mm and it is more
soluble than powder.
Example: Ampicillin granule, lspaghula husk as effervescent granule.

Suppository:
It is the solid form of drug which is administered through per rectal route of the patient.

Example: Analgesic suppository, Glycerin suppository.

Ointment:

 It is a semisolid preparation.
 Insoluble in water.
 It is oil based.
 Example: Petroleum jelly, antibiotic (chloramphenicol, neomycin), antifungal
(clotrimazole).
Paste:

 Semisolid preparation.
 Used externally.
 Example - Zinc oxide paste.

Cream:

 Semisolid preparation.
 Less greasy than ointment and easier to apply.
 Example: Emollient cream.

Arnab Mazumdar Avi (26th/16) 21 | P a g e

Solution:
It is a homogenous preparation containing one or more dissolved ingredients in a
suitable vehicles.
Example: Nasal solution.
Suspension:
It is a heterogeneous system of liquid dosage form of drug in which finely divided solid
particles ranging from 0.5 to 5 micrometer are suspending in a liquid vehicle by
suspending agent.

Example: Antacid suspension, Antibiotic suspension.

Emulsion:
It is a two phase system prepared by intimate mixture of two immiscible liquids, one of
which is uniformly dispersed as globules throughout the other.
Example: Cod liver oil, Castor oil.
Aerosol: Surface spray, foam spray.

Gas: Nitrous Oxide

Volatile liquid: Halothane
Difference between –

Traits Cream Ointment

1. Nature Water-based and has Oil-based and not able to
capability to spread spread
uniformly
2. Composition Oil- 50% and water- 50% Oil- 80% and water- 20%
3. Appearance Less greasy and has lighter More greasy and has
consistency thicker consistency
4. Absorption Quickly absorbed by the Slowly absorbed and stays
skin longer over skin.
5. Function Suitable to use both in Suitable to use in small skin
small and large areas of the lesions
skin
6. Application on dry skin Cream promotes skin Best used in dry skin
dryness and therefore not
suitable for use.

Arnab Mazumdar Avi (26th/16) 22 | P a g e

Difference between –

Tablet Capsule
1. It does not have a shell. 1. It has a shell.
2. It needs both disintegration and 2. It needs only dissolution.
dissolution.
3. Onset is comparatively slower. 3. Onset is comparatively faster.
4. Unwanted taste cannot be avoided. 4. Unwanted taste can be avoided.

Arnab Mazumdar Avi (26th/16) 23 | P a g e

 ROUTES OF DRUG ADMINISTRATION
th th
*May ’22, May ’18, Nov ’17, T 25 , T 24 ] What are the available drug delivery systems? What are the routes of
drug administration?

Routes of drug administration / drug delivery systems:

A. Systemic route: (Drugs that go to the site of action through circulation)
1. Enteral route ("Enteron” means within or by the way of GIT, all these go through
mucous membrane)
 Oral
 Rectal
 Sublingual
 Buccal
 Nasogastric
 Colonic
2. Parenteral route (“Parenteral” means other than alimentary canal/enteron,
usually administered through injection)
 Intra-venous
 Intra-muscular
 Subcutaneous
 Intra-dermal
 Intra-arterial
 Intra-articular
 Intra-thecal
 Epidural
 Intra-cardiac
 Intra-peritoneal
 Intra-pleural
B. Local/Topical/Site specific route: (Applied to a localized area and the action is
confined to that area)

 Epidermal
 Transdermal
 Conjunctival
 Inhalational
 Nasal
 Vaginal

Arnab Mazumdar Avi (26th/16) 24 | P a g e

*May ‘22+ Discus advantages & disadvantages of 3 important routes of drug administration.

Oral route:
Formulation: tablet, capsule, powder, solution, suspension
Advantage:
1) Very safe, easy, cheap, painless, convenient.
2) Self medication is possible.
3) Ambulatory patients can utilize this route.
4) Self satisfaction.
5) No disturbance of daily activities.
Disadvantage:
1) Irritant and unpleasant drug can not be administered because of nausea,
vomiting and ulceration (NSAIDs, Steroids).
2) Onset is slow.
3) Unsuitable for acute emergency cases because of delayed onset of action.
4) Can not be given in unconscious patients.
5) Bioavailability is less than 100%.
6) Gastric HCL and intestinal juices may destroy the drugs (Insulin, Heparin)
Sublingual route:

Formulation: tablets, aerosol, spray

Drugs given: nitroglycerin (GTN), ondansetron.
*Nov ’17, May’18+ Advantages of sublingual route.

Advantages:
1) Immediate effect is obtained.
2) Avoid first pass biotransformation as drugs are directly administered to systemic
circulation (directly drain into superior vena cava).
3) 100% bioavailability.
4) Drug can be spitted out after optimum action.
5) Drugs such as Nitroglycerin, Nifedipine, Clonidine etc.

Arnab Mazumdar Avi (26th/16) 25 | P a g e

Disadvantages:
1) Irritant drugs cannot be given.
2) Frequent administration is not possible because the salivation and the drug may
be swallowed.
3) Cannot be given in unconscious patients.
4) Water soluble drugs cannot be given.
Rectal route:
Formulation: suppositories, ointment, jelly, solution

Advantages:
1) Irritant drugs (drugs with bad taste and smell) can be given (irritant to stomach).
2) Suitable for unconscious patients and patient with vomiting or when patient
cannot take drugs through oral route.
3) Also suitable for patients who are extremes of age (old or children).
4) Suitable for local effect
Disadvantages:
1) Crude process, patient may be embarrassed.
2) It hampers the privacy of the patient
3) Rectal inflammation or irritation can occur on repeated use.
4) Absorption may be impaired if rectum is full of faces.
5) Drugs such as Paracetamol, Diclofenac and Domperidone suppositories.
Buccal route: Longenze, ascorbic acid.

Nasogastric route: Feeding unconscious patients or for patients who are unable to take
food orally.

Colonic route: Barium enema for visualization of colon.

Intravenous route:

Formulation: solution, suspension.

Drugs given: Thiopental Na, heparin

Arnab Mazumdar Avi (26th/16) 26 | P a g e

 th
*May ’18, T 25 ] Advantages & disadvantages of intravenous route.

Advantages:
1) Suitable for emergency cases.
2) Rapid onset of action 100% bioavailability.
3) Avoid first pass biotransformation, i.e. not destroyed by GIT and Liver.
4) Large volume of drugs can be administered.
5) Reliable and suitable route for irritant drugs.
6) Can be given in unconscious, vomiting, non cooperative and diarrheal patients.
7) Administration of drugs can be stopped immediately if adverse effects develop.
Disadvantage:

1) Invasive painful procedure.

2) Self administration is difficult, so skilled person is required.
3) Strict aseptic precaution is needed.
4) Expensive.
5) Risk of infection, hypersensitivity reaction, pyogenic infection, thromboembolism
and hemolysis may occur.
6) Sometimes, it is difficult to inject children, female and obese person.
Intramuscular route:

Site: usually gluteus maximus, deltoid muscle and thigh.

Formulation: solution, suspension, depot preparations.
Drugs given: benzyl penicillin, diazepam
Advantages:

1) Reliable route for irritant drugs.

2) Repository/Depot preparation can be used, eg: Medroxy progesterone, procaine
penicillin.
3) More rapid and uniform absorption.
4) Absorption is more rapid than subcutaneous route.
Disadvantages:
1) Painful procedure.
2) May produce tissue staining, damage and hematoma formation.
3) Self administration is difficult or not possible
4) Large volume of drug can not be given (not more than 5 ml)
5) If adverse effect developed drugs can not be removed.

Arnab Mazumdar Avi (26th/16) 27 | P a g e

 6) Bioavailability is less than 100%.
Subcutaneous route (S/C):
Formulation: Solution, suspension
Site: Beneath the skin on Subcutaneous tissue
Drugs given: Insulin, adrenaline
Advantages:
1) Self-medication is possible because penetration is not needed
2) Small volume is usually administered (<2 ml)
3) It is safe and simple route

4) Process is slow and sustained

5) Bioavailability 75-100%.

Disadvantages:
1) Poor absorption in peripheral circulatory failure

2) Necrosis may occur at the site of injection

3) Repeated injection may lead to lipodystropy.

Intradermal route:
Formulation: Vaccine, solution.

 Introduced between dermis and epidermis

 It is painful
 <0.4ml can be given.
Transdermal route:
Formulation: Patch

 Medicine is absorbed through the skin at a fixed rate

 Only lipid soluble drugs are absorbed
 Avoid first pass metabolism
 Prolong duration of action
 Minimal adverse effect

Arnab Mazumdar Avi (26th/16) 28 | P a g e

  Continuous method of administration of drug which maintain steady-state
plasma concentration.
 Drugs such as fentanyl, nitroglycerine, nicotine, estrogen & progesterone for
birth control.
 Relatively expensive.
Epidermal route:

Formulation: Cream, ointment, lotion, paste, patch, jelly.

 Highly lipid soluble drug absorbed through skin

 Effects are almost local
 Applied on keratinized epithelium
 May cause irritation, sensitization, and undesired systemic effects.
 Drugs such as local anesthetics, steroids.
Inhalation route:

Formulation: Gas (volatile anesthetics), aerosol (bronchodilator), powder (sodium

chromoglycate). It may retain in the respiratory tract.
Advantages:

 Desired site of action

 Rapid onset of action
 Avoid systemic adverse effect
 Avoid first-pass biotransformation
 Dose can be adjusted
Disadvantages:

 Poor ability to regulate the dose

 Can cause irritation of respiratory tract
 Oropharyngeal cadidiasis and hoarseness of voice may occur with prolong
steroidal inhalation.
 Drugs such as salbutamol, inhaled general anesthetics, Sodium chromoglycate.
Conjunctival route:
Drugs like chloramphenicol, mydriatics, and miotics
Nasal route:
Zylometazoline (as drop), steroid (as spray)

Arnab Mazumdar Avi (26th/16) 29 | P a g e

Vaginal route:
Drugs like Nystatin for fungal infection, normal saline for diagnosis of patency of uterine
tube.
Urethral route:
Formulation: Jelly

 Used for local anesthetic during catheterization.

# Bioavailability:

It is the fraction of unchanged drug that reaches the systemic circulation following
administration by any route.
I/V route = 100% bioavailability
# First pass metabolism:
When a drug is greatly absorbed before entering the systemic circulation.
# Routes that avoid first pass metabolism –

 Emergency Routes
# What are the emergency routes?

 I/V (most common) [when asked, say I/V route only. If asked for more, then
mention the rest]
 I/M
 Sublingual
 Inhalation
 Per rectal
# Why so many routes?

1) Due to different physiochemical properties of drugs. Example –

 Insulin is a polypeptide can not be administered orally. If given, it is digested
by gastric proteolytic enzyme. That is why it is administered parenterally.
 Antacid works in gastric environment but Procaine Penicillin doesn’t work.
2) To gain access to the site of action easily, example - anesthetics.
3) To get rapid action of drugs, example - intravenously (I/V).
4) To prolong the duration of action, example - subcutaneously (S/C).
5) To avoid adverse effects, example - oral salbutamol produce cardiac arrhythmia.
But in inhalation salbutamol can not produce cardiac arrhythmia.

Arnab Mazumdar Avi (26th/16) 30 | P a g e

# Water soluble (small molecule) drug is given in – I/V route
# Lipid soluble (large molecule) drug is given in – any route (oral/sublingual/buccal etc.)
# Why per rectal route is better than oral route?
1) Relatively quick onset of action.
2) It can be used in case of unconscious patients.
3) Can be used in old aged patients or in children.
# Name some drugs that can not be given orally –
1) Insulin: Insulin is a polypeptide can not be administered orally. If given, it is
digested by gastric proteolytic enzyme. That is why it is administered
parenterally.
2) Benzyl & Procaine Penicillin: These are acid labile. They are destroyed by gastric
juice.
3) Amikacin: They are highly soluble and bioavailability is less than 1%.
4) Nitroglycerin: If given orally, it undergoes extensive first pass metabolism.
5) Oxytocin: Destroyed in stomach & intestine.
6) Dobutamine: Metabolized in the liver
7) Heparin: Must be given parenterally, because it doesn’t readily cross
membranes.
8) Methicillin: It is acid labile so destroyed by gastric juice.

Effect of route of administration on drug action:

1. Onset of action:
 Oral route → Slow onset.
 I/V, I/M, sublingual, inhalation → Rapid onset of action.

2. Duration of action: Oral route → Prolong duration of action.

3. On biotransformation: Oral route→ first pass metabolism→ Decreased action.

4. A drug may have entirely different uses through different routes; eg –

 Streptomycin:
- When used in I/M route→ Anti-tubercular effect.
- When used orally → No action in lung→ Acts as gut sterilizer.

Arnab Mazumdar Avi (26th/16) 31 | P a g e

  MgSO4:
- When taken orally → Acts as purgatives.
- When given I/V → Acts as anticonvulsants in eclampsia.
- When given as paste over sprained joint → Decreases swelling.

Arnab Mazumdar Avi (26th/16) 32 | P a g e

 ABSORPTION OR BIOTRANSPORT OF DRUGS
th th
[TS 25 , T 24 ] Define absorption.

Definition:
Absorption of drug means passage of drug from its site of administration (except I/V)
into the systemic circulation by crossing the biological membrane or barrier.
Overview:

 To get therapeutic effects, the drugs must get into systemic circulation.
 If a drug is administered intravenously, it directly reaches the systemic
circulation.
 In case of other parenteral and enteral route, the drug must pass through some
barriers to get into circulation.
 In case of oral administration, drugs cross the intestinal mucous membrane.
 In case of I/M or I/V route, they must cross the capillary wall to reach the
circulation.
th
*Nov ’19, T 25 ] What are the processes of drug absorption? Name the process of passage of drugs across the cell
membrane with example.

Process of Biotransport:
1. Passive transport
 Simple (passive) diffusion
 Filtration
2. Specialized transport
 Active transport
 Facilitated diffusion
 Endocytosis
 Ion-pair transport
Sites of drug absorption:

1) Alimentary tract:
a. Oral cavity:
 Less drug absorption occurs due to less surface area and short time
of absorption.
 Absorption occurs by simple diffusion.
b. Stomach:

Arnab Mazumdar Avi (26th/16) 33 | P a g e

  Less drug absorption occurs due to less surface area and short time
of absorption.
 Absorption occurs by simple diffusion.
c. Small intestine:
 More drug absorption occurs due to more surface area and greater
blood supply than stomach.
 Non-ionized drugs:
- Absorption occurs by simple diffusion.
 Ionized drugs:
- By filtration (eg, methyl dopa, levodopa, fluorouracil).
- By active transport (eg, Fe-specific carrier, Ca2+ by
vitamin D dependent carrier)
d. Rectum:
 Absorption occurs by simple diffusion.
 Slow and incomplete absorption.
 In lower 2/3rd of rectum: Drug bypasses liver & enters systemic
circulation → No first pass metabolism (FPM).
Drug → Absorb through middle & inferior rectal vein → hypogastric
vein → inferior vena cava not portal vein → hepatic first pass
metabolism (FPM).
 In upper 1/3rd of rectum: Drug Absorb through superior rectal vein
→ portal circulation → Liver → first pass metabolism.
Example - aminophylline, indomethacine, paracetamol, diclofenac,
magnesium sulphate, anti-hemorrhoidal drug, aspirin.
2) Subcutaneous tissue:
 By simple diffusion through capillary wall.
 Less absorption than IM route due to less blood supply to subcutaneous
fat.
 Example - insulin, adrenaline, steroid, progesterone, levonorgesterol.
3) Muscle:
 By simple diffusion through capillary wall.
 More absorption than S/C route due to more vascularity.
 Example - depot preparation, vaccine, injection.
4) Skin:
 Absorption occurs by passive process.
 Example - silver sulphadiazine, gentamycin, OPC, steroid.
5) Respiratory tract:
 Rapid absorption due to more vascularity and more surface area.
 Example –
 Salbutamol - aerosol (bronchodilator)

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  General anesthetic (Volatile gas)
 Na. Chromoglycate - inhaled vapor.
 Lignocaine (Local anesthetic) - spray during intubations.
6) Eye
 Absorption occurs by simple diffusion
Simple diffusion:
Transfer of drug through a biological barrier from the area of higher concentration to
lower concentration without the help of carrier and expenditure of energy.
Criteria:

 It is commonest
 Process is slow
 Carrier not needed
 Energy not required
 In passive diffusion, molecules cross the lipid membrane in a unionized form.
 Obeys Fick's Law i.e.;
Diffusion ∝ Cross sectional area and concentration gradient
It depends on concentration gradient, lipid-water partition coefficient, molecular
size and weight of the pKa of the drug and pH of the local fluid.
Rate of diffusion = DA (Ch-CL)
X
Here, D = Diffusion coefficient
A = Surface area
(Ch-CL) = Concentration difference
X = Membrane thickness
Example: Aspirin, Barbiturates, Morphine, Pethidine etc.
Filtration:
It is the process by which water soluble drug of relatively low molecular weight crosses
the biological membrane through pores as a result of hydrodynamic pressure gradient
across the membrane.

Sites:

 GIT
 Glomerular membrane – urea, glucose, ethylene glycol
 Capillary endothelium – urea, insulin

Arnab Mazumdar Avi (26th/16) 35 | P a g e

Criteria:

 It is less common
 It depends on
- Concentration gradient
- Molecular size of the drug
- Filtering force
Example: Urea, Glucose, Ethylene glycol, Insulin.
Facilitated diffusion:

It means the passage of drug across the biological membrane along the concentration
gradient by the protein carrier mediated transport system that shows saturability and
selectivity.

Criteria:

 Less common
 Quick process
 Depend on concentration gradient
 Carrier needed
 Require no energy
 Saturability and selectivity is present
Example: Tetracycline, Glucose, Vitamin B12.
Active transport:
Active transport means transfer of drug from the area of lower concentration to the
area of higher concentration with the help of carrier and expenditure of energy.
Sites:

 Neuronal membrane
 Choroids plexus
 Hepatocytes
 Renal tubular cells
Criteria:

 Less common process

 Occurs against concentration gradient
 Require carrier and energy

Arnab Mazumdar Avi (26th/16) 36 | P a g e

  It is unidirectional
 Here the drug molecule combines with a specific mobile carrier protein on one
side of the membrane forming drug-carrier complex. This complex then diffuses
across the membrane to the opposite side which then dissociates and releases
the drug. The carrier protein can then return to its initial site to bind more drugs.
Examples: Methyl dopa, Levo-dopa, 5-Fluorouracil and 5-Bromouracil.
Endocytosis:
It is the process by which the drug molecule/particle is engulfed by the cell membrane
pseudopodia and releases the drug intracellularly. It requires energy, Ca 2+, and
microfilaments.
It is of 2 types –

 Pinocytosis: It is the fluid phase endocytosis by which sucrose is absorbed.

 Phagocytosis: It means adsorption phase endocytosis by which insulin is
absorbed.
lon-pair transport:

Highly ionized lipophobic drug which combine reversibly with some endogenous
substance such as mucin in GIT to form a neutral ion-pair complex which then
penetrates the membrane by simple diffusion.
Examples: Vitamin A, D, E, K, neostigmine and some anticancer drugs.
th
*May ’22, May ’20, T 24 ] Difference between simple diffusion & active transport.

Difference between –

Traits Simple diffusion Facilitated diffusion Active transport

1. Movement Towards Towards Against
electrochemical electrochemical electrochemical
gradient (downhill gradient (downhill gradient (uphill
process) process) process)
2. Energy Not needed Not needed Needed
3. Carrier Not needed Needed Needed
protein
4. Speed Slow Medium Fast
5. Saturability Not saturated Saturated Saturated
6. Membrane Not needed May or may not be Must be present
present

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7. Diffusion Unlimited Limited (due to Limited (due to
capacity saturation of carrier) saturation of carrier)
8. Direction of Can operate Usually unidirectional
movement bidirectionally
9. Transported Lipid soluble Lipid insoluble
substances
10. Example Aspirin, Barbiturates, Tetracycline, Glucose, Methyl dopa, Levo-
Morphine, Pethidine Vitamin B12, Amino acid dopa, 5-Fluorouracil
and 5-Bromouracil
th th
[TS 25 , T 24 ] Discuss the factors modifying drug absorption.

Factors Modifying Drug Absorption:

A. Factors related to drugs:

 Physical state of drug

 Molecular weight and Size
 Lipid-water partition coefficient
 pKa of drug/ionization constant
 Disintegration
 Dissolution
 Concentration gradient
 Inactivation
 Interaction with other drugs.

B. Factors related to patient:

 pH of the gut
 Mucosal surface area
 Regional blood flow
 Gastrointestinal diseases
 Bowel transit time

Factors Related to Drugs:

Physical state of drug:

 Absorption of drug in decreasing order of frequency -

Gaseous > Liquid > Solid.

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Molecular weight and size:

 Lipid soluble drug of any size can be easily absorbed. So size is not a matter for
absorption of lipid soluble drug rather it is applied for water soluble drug.
 Crystalloid is absorbed more than colloid - Crystalloid >
Colloid.
 In most drugs, molecular size ranges from 100-1000. Molecular weight more than
1000 does not diffuse easily through biological membrane.
 Drugs with low molecular weight crosses the small pore of epithelial lining; i.e.,
Ethanol (MW-46), N2O (MW-44).
 Drugs with high molecular weight cannot readily cross through biological
membrane; i.e., Insulin (MW-5808).
 So smaller the drug size, greater the absorption.
Lipid-water partition coefficient (LWPC):

 It means relative solubility of a drug in lipid as compared to water.

 The Higher the LWPC, the higher is the affinity of drug for the cell membrane and
more readily drug is absorbed.
 Phenobarbitone has a high LWPC which absorbs very rapidly.
 Less the LWPC, less absorption occurs. Urea has a very low LWPC of 0.0016 which
absorbs very slowly.
*May ‘20+ Short note: Ionization constant.

pKa of drug / lonization constant:

 pKa of a drug is that pH at which concentration of ionized and unionized forms

are equal.
 Most drugs are weak acids or bases that are present in solution as both the non-
ionized and ionized forms.
 Ionized drug draw water from solution due to their electrostatic charge → Form
hydrostatic shell → large size of the molecule → less penetration through the
pore of cell membrane → decreased absorption.
 Weak acidic drugs are best absorbed in stomach because of its acidic
environment. Alkaline drugs are best absorbed in small intestine which has a
higher pH.
 Ampicillin, Aspirin, Phenobarbitone are acidic drugs.
 Morphine, Propranolol, Chlorpromazine are basic drugs.
 Since pH of urine is acidic, a weakly acidic drug can be extensively reabsorbed
into the circulation from urine. If pH is increased, excretion can be increased.

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  lonized drugs are lipid insoluble, so absorption is decreased. Examples: Heparin,
Ipratropium, Suxamethonium, Tubocurarine etc.
 Non-ionized drugs are lipid soluble, so absorption is increased. Examples: Digoxin,
Prednisolone etc.
 ↑ ionization ↓ lipid solubility ↓ absorption ↓
ionization ↑ lipid solubility ↑ absorption
Disintegration:

 Break down of solid drug into small particles within GIT is called disintegration.
 More rapid disintegration means more rapid absorption. Tablet needs
disintegration and dissolution before absorption whereas capsule needs only
dissolution in GIT. So absorption of capsule > tablet.
Dissolution:

 It means formation of solution after disintegration of drug in GIT which facilitate

absorption.
 More rapid dissolution means more rapid absorption. Capsule needs only
dissolution, whereas tablets need both disintegration and dissolution.
 Solution and suspension does not require disintegration and dissolution. So,
absorption is usually rapid in solution and suspension.
Concentration gradient:

 High dose means more concentration gradient across the membrane, so more
absorption.
 Low dose means less concentration gradient across the membrane, so less
absorption.
Inactivation/First pass effect:

 Drugs may be inactivated or metabolized within GIT before they are absorbed;
example - insulin, penicillin G. They are inactivated by gut enzyme. So no chance
of absorption if given orally.
 Even with complete absorption, the absorbed portion may not reach the systemic
circulation because some drugs are partially metabolized in liver. For example
nitroglycerin is metabolized in Liver.
Interaction with other drugs:

 When two drugs are administered simultaneously, one drug may modify the
absorption of another drug.

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  Iron, calcium, magnesium reduce absorption of tetracycline by chelation.
 Antacid also reduce the absorption of tetracycline from GIT [Tetracycline forms
an insoluble complex (chelation) with Ca2+.
 Vitamin C enhances the absorption of iron.
Factors Related to Patients
pH of the gut:

 pH of the environment greatly influences the ionization of drug.

 Acidic drug in acidic environment are less ionized, therefore absorption of drug is
more.
 Acidic drug in basic environment are more ionized, therefore absorption of drug
is less.
 Basic drug in basic environment are less ionized, therefore absorption of drug is
more.
 Basic drug in acidic environment are more ionized, therefore absorption of drug
is less.

Factors Increased gastric Decreased gastric

emptying rate emptying rate

Physiological Liquids, gastric distension Solids, acids, fat

Pathological Chronic pancreatitis Acute abdomen,

trauma and pain
Pharmacological Metoclopramide, Anticholinergic drugs,
cholinergic drugs morphine

Mucosal Surface Area:

 Surface area is proportionate to absorption.

 In intestine surface area is large, so absorption is more whereas in stomach
surface area is less, so absorption is also less.
 In gut, absorption follows this order - Jejunum >
Duodenum > Stomach.

Rate of gastric Emptying:

 It markedly influences the rate of drug absorption.

 The greater the rate of gastric emptying, the faster the rate of drug absorption
should be and vice versa.

Arnab Mazumdar Avi (26th/16) 41 | P a g e

  In general, factors that increase the gastric emptying rate will also increase the
drug absorption unless it dissolves slowly. There are some factors which influence
gastric emptying rate and subsequently the drug absorption.

Bowel Transit Time:

 It is the time required for particular food stuff to pass through the bowel.
 It is mainly dependent on motility of the bowel. More bowel transit time means
more absorption.
 Increase bowel motility (Metoclopramide) decrease bowel transit time, therefore
less absorption.
 Decrease bowel motility (Atropine) increase bowel transit time, therefore more
absorption.
Regional Blood Flow:

 More the blood flow, more the absorption.

 In intestine, more blood flow means more absorption.
 In stomach less blood flow and less absorptive surface area, so less absorption.
 In shock and cold, less vascularity. So less absorption.
 In heat and fever, more vascularity. So more absorption.
 After I/M injection of drug, if massage is done then there is heat production. So,
more absorption.

GIT diseases:

 Celiac disease and cron's disease may change the pattern of absorption so that
more drugs are absorbed from GIT.
 Gut edema in CCF patients may reduce absorption of diuretics.
Presence of food in gut:

 Most drugs are better absorbed in empty stomach. In full stomach drug may bind
with food particle and may excrete with it.
 Food interferes with the absorption of water soluble drugs such as ampicillin,
doxycycline, INH, levo-dopa.
 Lipid soluble drugs such as propranolol, spironolactone, and riboflavin are more
absorbed in presence of food.
 Gastric irritant drugs such as aspirin should be given just after meal; i.e. in full
stomach to prevent gastric irritation.
Bioavailability:

Arnab Mazumdar Avi (26th/16) 42 | P a g e

The fraction of unchanged drug that reaches the systemic circulation following
administration by any route is called bioavailability.

 Clinician primary concern with this term rather than absorption.

 Extent of absorption is the total amount drug that undergoes absorption and it is
directly proportional to bioavailability.
 First pass biotransformation is inversely proportional to bioavailability.
 Bioavailability is expressed as a percentage (%).
 In I/V administration, bioavailability=100%.
 If 50 mg drug is administered and 40 mg drug absorbed then bioavailability is
80%.

Factors Modifying bioavailability:

1) Routes of drug administration
2) Hepatic first-pass elimination or loss
 Hepatic first-pass biotransformation
 Hepatic excretion
3) Pharmaceutical factors (factors of absorption)
Routes of drug administration, bioavailability and general characteristics –

Route Bioavailability Characteristics

Intravenous 100% Most rapid onset

Intramuscular < or equal to 100% Large volume, often
feasible, may be painful
Subcutaneous < or equal to 100% Smaller volume than I /M,
often, painful
Oral < 100% Most convenient, first-pass
effect may be significant
Rectal < 100% Less first-pass effect than
oral
Inhalational < 100% Onset is very rapid
Transdermal < or equal to 100% Slow absorption, first-pass
effect almost nil, prolong
duration of action
Sublingual 100% Very rapid onset

Hepatic First-pass effect:

Arnab Mazumdar Avi (26th/16) 43 | P a g e

  Bioavailability is inversely proportional to Hepatic first pass elimination.
Importance of Bioavailability:

 To compare different formulation produced by different company.

 To compare the different formulation of same drug.
Bioequivalence:
Drug products are pharmaceutically equivalents if they contain same active ingredients
and are identical in strength or concentration, dosage form and routes of
administration. Two
pharmaceutically equivalent drug products are considered to be bioequivalent when the
rates and extents of bioavailability of the active ingredient in the two products are not
significantly different under suitable test condition.
rd
*May ’19, T 23 ] Short note: Pre-systemic clearance.

First pass metabolism / Pre-systemic clearance:

When a drug is greatly absorbed before entering the systemic circulation.

Sites of first pass metabolism:

 Liver (main site; hence called first pass hepatic metabolism)

 Intestinal wall
 Stomach
 Lungs
Clinical significance of hepatic first pass metabolism:

 A significant amount of drug may be lost before entering into systemic circulation
due to first pass metabolism.
 Due to first pass metabolism, higher dose is required.
 An alternative route should be chosen to avoid first pass metabolism.
Factors that modify first pass hepatic metabolism:

 Routes of drug administration

 Hepatic circulation
 Hepatic bio transforming enzyme activity
 Hepatic diseases

Some drugs that undergo first pass hepatic metabolism:

Arnab Mazumdar Avi (26th/16) 44 | P a g e

  Oral
- Propranolol
- Verapamil
- Salbutamol
- GTN
- Morphine
- Pethidine
 Non-oral
- Isoprenaline
- Lidocaine
- Hydrocortisone
- Testosterone

Routes that avoid first pass metabolism –

 Emergency Routes
 I/V (most common) [when asked, say I/V route only. If asked for more,
then mention the rest]
 I/M
 Sublingual
 Inhalation
 Per rectal
*May ‘21+ Can drug action be prolonged? If yes, how?

Methods for delaying drug absorption:

A. By altering the route:

 S/C insulin→ prolonged action.

B. By altering the formulation:

 Gaseous formulation - rapid absorption & action.
 Sustained release (SR) formation - delayed absorption.
 Depot release preparation (subcutaneous pellets) - prolong absorption.

C. By adding 2nd substrate with drug:

 Vasoconstrictor + LA: Adrenaline (vasoconstrictor) + local anesthetic →
vasoconstriction → ↓blood flow → ↓absorption of LA → prolong action.
 Insulin + protamine: Insulin alone has the half-life of 15-30 min. But Insulin
+ protamine → prolong action.
 Penicillin + Benzathine: Penicillin alone → short duration of action. But
penicillin + Benzathine → prolong action (one month)

Arnab Mazumdar Avi (26th/16) 45 | P a g e

Factors accelerating drug absorption:

 Application of heat: Heart → vasodilatation → ↑blood flow→ ↑absorption

 Massage: ↑Local blood flow → ↑absorption
 By addition of some adjuvant: Phylline → ↑absorption of mercurial diuretics.
 High dose

Arnab Mazumdar Avi (26th/16) 46 | P a g e

 DISTRIBUTION OF DRUGS

Definition:
It is the process by which a drug reversely leaves the blood stream and enters into the
interstitium & cells of the tissue. Or,
Distribution of drug means dividing and spreading of drug to the tissue.
After absorption drugs reaches the systemic circulation. Then a portion of circulating
drug will subsequently pass the cellular boundary to distribute into various tissue fluids.
Since target organ or site of action is not usually the blood, so the drug should penetrate
tissues to produce its action.

After absorption drug may:

 Remain in protein bound form

 Produce pharmacological effect
 Store in tissue reservoir
 Undergo biotransformation and excretion
Major compartment of distribution:

1) Fluid compartment (70%)

 Plasma compartment - 4L
 ECF compartment - 14L (1/3rd of TBW)
 Total body water (TBW) - 42L
2) Solid compartment (30%)
 Bone
 Muscle
 Fat (25% of TBW)
Drug in plasma compartment possess following criteria –

 Drug having large MW > 1500; eg - Heparin, Dextran

 Extensively bound to plasma; eg - Warfarin
 Require only 10 minutes for equilibrium
 They have low volume of distribution; eg - Evans blue, Heparin, Dextran,
Warfarin, Aspirin
Drugs in extracellular fluid compartment possess following criteria –

 Highly ionized drug

Arnab Mazumdar Avi (26th/16) 47 | P a g e

  Low molecular weight
 Water soluble, so can’t enter into brain and tissue
 Require only 30 minutes for equilibrium; eg – Tubocurarine, Gentamicin
Drugs in total body water possess following criteria –

 Low molecular weight

 Lipid soluble, so move through the cell membrane into intracellular fluid
 Require 1 hour for equilibrium; eg - Ethanol, Chloroquine, Tricyclic
Antidepressant (TCA)

Factors Influencing Distribution of Drugs:

 Physiological properties of drug

 Regional blood flow
 Blood-lipid partition coefficient (BLPC)
 Binding with plasma protein
 Binding with tissue constituent / Sequestration of drugs
 pH of the media
 Permeability across the barrier / Physiological barriers to distribution
- Blood placental barrier
- Blood brain barrier

Physiological properties of drug:

 Solubility of drug: Lipid soluble drug distribute intracellularly so can cross blood
brain barrier. Water soluble drug distribute extracellularly.
 lonization of drug: Polar or ionized drug are decrease lipid solubility so they
distribute extracellularly. Nonpolar or unionized are lipid soluble so they
distribute intracellularly.
 Size of the drug: Crystalloid distribute intracellularly whereas colloids distribute
extracellularly.
 Cardiac output: More cardiac output more distribution, less cardiac output less
distribution.
Regional blood flow:

 Rapid distribution: Within few minutes in highly perfused organ; eg – brain, liver,
kidney.
 Intermediate distribution: Within few minutes to few hours in moderately
perfused organ; eg – muscle.

Arnab Mazumdar Avi (26th/16) 48 | P a g e

  Slow distribution: Takes hours or more in less perfused organ. Act as reservoir;
eg - fat.
Blood-Lipid partition coefficient:

 Increase lipid solubility, can move through the cell membrane and enter into
intracellular fluid.

Binding with plasma protein:

 It means reversible association of drugs with plasma proteins.

 Acidic drugs such as phenytoin, warfarin, and phenylbutazone bind
predominantly to albumin. Binding is reduced in cirrhosis, nephritic syndrome
and CCF when plasma concentration of albumin is low.
 Basic drugs such as chlorpromazine, quinidine binds largely to globulin and α1
acid glycoprotein.
 The total amount of plasma protein binding of a drug depends on its protein
concentration, its affinity for plasma proteins and plasma protein binding sites.
 The high binding drug has the ability to displace the least binding drugs; eg -
Aspirin competes with Warfarin for the same protein binding site.
Warfarin + Aspirin: Increase free warfarin in blood → Enhance anticoagulation
(Bleeding).
*May ’17, Nov ‘18+ Importance of plasma protein binding of a drug.

Importance of plasma protein binding:

 Plasma protein binding regulates the concentration of drugs in plasma.

 Protein bound drugs are inactive and acts as a reservoir.
 Protein binding can prolong the half-life because it is not filtered, not bio
transformed, and not eliminated.
 Bound drugs are less likely to produce adverse effects.
 Hypoalbuminemia secondary to severe liver disease or the nephrotic syndrome
results in reduced binding and an increase in the free/unbound drug which leads
to toxicity.
 Drugs may influence protein binding of other endogenous substances or drugs.
The binding of bilirubin to albumin may be inhibited by sulfonamide. This can be
hazardous in neonates producing Kernicterus.

Arnab Mazumdar Avi (26th/16) 49 | P a g e

*Nov ‘18+ What interaction may occur at the level of protein bound drug?

Clinically important drug interaction at the level of plasma protein binding:

A drug having more affinity to plasma protein can displace another drug having less
affinity for the same binding site. So, the displaced drug becomes free which is
pharmacologically active & produces action.

Displacing drug Displaced drug Result / Effect

 Sulfonamide
 Salicylates  Bilirubin Kernicterus (in new born)
 Vitamin K
 Sulfonamide  Methotrexate Agranulocytosis
 Salicylates
 Sulfonamide  Tolbutamide (oral
 Salicylates hypoglycemic agent) Hypoglycemic shock
 Phenylbutazone
 Salicylates  Sulfonamide Sulfonamide toxicity
 Quinidine  Digoxin Digoxin toxicity
 Valproate  Phenytoin Phenytoin toxicity
 Indomethacin  Warfarin Bleeding
 Phenytoin
th th
*May ’22, T 25 , T 24 ] Difference between free drug & plasma protein bound drug. What are the importance of
free drug.

Comparison between -

Free drug Plasma protein bound drug

1. Active form 1. Inactive form
2. Can produce pharmacological effect 2. Can’t produce pharmacological effect
3. No storage form 3. Storage form
4. Undergoes biotransformation 4. No biotransformation
5. It can be excreted 5. It can’t be excreted
6. No drug interaction 6. Drug interaction at distribution level
7. Short duration of action 7. Sustained action/long duration of action
8. Not produces prolong toxic effect 8. Produces prolong toxic effect

Sequestration of drugs / Binding with tissue constituents:

 Drugs will not always be uniformly distributed to and retained by body tissues.
The concentrations of some drugs are either is higher or lower in particular
tissue.

Arnab Mazumdar Avi (26th/16) 50 | P a g e

  It means special distribution of drugs in the certain tissue of the body due to
special affinity between particular drug and particular body constituents. Such as:
- Tetracycline - deposited in bone and teeth (because of high affinity for
Ca2+)
- Phenothiazine and chlorpromazine - deposited in Retina
- Iodine - Deposited in thyroid gland
- Thiopental sodium - Deposited in adipose tissue

pH of the media:

 Decreased pH of the ECF → Increase intracellular concentration of acidic drug

and decrease intracellular concentration of basic drug.
 Increased pH of the ECF → Increase intracellular concentration of basic drug and
decrease intracellular concentration of acidic drug.
Blood Brain Barrier (BBB):

 Blood brain barrier is a barrier between plasma & extracellular space of brain.
 The drug will not be distributed uniformly in all the tissues due to some
physiological barriers such as BBB.
 Most drugs can’t enter the brain while some drugs can. This is due to the
presence of tight junction between the endothelial cells of brain capillaries.
 The drugs which can pass through blood-brain barrier have low ionization at
plasma pH, high LWPC and minimal plasma protein binding.
 Thiopental Sodium can very easily cross the BBB. On the other hand, the highly
ionized drug such as Benzyl penicillin can’t cross BBB. But in case of meningitis,
the permeability of this drug to BBB is increased and is useful for the treatment
of disease.
 In fetus BBB is not well developed, so chance of CNS toxicity is more.
 Propranolol can cross BBB, thus produce CNS adverse effect whereas Atenolol
can’t cross BBB. So, it is devoid of CNS adverse effect.

Blood placental barrier:

 Placental barrier has the general properties of a lipid membrane and allows the
transfer of non-ionized drugs with HLWPC by passive diffusion.
 Alcohol, morphine, all sedative hypnotics, and other CNS depressant drugs should
not be administered during pregnancy.
 The administration of drugs like cortisone, streptomycin, antineoplastic drugs in
first trimester may produce malformation of fetus (Teratogenic effects).

Arnab Mazumdar Avi (26th/16) 51 | P a g e

Redistribution:
It means distribute again. After administration, drugs are quickly distributed to the
organs that are highly perfused; eg – brain. After sometime, the highly lipid soluble
drugs are distributed into other tissues from the first organ of distribution. This
distribution of drug from one organ to another is called redistribution of drug.
Example - Intravenous anesthetic Thiopental sodium first distribute to brain, then it is
redistributed to muscle).

Drug Tissue
Iodine Thyroid
Tetracycline Bone & Teeth
Atropine Iris
Chloroquine Retina
th th th rd
*Nov ’18, May ’21, TS 25 , T 25 , T 24 , T 23 ] Short note: Plasma half-life. Define half-life of a drug. What
information will you get if it is said that t1/2 = 12 hours?

Half-life (T1/2):
It is the time by which the concentration or effect of the drug decline by one half or
50%. CL = Clearance

0.7 = ln 2 = constant

Vd = Volume of distribution

For example: If 8 mg of a drug is administered into blood, blood concentration becomes

4 mg (50%) after 20 minutes. So plasma half-life is 20 minutes.

 Half-life of paracetamol is 2 hours

 Half-life of diazepam is 43 hours
 Half-life of digoxin is 50 hours
It has two phases- Half-life of distribution and Half-life of elimination.

It can be measured as:

1. Plasma half-life: It is the time during which the plasma concentration of a drug
falls by one half.
2. Biological effect half-life: It is the time in which pharmacological effect of a drug
itself or any of its active metabolites declined by one half.
3. Biological half-life: It is the time in which the total amount of drug in the body
after equilibrium of plasma with the components becomes half.

Arnab Mazumdar Avi (26th/16) 52 | P a g e

Factors effecting half-life:

 Route of administration: Dopamine has short half-life of 2 minutes which needs

continuous I/V infusion.
 Plasma protein binding drug: ↑PPB → ↑Half-life.
 Tissue binding of drug: ↑Tissue binding → ↑Half-life.
 Metabolism of drug: ↑Metabolism → ↑Half-life
 Excretion of drug: ↑Excretion → ↓Half-life
 Pathogenesis of kidney and liver: ↑Half-life
 Distribution of drug: Widely distributed drug → ↑Half-life
 Age of the patient: Half-life is increased with age. The half-life of diazepam
increases with increasing age.
Importance of half-life:

1. To formulate dosage schedule (amount of drug and dosing intervaly,

2. To determine the time to achieve steady-state plasma concentration
3. To predict the duration of action of drug 44)
4. Whether the drug itself is active or converted into active metabolite or both
5. Whether the drug has irreversible action or not
6. Presence of disease in the organ of metabolism or excretion.

Volume of distribution:
It may be defined as the volume of body fluid in which a drug appears to be distributed
with a concentration equal to that in plasma.

Factors modifying Vd:

 Lipid-water partition coefficient (LWPC) of drugs.

 pKa value of drugs.
 Degree of plasma protein binding (PPB).
 Affinity for different tissues.
 Fat & lean body mass ratio (vary with age, sex, obesity).
 Pathological conditions such as CCF, CLD, uremia etc.
Importance of Vd:

 It is used to calculate the loading dose.

Arnab Mazumdar Avi (26th/16) 53 | P a g e

If a drug is highly tissue bound, then the plasma concentration will be low and the
volume of distribution becomes very large.

Drugs with large volume of distribution:

 Amitriptyline
 Phenothiazine
 Digoxin
 Chloroquine
Drugs with low volume of distribution:

 Theophylline
 Aspirin
 Phenytoin
 Heparin
 Furosemide / Frusemide

Clearance (CL):
The volume of fluid from which a drug is completely removed in a given period of time is
called clearance. The unit is volume/time.
Total clearance = Renal clearance + Hepatic clearance

Clearance provides an indication of the ability of the kidney and liver to dispose the
drug. Clearance values can be used to plan the dose regimen.

Dosing rate for I/V infusion = CL x CPss

Steady State / Steady state plasma concentration (CPss):

When a drug is given repeatedly over a period of time a balance is eventually achieved
between input and output. This balance gives rise to a constant amount of drug the
body reflected in the plasma as a Steady state.

Steady state is usually achieved within 4-5 half-lives for most of the drugs governed by
first-order kinetics. For example, a drug with 1 hour half-life would be expected to be in
a steady state after more than 20 hours of infusion.

Arnab Mazumdar Avi (26th/16) 54 | P a g e

 rd
[T 23 ] Short note: Order of kinetics.

Order of reactions / Order of Kinetics:

The mode of administration of different drugs is not same. For example, digoxin is given
in once daily dose; whereas paracetamol needs thrice daily doses. Drugs usually follow 2
processes for their pharmacokinetic behavior in the body:
1. First-order process / kinetics
2. Xero-order process / kinetics

Zero order kinetics

Plasma concentration of drug

First order kinetics

Time

Most of the drugs follow the first order kinetics where drug metabolizing enzymes
remain unsaturated.

Few drugs can follow zero order kinetics where drug metabolizing enzymes become
saturated so that constant amount is removed per unit time.
th
*Nov ’18, T 25 ] Short note: First order kinetics. What do you mean by first order & xero order kinetics, give
example.

First-order process/kinetics:
It is the fixed percentage of drug that is eliminated per unit of time.

Example - low dose Aspirin (75 mg) [it has anti-platelet effect], Phenobarbitone,
Paracetamol, Diazepam, Atropine.
Xero-order process / kinetics:
It is the fixed amount of drug that is eliminated per unit of time.

Example – high dose Aspirin (300 mg) [it has anti-inflammatory effect], Phenytoin,
Alcohol.

Arnab Mazumdar Avi (26th/16) 55 | P a g e

Drug selectivity / selective distribution of drug:
It means special distribution of drug in certain tissue of the body due to special affinity
between particular drug & particular body constituents. The drugs exist in these tissues
in highest concentration compared to plasma. This phenomenon is called cellular
reservoir of drug and the tissues are called selective reservoir. It is due to presence of
nucleoprotein in the tissue.
Examples:

Tissue / Organ Drugs

Thyroid Iodine
Heart Digoxin, Quinidine
Liver Chloroquine, Doxycycline, Iron, Digoxin
Brain Chlorpromazine, INH
Retina Chloroquine
Bone & Teeth Tetracycline, Calcium, Iron, Lead
Iris Atropine, Ephedrine
Fat Morphine. Thiopental Na, OPC, Barbiturate
Hair & Nail Arsenic, Heavy metal
Lungs TCA, Amiodarone
Gastric parietal cell Omeprazole

Arnab Mazumdar Avi (26th/16) 56 | P a g e

 BIOTRANSFORMATION OF DRUGS
rd
*May ’19, T 23 ] Short note: Biotransformation.

Definition:
Biotransformation is defined as the molecular alteration of drugs within the living
organism either with (mostly) or without enzymes for its ultimate excretion.
th th th rd
[TS 25 , T 25 , T 24 , T 23 ] What are the objectives & sites of biotransformation?

Objectives:
Conversion of lipid soluble drugs into water soluble drugs for its elimination from the
body.

 To decrease the lipid solubility of drug

 To increase water solubility of drug
 To convert non-ionized drugs to ionized or polar drug
Site of biotransformation:

Main organ → Liver (99%)

Other organs → Lungs, Kidneys, Intestinal mucosa, Adrenal glands, Skin, Placenta, RBC,
Intestinal flora, Spleen, Brain, Gonads
Organelles → Smooth endoplasmic reticulum, Mitochondria, Cytoplasm

Enzymes involved:
The enzymes involved in biotransformation are –

 Microsomal enzymes
 Non-microsomal enzymes
Microsome:

After centrifugation and ultracentrifugation of endoplasmic reticulum, sac / bag

containing tiny droplets retain at the bottom of the test tube. These are known as
microsome and enzymes are called microsomal enzymes.

Microsomal enzymes:
These enzymes are present in smooth endoplasmic reticulum of liver, kidneys & GIT.
Example –

Arnab Mazumdar Avi (26th/16) 57 | P a g e

  Mixed function oxidase
 Glucoronyl transferase
 Cytochrome oxidase P450
 Dehydrogenase
 Hydroxylase
 Reductase

 Drugs are mostly metabolized by microsomal enzyme.

 Highly lipid soluble drug can enter the microsome.
 The endogenous substances of the body are also metabolized by microsomal
enzymes. Eg - Bilirubin, T3, T4, Steroid etc.

Non- microsomal enzymes:

These enzymes are present in cytoplasm, mitochondria and extracellular spaces of
different organ. These are formed mostly in liver, kidney, plasma & other tissues. Less
lipid soluble drugs are metabolized by non-microsomal enzymes which can’t the
microsomal membrane. Example –
 Acetyl transferase Esterase
 Amidase
 Hydrolase
 Methyltransferase
*May ‘21+ Why biotransformation is necessary?

Results of biotransformation:
1. Active drugs are transformed into inactive compound (most common).
 Morphine → Morphine glucoronide
 Acetylcholine → Choline + Acetyl CoA
 Sulfonamide → Acetyl sulfonamide
2. Active drugs are converted into other active drug metabolites.
 Diazepam → Oxazepam
 Amitriptyline → Nortriptyline
 Phenacetin → Paracetamol
 Heroin / Codeine → Morphine
 Digitoxin → Digoxin
 Chloroquine → Hydroxychloroquine
3. Inactive drugs (prodrugs) are transformed into active drugs.
 Prontosil → Sulfanilamide / Sulfonamide
 Enalapril → Enalaprilat

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  Talampicillin → Ampicillin
 Levodopa → Dopamine
4. Toxic drugs are transformed into less toxic substances.
 Phenacetin → Paracetamol
 Morphine → Morphine glucoronide
5. Non-toxic drugs are converted into toxic drugs.
 Parathion → Paraoxon
 Malathion → Malaoxon
rd
*Nov ’17, T 23 ] Write down about phase I & phase II reactions of biotransformation with example.

Process of biotransformation:

 Phase I or Non synthetic process

 Phase II or Synthetic process or conjugation / Referred Phase (Conjugate with
some endogenous substances)
Phase I reaction:
This reaction usually converts the parent drugs to a more polar metabolites by adding or
removing a functional group (-OH, -NH2, -SH, -COOH). No new product synthesis takes
place.

Criteria of a drug in phase I reaction:

 It may retain activity

 It may lose activity
 It may gain activity
 Decrease lipid solubility of drug
 The phase is catabolic in nature
 Many phase I products are not eliminated rapidly due to insufficient polarity & go
to phase II subsequently. If phase I metabolites are sufficiently polar, they may be
readily excreted without going to phase II reaction.
Phase I reactions are –

1. Oxidation:

 Microsomal
- Codeine → Morphine
- Acetanilide → Paracetamol
- Phenobarbital → Hydroxyphenobarbital
 Non-microsomal
- Adrenaline / Nor adrenaline → Vanillyl Mandelic Acid (VMA)

Arnab Mazumdar Avi (26th/16) 59 | P a g e

2. Reduction

 Microsomal
- Cortisone → Hydrocortisone
 Non-microsomal
- Acetic acid → Ethanal → Ethanol
3. Hydrolysis

 Microsomal
- Mepiridine → Mepiridinic acid
 Non-microsomal
- Acetylcholine → Acetate + Choline
*May ’21, May ‘17+ Discuss conjugation reaction. Outline phase II biotransformation & its importance.

Phase II or Synthetic process:

Parent drugs or phase I metabolites undergo conjugation with an endogenous substance
to yield a drug conjugate complex which are polar and readily excretable through the
kidneys. The endogenous substances are glucoronic acid, acetic acid, methyl group,
amino group. Here new product synthesis takes place.
Criteria of Phase II reactions:

 Drug losses its activity

 Complete loss of lipid solubility
 The phase is anabolic in nature
 Drugs become polar
 Drugs are readily excretable through kidney or bile
 These reactions require high energy

Phase II reactions are -

1. Microsomal
Glucoronyl
 Glucoronide conjugation
transferase
- Morphine + UDP glucoronide Morphine glucoronide + UDP
2. Non Microsomal:

 Sulfation
- Sulphate conjugation
 Methylation
- Methyl conjugation

Arnab Mazumdar Avi (26th/16) 60 | P a g e

  Acetylation
- Acetyl conjugation
 Glycine / amino acid conjugation

Absorption Metabolism Elimination

Phase I Phase II

Drug Conjugate
Drug metabolite with
modified activity Conjugate

Drug
Inactive drug
metabolite Conjugate

Drug

Lipophilic Hydrophilic

Figure: Phase I & phase II reactions, and direct elimination in drug biodisposition. Phase II reactions may also
precede phase I reaction.

# Usually after completion of phase I reactions, drugs enter phase II reaction. However,
some drug first enter phase II reaction, then phase I; eg – Isoniazid.
Entero-hepatic recycling:

Glucoronidation increases the molecular weight of drugs which favors its excretion in
bile. Excreted drugs through bile can be metabolized by normal flora of intestine. The
drugs get free again & are reabsorbed again & undergo same fate. This is called entero-
hepatic recycling.

Drugs that undergo entero-hepatic recycling:

 OCP (Estrogen + Progesterone)

 Tetracycline
 Opioids (Morphine, Pethidine)
Importance:
 Prolongation of effect – increases the life time of drug, so small amount of drug is
enough; eg: OCP
 Local effect

Arnab Mazumdar Avi (26th/16) 61 | P a g e

  Drug toxicity
 Microsomal & non-microsomal enzyme deficit in premature babies

Enzyme induction:
It is the process of increasing the synthesis & activity of drug metabolizing enzyme by
administration of inducer.

Inducer Drug whose metabolism is Effect

induced
1. Rifampicin OCP Failure of contraception
Warfarin Decreased anticoagulation
OCP Failure of contraception
2. Phenobarbitone Warfarin Decreased anticoagulation
Chloramphenicol No Gray baby syndrome
3. Phenytoin OCP Failure of contraception
Warfarin Decreased anticoagulation
4. Phenylbutazone Warfarin Decreased anticoagulation
*May ‘20+ What is the importance of microsomal enzyme induction?

Significance of enzyme induction:

 Therapeutic failure of primary drug.

 Development of tolerance.
 Development of drug toxicity.
 May cause disease.
 Metabolism of some endogenous substance is also increased; eg – steroids,
bilirubin.
 It causes individual variation of drug response.
*May ‘17+ What is enzyme inhibition?

Enzyme inhibition:
It is the process of decreasing drug bio-transforming enzyme activity, particularly
cytochrome P450 microsomal enzymes.

Inhibitor Drug whose metabolism is Effect

inhibited
1. Cimetidine Warfarin Hemorrhage
2. Chloramphenicol Warfarin Hemorrhage
3. Metronidazole Tolbutamide Hypoglycemic shock
4. Allopurinol Azathioprine Bone marrow suppression

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5. Azithromycin
6. Clarithromycin

Significance of enzyme inhibition:

 Reduced metabolism of primary drug which increases its effectiveness.

 Decreased cost of therapy by decreasing the dose with the help of an enzyme
inhibitor.
 Increased chance of toxic effect by primary drugs.

Factors modifying biotransformation of drugs:

1. Personal factors:
*May ‘20+ How age modify biotransformation.

 Age:
- The premature neonates and infants are less capable of biotransforming
drugs than the adult patients. The enzymes responsible for
biotransformation of drugs are poorly developed in patients of these age
groups.
- Phenytoin, Carbamazepine, Chlorpromazine, Phenobarbital and
Ethosuxemide are given in higher doses to children than adult. This is due
to increased rate of biotransformation of these drugs in children.
- In neonates, especially premature one, Chloramphenicol may cause Grey
baby syndrome characterized by cyanosis, abdominal distention, vomiting
and loose green colored stool due to inability to metabolize the drug as a
result of Glucoronyl transferase enzyme deficiency.
- Older people shows decreased function of enzymes and may have
circulatory impairment of liver and kidneys. So, many drugs should be
given in lower doses in elderly people.
- Streptomycin undergoes less biotransformation in old people, resulting in
adverse effects in conventional doses.
- The first pass biotransformation is decreased in older people, resulting in
increased systemic bioavailability of high first-pass drugs; eg - Propranolol.
 Sex:
- In comparison to men, some women may show increased sensitivity to
certain drugs. This is due to relatively smaller body weight and hormonal
effect.
- Sex differences in drug metabolism do not exist among neonates.

Arnab Mazumdar Avi (26th/16) 63 | P a g e

 - Males have higher mixed function oxidase activity than female because
testosterone induces microsomal enzymes whereas estradiol decreases
their activity.
 Nutrition:
- Malnutrition impairs the biotransformation of drugs.
- It includes the deficiency of protein, fat, vitamin A, riboflavin, vitamin C.
 Alcohol:
- Intake of alcohol alters the biotransformation of drugs.
- Acute intake of alcohol inhibits the biotransformation.
- Chronic alcohol intake increases the biotransformation.
 Tobacco smoking:
- The biotransformation of some drugs such as Theophylline, Caffeine, and
Imipramine are several times higher in smokers than in non-smokers.
- Tobacco smoking is a rich source of benzopyrene which is a potent enzyme
inducer.
- The half-life of Theophylline is about 8 hours in adult non- smoker and
about 4 hours in adult smoker.
 Pregnancy:
- The biotransformation of drugs may be altered in pregnancy.
- Demethylation of Pethidine is reduced in pregnancy.
2. Genetic factors:

 It is an important factor which can modify biotransformation.

 The population is clearly divided into rapid and slow acetylator (acetyl
transferase) on the basis of their ability to biotransform Isoniazid. The ratio of
fast and slow acetylators is 40:60 in Europe, 85:15 in Japan.
 The rapid acetylators metabolize Isoniazid rapidly to acetyl isoniazid which is
excreted in urine. So, rapid acetylators need large dose of drugs to get
therapeutic effects.
 Slow acetylators metabolize isoniazid in a slower rate and are subjected to
isoniazid toxicity, such as peripheral neuropathy. So, low dose is given.
 Pseudo cholinesterase enzyme deficiency leads to prolonged apnea in anesthesia
with succinylcholine administration.
3. Pathological factors:
Acute and chronic liver diseases markedly modify the rate and extent of
biotransformation. The half-life of diazepam in patients with liver cirrhosis is greatly
increased with prolongation of their effects. Cardiac disease by limiting blood flow to
liver may impair the disposition of flow limed drugs; eg - Imipramine, Isoniazid,

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Lidocaine, Morphine and Propranolol. Similarly, renal and pulmonary diseases may
modify the biotransformation of Insulin or Isoprenaline.

 Liver disease
 Nephrotic syndrome
 Hypothyroidism decreased biotransformation
 Hypopituitarism
 Hyperthyroidism – increased drug biotransformation
 Kidney disease – decreased insulin biotransformation
 Pulmonary disease – decreased Isoprenaline biotransformation
4. Drugs:

 Simultaneous administration of more than one drug may increase or decrease

the biotransformation of administered drugs.
 Example - biotransformation of warfarin is increased if administered with
phenobarbitone as it is an enzyme inducer and biotransformation of warfarin
decreased in presence of cimetidine as it is an enzyme inhibitor.
5. Environmental factors:

 Urban people have more exposure to hydrocarbon which induce microsomal

enzyme and increase metabolism of drug.
 Rural & high altitude living people have less exposure to hydrocarbon, so
decreased microsomal enzyme activity & decreased metabolism of drug.
*May ’17, May ’21+ Discuss that lipid solubility of drug affecting their pharmacokinetic properties. Solubility
interferes drug absorption – discuss it.

Solubility status of drug influences every aspect of pharmacokinetic properties of

drug:
1. Absorption:
 Increased lipid solubility → Increased absorption (Absorption ∞ Lipid
solubility)
 More water solubility → Less absorption
2. Distribution:
 Lipid soluble drugs → distribute mainly intracellularly
 Water soluble drugs → distribute mainly extracellularly
3. Biotransformation:
 Most of the drugs metabolizing enzymes are located intracellularly. So
more lipid soluble drugs enter the cell faster than water soluble drugs and
are metabolized earlier

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 4. Excretion:
 More lipid soluble drugs are more reabsorbed
 More water soluble drugs are more excreted

Arnab Mazumdar Avi (26th/16) 66 | P a g e

 EXCRETION OF DRUGS

Definition:
Excretion or drug means the transportation of unaltered or altered form of drug out of
the body.
 The rate of excretion affects the duration of action of drug. The faster the
excretion, the lower the drug concentration in body and sooner the effects of the
drugs will be disappeared. On the other hand, a drug that is excreted slowly, the
level is maintained at higher concentration and the effect will continue for long
period.

Routes of drug excretion:

1. Major routes
 Renal
 Hepato-billiary
 Gastro-intestinal
 Pulmonary
*May ’18, Nov ‘19+ Name the minor routes of drug elimination with example.

2. Minor routes
 Sweat
 Saliva
 Breast milk
 Vagina
 Tear
 Hair / Nails
Properties for Excretion:
 Should be water soluble.
 Should be ionized and polar.
th th
*Nov ’19, T 25 , T 24 ] Discuss the renal mechanism of drug excretion.

Principles of drug excretion though kidney / Renal Excretion:

Kidney is the most important organ for excretion of drugs and their metabolites. The
excretion by kidney involves 3 basic mechanisms –
1) Glomerular Filtration

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 2) Active Tubular Secretion
3) Tubular Reabsorption

The first two processes are to remove the drug out of the body, while reabsorption
tends to retain it. So, the amount that finally appears in the urine will represent the
balance between filtered, reabsorbed and secreted drugs.
Renal Excretion = (Glomerular filtration + Tubular secretion) – Tubular reabsorption

1) Glomerular filtration:
It is the passive process. Glomerular filtration depends on-

 Molecular weight of the drug: Drugs with MW <10,000 Dalton are easily filtered.
Drugs with MW >50,000 Dalton are not filtered except heparin, dextran, protein,
hormone.
 Plasma protein binding (PPB): Only free drugs are filtered through the
glomerular membrane. Plasma albumin (MW 68000) is almost completely
impermeable, but most drugs-with the exception of macromolecules such as
heparin- cross the barrier freely. If a drug binds appreciably to plasma albumin,
its concentration in the filtrate will be less than the total plasma concentration. If,
like warfarin, a drug is approximately 98% bound to albumin, the concentration in
the filtrate is only 2% of that in plasma, and clearance by filtration is
correspondingly reduced.
 Concentration of drug in plasma
 Renal blood flow: In shock → ↓renal blood flow → ↓drug excretion.
 GFR: Congestive cardiac failure, renal failure → ↓GFR → ↓drug excretion
 Polarity of drug:
 Charged drug → slowly filtered
 Neutral drug → rapidly filtered
2) Active tubular secretion:

Tubular secretion is an active process. The cells of the proximal convoluted tubule
actively transport drugs from the plasma into the lumen of the tubule. There are at least
two types of transport systems –

 Acidic / anionic transport protein: Transport acidic drugs (eg - metabolites of

glycine, sulfate or glucuronic acid or conjugates). Unchanged drugs such as
penicillin can also be secreted.
 Basic / cationic transport protein: Transport basic drugs (eg - morphine,
amiloride, histamine, ethambutol, hexamethonium, catecholamines etc.).

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3) Tubular reabsorption:
The reabsorption of drug from the lumen of the distal convoluted tubules into the
plasma occurs either by simple diffusion or by active transport. Most drugs are
reabsorbed by simple diffusion. Passive tubular reabsorption delays drug excretion.
Extent of reabsorption depends on –

 Lipid solubility: Lipid soluble drugs are more reabsorbed. Water soluble drugs are
more excreted.
 Degree of ionization/ pH of drugs:
 Acidic drug in acidic urine → less ionization → more lipid soluble → more
reabsorbed.
 Alkaline drug in alkaline urine → less ionization → more lipid soluble →
more reabsorbed.
 Acidic drug in alkaline urine → more ionization → less lipid soluble → more
excreted.
 Alkaline drug in acidic urine → more ionization → less lipid soluble → more
excreted

1) Free drug enters into

Glomerular filtrate

2) Active
secretion Proximal
tubule

Loop of
Henle

3) Passive reabsorption of
Distal
lipid soluble, un-ionized
tubule
drug which has been
concentrated so that the
intra luminal concentration Collecting
is greater than that in the duct
perivascular space Ionized, lipid insoluble
drug into urine

Figure: Urinary elimination of drugs and metabolites by glomerular filtration, tubular secretion and
tubular reabsorption.

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Renal excretion of drug can be increased by -

 By changing the pH of the urine:

- Acidic drug (eg - Phenobarbitone) can be excreted more by making the
urine alkaline (as with NaHCO3).
- Alkaline drug (eg - Morphine, Pethidine) can be excreted more by making
the urine acidic (as with NH4CI).
 Diuretics: Diuretics increase excretion of drugs.
 Intake of plenty of water causes excretion of drugs by diuresis.
 IV infusion of normal saline, plasma or blood cause excretion of drugs by diuresis.
Biliary Excretion / Excretion by Liver:
The conjugated drugs are excreted by hepatocytes in bile. Excretion depends upon the
hepatic blood flow. Some drugs; eg - Phenobarbitone, Spironolactone increases the rate
of bile flow.

Excretion of drugs through the bile provides a backup pathway when renal function is
impaired. After excretion through the bile into the intestine, certain amount of the drug
is reabsorbed into the portal vein leading to enterohepatic circulation which can prolong
the duration of action of the drugs. Such a continuous recirculation tends to prolong the
presence of drug in the body and may lead to drug induced toxicity.
Benzodiazepines, Cardiac glycosides, Chlorpromazine and Indomethacin undergo
extensive enterohepatic circulation.

Tetracycline (Doxycycline), Diazepam, Cardiac glycosides, Chlorpromazine and

Indomethacin excrete through bile.
*May ’18, Nov ‘19+ Outline the therapeutic importance of biliary excretion.

Therapeutic importance of biliary excretion:

 Drugs which are excreted through biliary route have increased duration of drug
action due to enterohepatic recycling.
 In liver failure, biliary excretion is impaired and drug concentration is increased
leading to toxicities. So, dose of the drugs which are excreted through biliary
route, should be decreased in liver failure.
Pulmonary excretion / excretion by lungs:
Rapidly vaporized drugs such as Alcohol, volatile general aesthetics are eliminated from
the body through respiratory tract. The rate of excretion depends on -

 Volume of air exchange

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  Depth of respiration
 Rate of pulmonary blood flow
Intestinal excretion / excretion by GIT:
When a drug is administered orally, a part is not absorbed and excreted in feces. Drug
that have slow absorption and form unabsorbable complexes with food or other
substances are excreted in feces in large amount. Drugs which do not undergo
enterohepatic circulation are subsequently passed into stool. Drugs may alter the color
of stool.

 Iron → Black
 Rifampicin → Reddish orange
 AI(OH)3 → White spot

Mammary Excretion / Excretion by Milk:

There are so many drugs excreted in milk. Lactating mother should be very cautious
about the intake of drugs because some are excreted in milk which may enter into the
baby and may cause harmful effects to the baby.
Example - Sulfonamide, Tetracycline, Anti-thyroid drugs, Benzodiazepine, Penicillin,
Aspirin etc.
pH of milk is 6.5 i.e., slightly acidic than plasma, so weakly basic drugs remain in ionized
form and excreted in milk. Aspirin, Caffeine, Diazepam, Frusemide, Morphine,
Streptomycin, and Tetracycline are excreted in milk.
Clinical importance of breast milk elimination of drugs:

 If a lactating mother takes CNS depressant drugs, it will pass to baby via milk and
will cause CNS depression to the baby.
 If a lactating mother takes tetracycline, it will pass to baby via milk, deposit to
bone & teeth and will cause growth retardation
Caution of diazepam administration in a lactating mother:
About 90% drugs (although at a trace amount) can reach the child through breast milk.
Diazepam → reaches to child through breast milk → skeletal muscle relaxation → child
will be unable to suck milk→ child remains sleeping.
Vaginal excretion of drugs:
Some drugs are excreted through vagina. The principle is applied for the treatment of
some diseases of vagina. For example, vaginal trichomoniasis is treated by oral

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administered of metronidazole because this drug is found in high concentration in
vaginal secretion.
*May ’18, Nov ‘19+ Mention the factors influencing drug excretion.

Factors influencing drug excretion:

 Solubility of drug particle (water/lipid solubility)
 Molecular weight of the drug
 Degree of ionization
 Concentration of drug
 Renal disease
 Cardiac disease; eg - CCF
 Plasma protein binding capacity
 GFR and Renal blood flow
 Rate of drug metabolism
th th
[TS 25 , T 25 ] Enumerate the process of drug excretion with example.

Routes Excreted Drugs

Renal  All drugs except plasma protein bound drugs
 Benzodiazepines
 Cardiac glycosides
Hepato-billiary  Chlorpromazine
 Tetracycline
 Indomethacin
 OCP
 Tetracycline
Gastro-intestinal  Rifampicin (anti-TB drug)
 Antacid
 Aminoglycoside
 BaSO4
 Alcohol
 Inhalational anesthetic
Pulmonary - Halothane
- Ether
- N2O (nitrous oxide)
 Morphine
 Phenobarbitone
Breast milk  Benzodiazepines
 Penicillin, Aspirin
 Tetracycline

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Vagina  Metronidazole
Skin (sweat)  Vitamin C
 Iron
 Morphine
 Methamphetamine
 Morphine
Saliva  Caffeine
 Phenytoin
 Rifampicin
Tear  Phenobarbital
 Methotrexate
Nails  Arsenic
Hair + Nails  Mercury
 Arsenic
 Lead
 Iron

Drug that excrete through multiple route: (VIVA)

 Metronidazole

It is an anti-amoebic drug. When it is excreted through saliva, it gives a metallic taste.

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 MECHANISM OF DRUG ACTION
th th
[TS 25 , T 25 ] How drugs act?

Processes by which drugs act:

Drugs may act by 2 ways –
1) Specific mechanism: Drugs go to the specific site, bind with receptor & form a
drug-receptor complex which causes the desired drug actions. Most of the drugs
act by this mechanism.
 Receptor mechanism
 Enzyme mechanism
 Ion channel mechanism
 Carrier mechanism

2) Non-specific mechanism: In non-specific mechanism, the drugs don't bind to

specific receptor. Drugs act in 3 ways –
 By altering physio-chemical properties of cells
 By direct chemical interaction
 By physical means
Targets of drug binding:
 Receptor
 Ion channel
 Enzymes (eg - cholinesterase, dopa decarboxylase)
 Carrier protein (eg - Na+-K+ ATPase)
 Structural protein (eg - tubulin)
 Plasma protein
*May ‘22+ Define receptor.

Receptor:
Receptors are specialized target macromolecules to which drugs bind and initiate events
leading to alterations in biochemical and/or biophysical activity of a cell, and
consequently, the function of an organ.
Drug (D) + Receptor (R) → D-R complex → Response

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Classification of receptors:
A. According to location:
1. Membrane / cell surface receptors:
- α and β adrenoceptors
- Insulin receptor
- Cholinergic receptors
2. Cytoplasmic receptors:
- Steroid hormone receptors
3. Nuclear receptors:
- Thyroid hormone receptors
B. According to activity:
1. Pharmacological / Active receptor:
 They commonly participate to bind the drugs, having high affinity for
ligand.
 Example - Adrenoceptors (a, ẞ receptor), Cholinergic receptor.
 Only 1-2% of total receptors are active receptor.
2. Spare / Reserve receptor:
 Anatomically & functionally these receptors are same as pharmacological
receptor but they do not act normally.
 They come into action only if pharmacological receptors are exhausted or
blocked.
 90% ẞ receptors in case of heart.
 98-99% of total receptors are spare receptor.
3. Orphan Receptor:
 So called because their ligands are presently unknown or nonexistent.
 These are the nuclear receptor.
4. Silent/Dead receptors:
 Drug binds with these receptors without producing any pharmacological
response.
 They act as storage site and prolong the pharmacological effects.
 Example - plasma proteins.
th th th
*May ’22, May ’17, TS 25 , T 25 , T 24 ] Categorize receptors on the basis of mechanism of action. Outline
receptor interaction in brief.

C. According to mechanism of drug action / receptor-effector linkage:

1. Classical / physiological receptors: The receptors for which ligands are
physiologically or endogenously present in our body are called classical receptors.

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  Type I / ligand-gated ion channels (fast receptors):
o Nicotinic acetylcholine receptor
o GABAA receptor
*Nov ’17+ Outline type II mediated receptor with example.

 Type II / G-protein-coupled receptors (slow receptors):

o Muscarinic acetylcholine receptor
o Adrenoceptors (a, ẞ receptor)
o Glucagon receptors
o Opioid receptor
o Serotonin receptor
 Type III / tyrosine kinase linked receptors:
o Insulin receptors
o Growth factors receptors
 Epidermal growth factor (EGF)
 Platelet derived growth factor (PDGF)
 Transforming growth factor - β (TGF-β)
o Cytokine receptors
o Atrial natriuretic peptide (ANP)
o GTN
o Nitroprusside
 Type IV / nuclear receptors (Intracellular receptors):
o Steroid receptors
 Corticosteroids
 Mineralocorticoids
 Sex corticoids
 Vitamin D
o Thyroid hormone

2. Non-classical receptors: Receptors having no physiological / endogenous ligand

are called non-classical receptors.
 Regulatory proteins as receptors:
o Autacoids
o Hormones
o Neurotransmitters
 Enzyme as receptors:
o Dopa decarboxylase enzyme - receptor for Carbidopa
o Dihydrofolate reductase - Receptor for Methotrexate
o Acetyl-transferase enzyme - receptor for Acetylcholine

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  Transport protein as receptors:
o Na+-K+ ATPase - the membrane receptor for Digoxin
o H+-K+ ATPase - receptor for Omeprazole
 Structural protein as receptors:
o Tubulin is a receptor for anti-inflammatory drug such as Colchicine
o Microtubules
Role of receptor in pharmacology:
1. Receptor determines selectivity and specificity of drug action.
2. Receptor can identify whether a drug is agonist, antagonist, and partial agonist.
3. The magnitude of response can be determined from drug-receptor complex.
4. The drug combines with a specific receptor and drug-receptor interaction occur &
drug-receptor complex is formed (mostly reversible).
5. A chain of events occurs as a result of D-R complex.
- Drug action occurs
- D-R complex breaks down
- Receptor is ready for further reception
Receptor regulation:

1. Receptor up regulation / Supersensitivity:

Changes in receptor occupancy & affinity and prolong exposure of receptor with the
antagonist (or, prolong removal of agonist) leads to an increase in the sensitivity &
number of receptors. This is called receptor up regulation.

Example: The occasional exacerbation of ischemic heart diseases (IHD) on sudden

withdrawal of a B- blocker is due to up regulation.

Prolong blocking of B-receptor by the ß-blocker drug

Receptor up regulation & sensitization

On withdrawal, an "above-normal" number of receptors suddenly become accessible to

the normal neurotransmitters (noradrenaline & adrenaline)

Exacerbation of IHD (so B-blocker drugs should not be suddenly stopped, their dose
should be gradually tapered and then stopped if needed)

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Mechanism of up regulation:

 Increased formation of receptor & decreased degradation of receptors.

 Increase sensitization of receptor to agonist; eg - development of withdrawal
syndrome.

2. Receptor down regulation / Desensitization / Adaptation / Refractoriness:

Prolonged exposure to high concentration of agonist causes a reduction in the number
of receptors available for activation. This is called receptor down regulation. It causes
reduced response despite continued exposure to bioactive agonist. The vanishing
receptors are taken into the cell by endocytosis.
Example: Repeated use of B-agonist bronchodilator for the treatment of asthma results
in down-regulation or desensitization of β adrenoceptors.
Mechanism of down regulation:

 Changes in the receptors by

- Phosphorylation
- Tight binding of receptor with agonist
 Loss of receptor
 Exhaustion of mediator
 Increased metabolic degradation
 Physiological adaptation

Type of desensitization:
1. Homologous desensitization: Reduced response is evident only for specific
receptor that has been exposed to agonist.
2. Heterologous desensitization: In this type, response is reduced in receptors for
other agonists.

*May ‘19+ Compare receptor up regulation & down regulation.

Comparison between –

Receptor up regulation Receptor down regulation

Cause Occurs due to prolong exposure Occurs due to prolong exposure of
of receptor with the antagonist receptor with the agonist
Result Number of receptors is Number of receptors is decreased
increased

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 → Increased formation of → Changes in the receptors by
receptor & decreased √ Phosphorylation
degradation of receptors. √ Tight binding of receptor with
agonist
Mechanism → Increase sensitization of → Loss of receptor
receptor to agonist; eg - → Exhaustion of mediator
development of withdrawal → Increased metabolic
syndrome. degradation
→ Physiological adaptation
Sudden withdrawal of a β Repeated use of β2 agonist
Example blocker results in sudden bronchodilator for asthma results
increase in heart rate in down regulation of β2 receptors

Binding forces of drug-receptor interaction:

Frequencies of association & dissociation between the drug and receptor depends on
the –
1) Affinity between drug and receptor
- It is the tendency of a drug to bind with the receptor.
- Receptor has the affinity to bind with its specific drug. The affinity may
vary.
- The affinity for specific drug is increased if the receptors are empty (i.e.
when there is no drug bound to the receptor).
- When partially occupied by drug, the affinity of the receptor for that drug
will be reduced.
- The affinity of the receptor for drug depends on surrounding pH and the
concentration of electrolytes.
2) Types of chemical bond formation between drug and receptor
- The force that attracts the drug to its receptor and hold it in combination
with the receptor long enough to initiate the chain of events leading to the
effect is termed as chemical bond.
- 2 types of chemical bonds:
 Weak bond – reversible, short duration, bond energy is low (0.5
kcal/mol)
3 types – ionic bond, hydrogen bond, Van der Waal’s bond
 Strong bond – very strong, irreversible, long duration, bong energy
is high(100 kcal/mol)
3) Number of receptors
4) Concentration of drug in the biophase

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*May’17, May’18+ What are the consequences of drug-receptor interaction? Discuss receptor-effector linkage
following drug receptor interaction.

Consequences of drug-receptor interaction:

1. Post-receptor events of ion channel coupled receptor:
 Opening of ion channel
 Closing of ion channel
2. Post-receptor events of G-protein coupled receptors:
 Formation of 2nd messengers
 Inhibition of 2nd messengers
 Ca² release
 May open / close receptor-operated ion channel
3. Post-receptor events of tyrosine kinase receptors:
 Phosphorylation of proteins
4. Post-receptor events of DNA coupled receptors:
 Gene transcription.

Ligand:
They are the chemical substances which can combine with receptors.
Endogenous ligands are - neurotransmitters, hormone, autacoids (cytokines). Exogenous
ligands are - drug molecules.

1st messenger:
The extracellular ligands are called first messengers.
Examples –
 Hormones
 Neurotransmitters
 Drug itself
2nd messenger:

A 2nd messenger is one which is generated as a consequence of ligand-receptor

interaction. Drug or hormone communicates with intracellular metabolic processes by
2nd messenger.

Or, The intracellular mediators which are produced as a result of binding of the 1st
messengers with the receptors are called 2nd messengers. They are responsible for
ultimate physiological / pharmacological effects of the first messengers.

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Examples –
 Cyclic adenosine monophosphate (cAMP) – Activates various protein kinase
which control cell function by phosphorylation of enzymes, carriers & proteins.
 Cyclic guanosine monophosphate (cGMP) – Stimulates a cGMP dependent
protein kinase. Increased cGMP concentration causes relaxation of vascular
smooth muscle.
 Inositol triphosphate (IP3) – Increases free cytosolic Ca2+.
 Intracellular ionized Ca2+ - Causes contraction, secretion, enzyme activation &
membrane hyperpolarization.
 Calmoduline
 Diacylglycerol (DAG) – Activates protein kinase C which control cell functions by
phosphorylation of proteins.

Mechanism of drug action by classical receptors:

*May ‘19+ Explain with importance: receptor effector coupling through ligand gated ion channel.

1. Mechanism of drug action via ligand-gated ion channel coupled receptor

(ICCR) / direct control of ion channel

Drugs / ligand binds with ion channel coupled receptors (ICCR)

↓
Conformational change of receptors
↓
Opening of a central "transmembrane ion channel"
↓
Increases transmembrane conduction of the relevant ions (example - Na+, CI-,
K+)
↓
Alteration of the electrical potential across the membrane
↓
Drug action

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 rd
*May ’22, Nov ’17, T 23 ] Outline receptor-effector coupling through G-protein coupled receptor.
Outline type II mediated receptor with example.

2. Mechanism of drug action via G-protein coupled receptor (GPCR) / second

messenger action:

Extracellular ligands bind with G-protein coupled receptors

↓
Activation of G protein
↓
G protein regulates the activity of effector enzyme or ion channel
↓
Increase in the intracellular concentrations of second messengers such as
cAMP, calcium ion, and phosphoinositides and opening of ion channels
↓
Pharmacologic action

3. Mechanism of drug action by direct control of effector enzyme or tyrosine

kinase coupled receptor:

Tyrosine kinase linked receptors are present at the plasma membrane and
have 2 functional domains –
 An extracellular ligand binding domain, which is enriched in cysteine
residues
 A cytoplasmic domain, which possesses the tyrosine kinase activity as
well as the sites of auto phosphorylation.

Binding of drug or hormone with the extracellular domain of the receptor

↓
The resulting change in receptor conformation causes two monomers of the
receptor molecules to bind to one another non-covalently in the plane of cell
membrane
↓
The cytoplasmic tyrosine kinase domain becomes enzymatically active
↓
The tyrosine kinase then phosphorylate one another as well as additional
downstream signaling proteins
↓
Drug response

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 4. Mechanism of drug action by DNA coupled receptor:

A lipid-soluble drug crosses the plasma membrane

↓
Steroid binds with receptors in the cytoplasm and the drug-receptor complex
goes to the nucleus
Thyroid hormone binds with receptors in the nucleus
↓
Drug-receptor complex in the nucleus
↓
Drug-receptor complex binds with DNA & stimulates transcription of specific
gene
↓
mRNA synthesis
↓
Protein synthesis
Drug response
G protein:

G protein is a membrane protein consisting of 3 subunits (α, β, γ) that binds with GDP
and is always coupled with receptor.

Characteristics –

 Activity of G-protein depends on presence of GTP and magnesium.

 G-protein acts as an intermediate between receptor and enzyme (an effector).
 It has 3 subunits designated as α, β, γ.
 α subunit has GTPase activity.
 G-protein have three domain –
- Guanine nucleotide binding domain
- Domain for interaction with receptor Location
- Domain for interaction with effector
 Olfaction & vision is mediated by G protein coupled receptors.

Location –
G-protein located on the inner surface of the plasma membrane.

Types & function –

 Gs (s for stimulatory)
- stimulate adenyl cyclase after being activated by agonist

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 - activates calcium channel
 Gi (i for inhibitory)
- inhibit adenyl cyclase
- activates potassium channel
 Go - inhibit calcium channel.
 Gq - activates phospholipase C
 Gt - stimulates adenylyl cyclase present in eye.
 Golf - stimulates adenylyl cyclase present in nose
Non receptor mechanism of drug action:
1. By altering physiochemical properties of cells:
i. By stopping the streaming (rolling) movement of cell cytoplasm. Eg -
anesthetic drugs enter into the reticular system of brain→ cytoplasmic
streaming stop → anesthesia of the patient.
ii. By stabilization of cell membrane, so no ion exchange.
iii. By lowering surface tension.
iv. By inhibiting energy production / utilization of cell.

2. By direct chemical interaction:

i. Neutralization, example –
 Antacids directly interact with the gastric HCI and neutralize the
acid.
 Protamine sulphate (+ve charged) directly interact with heparin
(-ve charged) & neutralize the action of heparin.
ii. Chelation: Antacids chelate tetracycline.
iii. Anti-coagulation: Anti-coagulants (Oxalate, EDTA, citrate) trap Ca2+ of
blood → No coagulation of blood.

3. By physical means:
i. By osmosis:
 Purgatives: Milk of magnesia (MgSO4) is a purgative.
MgSO4 → Mg2+ + SO4- (osmotically active) →These ions attract
water from food and intestinal wall and form water jacket →
larger molecule → Stretch the intestine → ↑Peristalsis →
Defecation.
 Osmotic diuretics: Mannitol is filtered by glomerulus → not
absorbed → Retain large amount of water in the renal tubules
as it is osmotically active → Excreted with large amount of water
→ Diuresis.
ii. By adsorption: Activated charcoal adsorbs alkaloid poisons.

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 iii. By emollient & demulcent action: Mg trisilicate in PUD.
iv. By mass of drug: Bulk laxative.
v. Radioactivity: 131I.
Agonist:
If a drug binds to a receptor and produces a biological response that mimics the
response to the endogenous ligand, it is known as an agonist.
 Agonist has both affinity and efficacy to the receptor.
 Agonist has intrinsic activity (the ability of a drug once bound to activate the
receptor). Here intrinsic activity = 1.

→ →
Example –
 Phenylephrine is a α1 adrenoreceptor agonist, it produces effects that resemble
the action of endogenous ligand, norepinephrine.
 Salbutamol is an agonist to β adrenoceptors.
 Pilocarpine is an agonist to muscarinic receptors.

Partial Agonist:
The drug that combines with its specific receptor and evokes weak responses and also
prevents a full agonist from acting on that receptor is termed partial agonist.

Example –

 Nalorphine when administered alone produces relief of pain by blocking

morphine receptor. If Nalorphine is given to a Morphine treated patient, it
opposes the effect of morphine. So, Nalorphine is a partial agonist.
 Pindolol (β blocker) has a partial agonistic activity. The partial agonistic activity of
Pindolol is called “Intrinsic Sympathomimetic Activity (ISA)”.
 Clonidine
 Acebutolol

Criteria –
 Partial agonists have efficacies (intrinsic activity) between 0 to 1 that means
greater than zero, but less than that of a full agonist in which IA is 1. Even if all
the receptors are occupied, partial agonists cannot produce an Emax of as great a
magnitude as that of a full agonist.

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  Partial agonists are partial antagonist also; i.e. they have both antagonist and
agonist action. Individually it acts as a weak agonist but in presence of a potent
agonist it will acts as an antagonist.
Inverse agonist:
If a drug activates a receptor to produce effects that are specifically opposite to those of
the agonist, then the drug is called inverse agonist.
 Their IA is less than 0, reverse the activity of receptors and exert the opposite
pharmacological effect of agonist.
Example –

 The agonist action of benzodiazepines on the benzodiazepine receptor in the CNS

produces sedation, anxiolysis, muscle relaxation and controls convulsions.
 Substances called β-carbolines which also bind to this receptor cause stimulation,
anxiety, increased muscle tone and convulsions.
 Both of these drugs are inverse agonist. Both types of drug act by modulating the
effects of the neurotransmitter GABA.
Antagonists:
A drug that binds with its specific receptor and does not produce any response, rather it
may hinder the action of agonist is known as antagonist.

 Antagonist has affinity but no efficacy to the receptor.

 Here intrinsic activity = 0.

→ →

Example –
 Atropine is an antagonist of muscarinic receptor.
 Propranolol is an antagonist for ẞ receptor.
Types of antagonists:
1. Pharmacologic Antagonists:

When one drug antagonizes the action of another drug by acting on the same receptor,
it is called pharmacological antagonism.
a. Competitive antagonist: Competitive antagonists combine with the same site on
the receptor but their binding does not activate the receptor. Competitive
antagonists may be reversible or irreversible. Reversible, competitive antagonists

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 are not covalently bound, shift the dose-response curve for the agonist to the
right, and increase the ED50.
Example - The antihypertensive drug Prazosin competes with norepinephrine, at
α1 receptor, causing vasodilation and reducing blood pressure. The agonist, if
given in a high enough concentration, can displace the antagonist and fully
activate the receptors.

b. Noncompetitive antagonist: Noncompetitive antagonists bind to the receptor at

a site other than the agonist-binding site and either prevent the agonist from
binding correctly or prevent it from activating the receptor. Receptors
unoccupied by antagonist retain the same affinity for agonist, and the ED50 is
unchanged.
Example - Drugs such as Verapamil and Nifedipine prevent the influx of Ca2+
through the cell membrane and thus block non-specifically the contraction of
smooth muscle produced by other drugs.
2. Physiologic Antagonists:

A physiologic antagonist binds to a different receptor molecule, producing an effect

opposite to that produced by the drug it antagonizes.
Examples:

 Histamine binds with histamine receptors and cause bronchoconstriction. But

epinephrine binds with β2 receptors and cause bronchodilation
 Acetylcholine causes bronchoconstriction by acting on M2 receptor. Adrenaline
causes bronchodilation by acting on ß2 receptor.
3. Chemical Antagonists:
When one drug antagonizes the effect of another drug by simple chemical reaction, it is
called chemical antagonist. Here no receptors are involved.
Examples:
 Heparin (acidic) + Protamine sulphate (basic) → Chemical neutralization of
heparin
 Gastric acid (HCI) + antacid → Chemical neutralization of HCl → No HCl-induced-
peptic ulcer
 Dimercaprol + Lead → Chelation

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 th th
*May ’22, May ’17, TS 25 , T 25 ] Difference between physiological & pharmacological antagonism.

Difference between –

Pharmacological antagonism Physiological antagonism

1. Competitive / non-competitive 1. Always non-competitive
2. May be reversible or irreversible 2. Reversible
3. Acts by pharmacokinetic or 3. Acts by pharmacodynamic mechanisms
pharmacodynamic mechanisms
4. May antagonize in the same 4. Always antagonize in the same
physiological system or not physiological system
5. Dose dependent or not 5. Always dose dependent
6. Example: 6. Example:
- Adrenaline + Propranolol → - Acetylcholine + Adrenaline →
Antagonism Antagonism
- Adrenaline + Phenoxybenzamine → - Insulin + Glucagon → Antagonism
Antagonism

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 ADVERSE DRUG EVENTS

Drug action:
Drug action is the initial interaction of a drug with cells at the site of action and resultant
physiological & biochemical consequences are the drug effects.
Factors modifying drug action: [For more details – Blueprint 11th ed. Page-150]
A. Factors related to the patient:

1. Personal factors:
 Age
Newborn & children:
- Absorption of drug from the GIT is slower in neonates.
- Newborn has poor renal function.
- Hepatic drug metabolizing system is inadequate in newborn.
- Blood brain barrier is more permeable.
- More plasma protein binding
Elderly:
- Renal function progressively declines.
- Slower absorption.
- Lesser plasma protein binding.
- Increased or decreased volume of distribution.
 Sex
Testosterone increases enzyme activity whereas estradiol inhibits enzyme
activity. So men need larger dose & female need smaller dose.
In case of female following factors modify drug action:
- Menstruation
- Pregnancy
- Lactation
 Body weight and surface area
 Nutrition
Malnutrition impairs the biotransformation of drugs.
Some vegetables such as cabbage, cauliflowers stimulate the intestinal
biotransformation of some drugs
 Alcohol
Acute intake of alcohol inhibits the biotransformation of drug.
Chronic intake of alcohol increases the biotransformation of drug.

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  Cigarette smoking
Cigarette smoking is a rich source of benzopyrene, which is a potent
enzyme inducer. Biotransformation of some drugs such as theophylline,
caffeine and imipramine are several times higher in cigarette smokers.
2. Pathological conditions
- Meningitis
- GIT diseases
- Chronic liver disease
- Renal disease
- Thyroid disease
3. Immunological factor
- Type I reaction: Penicillin may cause anaphylactic shock.
- Type II reaction: Drug induced hemolytic anemia
- Type III reaction: Glomerulonephritis may be induced by penicillamine.
- Type IV reaction: Contact dermatitis.
4. Genetic factor
All key determinants of drug response; eg - transporters, metabolizing enzymes,
ion channels, receptors with their couplers & effectors are controlled genetically.
Few examples are:
- The population of rapid acetylator metabolizes isoniazid to acetyl-isoniazid
which is excreted in the urine. Slow acetylator metabolizes isoniazid in a
slower rate and is subjected to isoniazid toxicity such as peripheral
neuropathy.
- Glucose-6-phosphate dehydrogenase deficiency is responsible for
hemolysis when these patients are exposed to certain drugs like
primaquine, dapsone, quinolone etc.
5. Environmental factor
- Exposure to insecticides, carcinogens, tobacco smokes are known to
induce drug metabolism.
- People living in urban/town area are exposed to hydrocarbon →
Hydrocarbons induce hepatic microsomal enzyme → Rapid metabolism of
drugs → ↓Drug action.
- Persons working in insecticidal factory → Insecticides induce hepatic
microsomal enzyme → Rapid metabolism of drugs → ↓Drug action.
- People living in high altitude or hilly area → Inhibits hepatic microsomal
enzyme → ↓Metabolism of drugs → ↑Drug action.
- People working with radiation, asbestos, benzene → Susceptible to cancer.

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 6. Psychological factor
Efficiency of a drug can be affected by patient's belief, attitudes & expectations.
This is particularly applicable to centrally acting drugs; eg – a nervous & anxious
patient may require more general anesthetic drugs.
B. Factors related to the drug:

1. Route of administration
(From item 3 – routes of drug administration, page – 31)
2. Dose of drug
Some drugs in different doses produce different effects, eg - as for
phenobarbitone,
- 75 mg/kg is lethal dose.
- 1/2 of the lethal dose is anesthetic dose.
- 1/3 of anesthetic dose is hypnotic dose.
- 1/4 of anesthetic dose is sedative dose.
3. Time of administration
In relation to meal:
- Antacid/aspirin→ Effective after meal.
- Anthelminthic → After meal
- Foul-smelling & irritating drug (metronidazole) → After meal.
In relation to daytime:
- Sedatives at night → more effective.
- Statins at night → more effective.
4. Drug combination
5. Drug interaction
6. Cumulation
Any drug will accumulate in the body if rate of administration is more than the
rate elimination. However slowly eliminated drugs are particularly liable to cause
cumulative toxicity; eg - prolonged use of chloroquine causes retinal damage.
Drugs having high t1/2 shows cumulation. Eg – digitalis, phenobarbitone,
sulfonamide.
Advantage of cumulation: It is generally undesirable but desirable in the
treatment of CCF, epilepsy.
7. Tolerance (Addiction)
It refers to the requirement of higher dose of a drug to produce a response.
Tolerance is a widely occurring adaptive biological phenomenon.
8. Intolerance (Hypersensitivity)
9. Rate & extent of absorption
10. Distribution into body fluid
11. Plasma protein binding

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 12. Rate of metabolism & elimination
Drug interaction:
Drug interaction refers to the interaction between two or more drugs administered
simultaneously result in an alteration of pharmacological response of active drug.
Types of drug interaction:
1. Pharmaceutical interaction:
 Outside the body
Loss of potency can occur from drug combination outside the body:
- Thiopentone + Suxamethonium → Precipitation
- Diazepam + Infusion fluid → Precipitation
- Phenytoin + Infusion fluid → Precipitation

2. Pharmacokinetic interaction:
Drug interaction at –
 At the absorption level
- Tetracycline + Antacid / Ca / Al / Iron / NaHCO3 / Mg(OH)2
→ Decreased absorption of tetracycline
- Iron + Vitamin C → Increased absorption of iron

 At the distribution level

A drug having more affinity to plasma protein can displace another drug
having less affinity for the same binding site. So the displaced drug
becomes free which is pharmacologically active & produces action.
- Displacement from plasma protein binding site:
Displacing drug Displaced drug Result / Effect
Sulfonamide Bilirubin Kernicterus
Phenylbutazone Warfarin Bleeding

- Displacement from tissue binding site:

Quinidine + Digoxin → Quinidine displaces digoxin
- Direct interaction
Fe + Desferrioxamine → Neutralization → ↓Fe action/toxicity

 At the biotransformation level

- Enzyme induction
Enzyme induction by one drug increases biotransformation of
another drug and is a cause of therapeutic failure.

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 Inducer Drug whose Effect
metabolism is
induced
Rifampicin OCP Failure of contraception
Warfarin Decreased anticoagulation
OCP Failure of contraception
Phenobarbitone Warfarin Decreased anticoagulation
Chloramphenicol No Gray baby syndrome
Phenytoin OCP Failure of contraception
Warfarin Decreased anticoagulation
Phenylbutazone Warfarin Decreased anticoagulation

- Enzyme inhibition
Enzyme inhibition by one drug limits biotransformation of other
drugs and is a cause of intense drug action with a long duration.

Inhibitor Drug whose Effect

metabolism is
inhibited
Cimetidine Warfarin Hemorrhage
Chloramphenicol Warfarin Hemorrhage
Metronidazole Tolbutamide Hypoglycemic shock
Allopurinol Azathioprine Bone marrow suppression

 At the excretion level

When two drugs compete with each other for the same binding site of a
carrier protein for excretion, one influences the excretion of other.
Example:
- Quinidine + Digoxin → Quinidine inhibits active secretion of digoxin
→ decreased excretion of digoxin → increased duration of action of
digoxin.

3. Pharmacodynamic interaction:
 At the receptor level
1. Positive interaction / synergism
- Summation / addition
- Potentiation / super-addition

2. Negative interaction / antagonism

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Drug combination:
Simultaneous use of two or more drug separately or combination of drugs in a single
pharmaceutical formulation is known as drug combination.
It is of 2 types –
1. Fixed dose combination
- Co-trimoxazole = Trimethoprim (80 mg) + Sulfamethoxazole (400 mg)
- Sinemet = Levodopa (250 mg) + Carbidopa (25 mg)
Advantage:
- Convenient to use.
- Enhanced effect – provides synergistic drug action (cotrimoxazole)
- Minimization of unwanted effect
- Good patient compliance
- Prevention of emergence of drug resistance in antimicrobial therapy.

2. Non-fixed dose combination

 In TB.
Indications of drug combination:
1. To obtain synergistic effect (cotrimoxazole).
2. To minimize adverse effects.
3. To broaden the spectrum of antimicrobial activity.
4. To prevent emergence of drug resistance.
5. To increase plasma concentration of one drug by another.
6. To treat severe infection.
Result of drug combination / interaction:
1. Enhancement of drug effect (synergism)
When the net effect of two drugs used together is equal to or greater than arrhythmic
sum of the effect of individual drug, it is called drug synergism. It is of two types -

 Summation
When the effect of magnitude of combined drug is equal with arrhythmic
sum of effect of individual drug, it is called summation.
o Atenolol + Bendrofluazide in HTN
o Aspirin + Paracetamol for analgesia
 Potentiation
When the net effect of magnitude of combined drug is greater than the
arrhythmic sum of effect of individual drug, it is called potentiation.

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 o Sulfamethoxazole +Trimethoprim = Cotrimoxazole
o Levodopa + Carbidopa = Sinemet
Importance of synergism:
 To increase the efficacy of drugs.
 To reduce the toxic effects of drugs.
 To reduce the dose of drugs.
th th th
[TS 25 , T 25 , T 24 ] Define antagonism. Discuss types of drug antagonism with example.

2. Antagonism
It is the phenomenon when the net effect of one drug is reduced or abolished by
presence of another drug. It is of four types –

 Chemical antagonism
When one drug antagonizes the effect of another drug by simple chemical
reaction. Here is no receptor involved.
Example:
 Gastric acid (HCL) + Antacid → neutralization of gastric acid → No
HCL-induced-peptic ulcer

 Physiological / Functional antagonism

When two drugs influence a physiological system in opposite direction; i.e.
one drug canceling the effect of other is called physiological antagonism.
Example –
 Acetylcholine M2 receptor agonist cause bradycardia
 Adrenaline ẞ1 receptor agonist cause tachycardia
 Combination of both drug restore normal heart rate

 Pharmacokinetic antagonism
Here antagonists effectively reduce the concentration of the active drug at
its site of action. This can happen in various ways –
a) During absorption: Calcium + Tetracycline
Tetracycline forms insoluble complex with calcium which is not absorbed.
b) During distribution: Phenylbutazone + Warfarin → displaces warfarin →
↑warfarin level → anticoagulation.
c) During metabolism:
 Enzyme induction:
Phenobarbitone + OCP → ↑OCP metabolism → contraceptive
failure
 Enzyme inhibition:
Cimetidine + Warfarin → ↓Warfarin metabolism → Hemorrhage

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 d) During excretion:
One drug affects the rate of renal excretion of others.
 By inhibiting tubular secretion
Penicillin + Probenecid
 By alteration of urine flow
Frusemide + Indomethacin
 By alteration of urine pH
Acidic drug (aspirin): more excreted in alkaline urine
Basic drug (diazepam): more excrete in acidic urine

 Pharmacodynamic antagonism
When one drug antagonizes the action of another drug by acting on same
receptor. Types –
1) Competitive antagonism
 Reversible
o Here two drugs compete for same receptors site.
o Drug receptor bond is weak.
o In presence of competitive antagonist, higher concentrations
of agonist are required to produce a given pharmacological
response.
o The antagonism is said surmountable, i.e. the effect of an
antagonist can be overcome by increasing the dose of
agonist.
o Example – Ach + Atropine both acts on muscarinic receptor
 Irreversible
o Here two drugs compete for same receptors site.
o Drug receptor bond is covalent so irreversible.
o The antagonism is said insurmountable, i.e. the effect of an
antagonist cannot be overcome by increasing the dose of
agonist.
o Example – Adrenaline + Phenoxybenzamine both acts on α1
receptor
2) Noncompetitive antagonism
 Not concerned with same receptor binding.
 Antagonist blocks the response produced by agonist.
 The effect of an antagonist cannot be overcome by increasing the
dose of agonist; i.e. not surmountable.
 Example - OPC + Cholinesterase

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 Importance of drug antagonism:
 For specific antidote purpose, in case of acute poisoning; eg - pralidoxime
in OPC poisoning.
 To prevent adverse drug reaction; eg - Isoniazid used in TB cause
peripheral neuropathy, to prevent this use pyridoxine with isoniazid.
 For treatment purpose; eg - Antacid used in peptic ulcer disease.
Drug tolerance:
Gradual decrease of response to a drug due to repeated administration of that drug is
called tolerance. When tolerance develops, increased dose is required to get original
response.
Types:
 Innate tolerance (natural / pre-existing sensitivity / insensitivity)
 Acquired tolerance:
 Pharmacokinetic (metabolic / dispositional)
 Pharmacodynamic (functional)
 Acute tolerance
 Reverse tolerance
 Cross tolerance
Drug dependence:
Drug dependence is a state arising from repeated, periodic or continuous administration
of a drug that results in harm to the individual & sometimes to society. The subject feels
a desire, need or compulsion to continue using the drug & feels ill if abruptly deprived of
it (abstinence or withdrawal syndrome). Drug dependence includes both the terms
'addiction' and 'habituation".

Types of drug dependence:

 Psychological dependence
 Physiologic / Physical dependence:
 Tolerance
Drugs producing dependence:
 Morphine
 Heroine
 Pethidine
 Barbiturates
 Amphetamine

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  Alcohols
 Cocaine
 LSD
 Marijuana
 Diazepam
 Tobacco, Cannabis
Drug addiction:
Addiction is a state of chronic intoxication due to repeated consumption of a drug and
characterized by physiological & psychological dependence and a tendency to increase
the dose.
Drugs causing addiction:
 Morphine
 Heroine
 Pethidine
 Barbiturates
 Amphetamine
 Alcohols
 Cocaine
 LSD
 Marijuana

Drug habituation:
Drug habituation means desire to take a drug, but there is no compulsion. For example -
smoking, coffee or tea drinking etc.

Differences between –

Traits Drug addiction Drug habituation

1. Compulsion to Present Absent
take the drug
2. Tendency to Present Absent
increase the dose
3. Dependence Psychological & physical Some degree of psychological but
not physical
4. Withdrawal Characteristic symptoms None or mild
symptoms
5. Harm Both to the individual and If any, primarily to individual
society

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Drug abuse:
Drug abuse refers to use of a drug by self-medication in a manner & amount that
deviates from the approved medical & social patterns in a given culture at a given time.
Or, Drug abuse implies excessive (in terms of social norms) non-medical or social drug
use.
Drugs of abuse:
Drugs of abuse are often divided into two groups.
1. Hard:
Produces serious dependence; e.g. heroin, cocaine, opioids, barbiturates.
2. Soft:
Produces less dependence; eg, alcohol, benzodiazepines, amphetamines,
cannabis, hallucinogens, tobacco, caffeine.
Clinical features of drug abuse:
Depending on the actual compound, drug abuse may lead to –

 Health problems
 Social problems
 Morbidity
 Injuries
 Unprotected sex
 Violence
 Deaths
 Motor vehicle accidents
 Homicides
 Suicides
 Physical dependence
 Psychological addiction
th th th rd
[TS 25 , T 25 , T 25 , T 23 ] What is adverse drug reaction. Write types of adverse drug reactions with example.

Adverse drug reaction (ADR):

ADR is defined by WHO as “a response to a drug that is noxious and unintended and
occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of
disease, or for modification of physiological function.”

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Types of adverse drug reactions:
1. Type-A / augmented (dose dependent):

 Excessive therapeutic effects

 Pharmacological side effects
 Toxic side effects
 Secondary effects
2. Type-B / Bizarre (dose independent):

 Immunological process (hypersensitivity reactions)

 Idiosyncrasy (unwanted effects due to inherited abnormalities)
3. Type C (chronic):

Chronic reactions due to long term exposure; eg –

 Isoniazid (INH) induced neuropathy

 Analgesic nephropathy
 Levodopa induced dyskinesia
4. Type D (delayed effect):

 Carcinogenesis (delayed effects following prolong exposure)

 Teratogenesis (short term exposure at a critical time)
5. Type E / withdrawal reactions (ending of use):
Here discontinuation of chronic therapy is too abrupt; eg –

 Sudden / abrupt withdrawal of corticosteroids therapy causes iatrogenic

Cushing's syndrome
 Withdrawal syndrome after opioid analgesic

Type A / Augmented adverse drug reaction:

This reaction will occur in everyone if enough of the drug is given because they are due
to excess of normal, predictable, dose related, pharmacodynamics effects. They are
common and skilled management reduces their incidence.

Example:

 Postural hypotension with antihypertensive

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  Hypoglycemia with insulin
 Hypokalemia with diuretics
Type A reactions also include those that are not directly related to the desired
pharmacological action of the drug (eg - dry mouth that is associated with tricyclic
antidepressant).
Criteria:

 Augmented
 Dose dependent
 Predictable
 Morbidity more, mortality less
 More common, mostly preventable and reversible
Process:
1) Excessive therapeutic effects:
- Insulin / OHA → produces hypoglycemia
2) Pharmacological side effects:
Adverse effect within normal therapeutic dose is called side effect; eg –
- Morphine (analgesic) → produces constipation
3) Toxic side effects:
Adverse effect due to over or excess of therapeutic dose is called toxic side
effect; eg –
- Drugs with high TI → less toxic effect
- Drugs with low TI → more toxic effect
4) Secondary effects:
Secondary effects are the indirect consequences of a primary drug action; eg –
- Vitamin deficiency or opportunistic infection which may occur in patients
whose normal bowel flora has been altered by antibiotics.
- Diuretic induced hypokalemia causing digoxin intolerance.
Type B / Bizarre adverse drug reaction:
It occurs in few percentage of population due to inherited genetic abnormality or
immunological process.
Example:

 Intolerance
 Hypersensitivity
 Pseudo allergy

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  Idiosyncrasy
Characteristics:

 Type B bizarre reactions occur only in some people

 Bizarre in nature
 Dose independent
 These effects are unpredictable for the individual
 Morbidity less than type A but mortality more
 Less common, generally more serious and require withdrawal of the drug and
some specific measures
 Suitable tests to characterize the individuals phenotype is performed; eg - skin
test (intradermal, patch)

Difference between –

Type A Type B
1. Predictable 1. Unpredictable
2. Usually dose dependent 2. Rarely dose dependent
3. High morbidity 3. Low morbidity
4. Low mortality 4. High mortality
5. Responds to dose reduction 5. Responds to drug withdrawal
6. Occurs in everyone if enough of the drug 6. Occurs only in some people
is given
7. It is either side effect or toxic effect; eg - 7. Mainly in the form of hypersensitivity
hypoglycemia and idiosyncrasy

Drug hypersensitivity:
Allergic reactions to drugs are an abnormal immune response resulting from interaction
of drugs or metabolites or a non-drug element in the formulation with the patient and
disease and subsequent re-exposure.

Classification of hypersensitivity:
1. Type I hypersensitivity or anaphylactic reaction

2. Type II or cytotoxic hypersensitivity

3. Type III or immune complex mediated hypersensitivity
4. Type IV or delayed or cell-mediated hypersensitivity

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Type I hypersensitivity or immediate hypersensitivity:
Allergy:
Allergy means altered reactivity of tissue or body to subsequent exposure to the same
antigen. It is considered as synonym of type I hypersensitivity.
Allergens:
They are the immunogens that can produce type I hypersensitivity.
Anaphylaxis / Anaphylactic reaction:

It may be defined as a rapidly developing hypersensitivity response triggered by

combination of antigen with IgE present on the mast cell or basophil in an individual
who is pre-sensitized to that antigen and leading to anaphylactic shock.
Example:

 Skin allergy
 Allergic rhinitis
 Allergic conjunctivitis
 Atopic bronchial asthma
 Allergic gastroenteritis
 Penicillin hypersensitivity
 Bite of honey bees
Drugs causing it:

 Penicillin
 Histamine
 Heparin
 Streptokinase
 Insulin preparation
 NSAIDs
 Cephalosporin
 Sulfonamide

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Mechanism:
First exposure of a person to a drug to which he is allergic –
A drug (eg - penicillin) enters into the body for the first time
Taken up by macrophage
Macrophage processes & presents antigen to helper T-cell

Helper T-cell stimulates B-cell

B cell transforms into plasma cells which produce IgE

IgE binds with receptors on the surface of mast cells and basophil (Sensitization)

Re-exposure (second & subsequent exposures) of the sensitized person to the same
drug –

The drug molecule binds with IgE on the mast cell & basophil
Degranulation of mast cells and basophils
Release of mediators (eg - histamine, serotonin etc.)

Increase vasodilatation, Increase vascular permeability, Increase glandular secretions (as

in asthma, allergic rhinitis), Contraction of smooth muscle, Anaphylactic shock
Anaphylaxis

Type II hypersensitivity (Antibody dependent cytotoxic type):

It is mediated by antibody (IgG or IgM)

Example:

 Hemolytic anemia by penicillin, sulfonamide, methyldopa, quinidine.

 Aplastic anemia by chloramphenicol, sulfonamide.
 Thrombocytopenia by phenylbutazone, quinidine, rifampicin, sulfonamide.
 Agranulocytosis by chloramphenicol, sulfonamide.
 SLE by hydralazine, sulfonamide.

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Mechanism:
Antigen + body protein: complex formation
Complex: induces formation of antibody
Antigen-antibody reaction with complement activation
Damage of cells

Type III hypersensitivity (Immune complex mediated type):

It is mainly mediated by IgG. It occurs in blood vessels. Tissue damage is mainly due to
activation of complements and platelets.

Example:

 SLE
 Rheumatoid arthritis
 AGN
 Serum sickness

Mechanism:
Formation of antigen antibody complexes

Fixation / activation of complexes to complements

The whole complex deposited in the vascular endothelium

Deposition causes either damage or blocking of the vessel

Body defense mechanism is stimulated

Macrophages phagocytize the complex

During phagocytosis lysosomal enzyme comes out & causes digestion and damages
of surrounding tissue and inflammation leading to
‘Serum sickness’ - Sulfonamide, penicillin, anticonvulsants & Stevens Johnson
syndrome - sulfonamide

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Type IV hypersensitivity (Lymphocyte mediated type)
It is T-lymphocyte mediated.
Example:

 Contact dermatitis.
Mechanism:
Antigen-antibody complex
(+) T-lymphocyte

Causes tissue damage locally

Contact dermatitis
Teratogenesis:
Greek word ‘teratos’ means monster. Teratogenesis means gross structural
malformation of fetus.
Fetal development passes through 3 phases –

1) Blastocyst formation (cell division occurs)

2) Organogenesis (1st trimester in pregnancy)
3) Histogenesis & maturation of function

Gross malformation can be produced only if teratogenic drugs act during

organogenesis (1st trimester in pregnancy).

Drugs causing teratogenicity:

 Thalidomide
 Methotrexate
 Tetracycline
 Warfarin
 Phenytoin
 ACE inhibitors
 Anti-thyroid drug
 Aspirin
 Androgens
 Progestins
 Alcohol, Lithium

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Drugs safe in pregnancy:

System Safe drugs

α-methyl dopa, Hydralazine, Atenolol,
Antihypertensive Metoprolol, Pindolol, Nifedipine, Prazosin,
Clonidine
Hematinics Oral Fe salts, Fe Dextran, Folic acid,
Vitamin B12
Antidiabetic Insulin (preferably human insulin)
Corticosteroids Inhaled & topical corticosteroids, Low dose
oral prednisolone
Thyroid hormone Thyroxin
Antithyroid Propylthiouracil
Antipsychotics Haloperidol, Trifluoperazine
Antidepressants Amitriptyline, Imipramine, Clomipramine,
Fluoxetine
Anticoagulants Heparin (unfractionated), Low molecular
weight heparin
Antiasthmatic Salbutamol, Salmeterol, Ipratropium
bromide, Beclomethasone, Budesonide,
Na-chromoglycate
Promethazine, Cyclizine, Dicyclomine,
Antiemetics Prochlorperazine, Metoclopramide,
Doxylamine
Drugs for PUD Ranitidine, Famotidine
Laxatives Dietary fibers, Lactulose, Ispaghula husk
Antidiarrheal ORS
Analgesics Paracetamol, Low dose ibuprofen
*May ‘18+ Short note: Idiosyncrasy.

Idiosyncrasy:
The word is derived from a Greek word. ‘Idios’ means - one's own, peculiar, distinct;
‘synkrasis’ means - mixing together.
This is a qualitative abnormal reaction to drug usually due to genetic abnormality.
Criteria:

 Reaction may occur at a low dose.

 Genetic factor responsible.
 Most commonly, this is caused by an enzymopathy; congenital or acquired.

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  They do not occur in most patients but when they do occur, they can be life
threatening.
Examples:

 Chloroquine and primaquine administration in an individual with the glucose-6-

PO4 dehydrogenase deficiency causes hemolytic anemia.
 Suxamethonium causes prolonged paralysis in patients with pseudo
cholinesterase deficiency.
 Troglitazone induced liver failure often leading to death or liver transplant.
 Clozapine induced agranulocytosis.
 Sulfonamide induced toxic epidermal necrolysis.
th
*Nov ’18, T 25 ] Differentiate between hypersensitivity & idiosyncrasy. Give example of each.
Differences between –

Traits Hypersensitivity Idiosyncrasy

Allergic reactions to drugs is This is a qualitative abnormal
an abnormal immune reaction to drug usually due
response resulting from to genetic abnormality
interaction of drugs or
1. Definition metabolites or a non-drug
element in the formulation
with the patient and disease
and subsequent re-exposure
2. Subtypes 4 subtypes No subtypes
3. Time of occurrence From the second exposure From the first exposure
Primaquine induced
4. Examples Penicillin hypersensitivity hemolytic anemia to an
individual with glucose-6-PO
dehydrogenase deficiency
Differences between –

Traits Side effects Toxic effects

Definition It is the unwanted effect that It is the severe form of side
develops within the therapeutic effect that develops on supra
dose therapeutic dose
Forms of Side effect may be the Toxic effect may occur with no
unwanted effect extension of main therapeutic relation to the main therapeutic
action; eg - dry mouth, blurred effect of the drug; eg -
vision occurs in atropine hepatotoxicity with rifampicin
therapy

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Predictability Side effects can be predicted Prediction of toxic effects is
before Rx is begun confirmed after monitoring of
the Rx
Avoidance Can be avoided Avoidable in some drugs &
unavoidable in some drugs
Relation with Side effects occur with drugs Drugs having high TI rarely
therapeutic index irrespective of therapeutic produce toxic effects when used
index in therapeutic doses

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 DOSE RESPONSE CURVE

Posology:
It is the science of dosages or a system of dosage.
Dose:
Dose is the amount of drug that is to be administered in a particular time, in a single
administration to get biological response.
Dosage:
Determination of the amount, frequency and number of doses of drug for a patient is
called dosage.

*May’19+ Define different doses with example.

Types of doses:
1. Therapeutic dose or effective dose (ED)
2. Booster dose
3. Toxic dose
4. Lethal dose
5. Fatal dose
6. Loading dose
7. Maintenance dose
8. Adult dose
9. Test dose
10. Ceiling dose
11. Maximum dose
12. Minimum dose
Therapeutic dose or effective dose (ED): The amount of drug that produces the
optimum/ expected therapeutic effect is called therapeutic dose.
Median effective dose (ED50): A dose that produces the desired effect in half of a
population is called ED50.
Booster dose: The amount of drug given some times (months/years) after the initial
dose to enhance the effect is called booster dose.

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Booster dose is commonly used in vaccines of some communicable disease; eg - the
booster dose of vaccines for HBV is given 10 months after the 3rd dose (schedule of HBV
vaccines is 0, 1, 2 & 12 months)
Toxic dose: It is the dose in excess amount which will produce serious toxic effect.
Median toxic dose (TD50): It is the dose which will produce toxic effect in 50% of test
animal.
Lethal dose: The amount of drug that causes death of certain percent (it may or may not
be 100%) of experimental animals is called lethal dose.
Median lethal dose (LD50): It is the dose which will cause death in 50% of test animals.

Fatal dose: The amount of drug which causes death of 100% of the test animals is called
fatal dose.

Loading dose: The loading dose is one or a series of doses that may be given at the
onset of therapy with the aim of achieving the target therapeutic concentration rapidly.
For example, the use of a loading dose of lidocaine in the coronary care unit to prevent
arrhythmia in myocardial infarction is standard.
If 10 microgram/ml is needed and Vd is 100L, then loading dose would be 1 gram.

Calculation: Because this requires filling the volume of distribution (Vd), the calculation
uses the volume of distribution (Vd) equation as:

Loading dose = Vd x Target plasma concentration

Indication of loading dose:

 When t1/2 of the drug is short, example – t1/2 of dopamine is 2 minutes.

 To provide rapid therapeutic effect in critically ill patient by I/V route.
 For long term safety, example – Dopamine, Lidocaine.
Maintenance dose: It is the dosing rate at fixed dosing interval which is required to
maintain target concentration for optimum therapeutic effect.
Maintenance dose = Dosing rate x Dosing interval
Dosing rate = Rate of elimination = Clearance of drug x Target concentration

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Adult dose: According to British pharmacopoeia, the dose in between 20-60 years of
age is known as adult dose. If age is below 20 years, or above 60 years, the dose should
be reduced.
Test dose: Amount of drug given initially (before giving full therapeutic dose) to see
sensitivity/ response of tissue to the drug is called a test dose.

Importance of test dose:

 To see the sensitivity of tissue to the drug; example - penicillin is given as test
dose to detect presence of any penicillin hypersensitivity.
 To see the potency of the drug.
 To see the nature of response.
Maximum dose: The maximum amount drug within which drug cannot produce any
toxic effects is called maximum dose.
Minimum dose: The minimum amount of drug that is required for any desired
therapeutic effect is called minimum dose.
Ceiling effect & ceiling dose: When the dose of a drug is increased progressively, the
effect of drug also increases progressively and ultimately reaches a steady level. If the
dose of the drug is again increased, there will be no more increase of drug effect. So,
this is the maximum effect that can be produced by that particular drug. This maximum
effect of a drug is called ceiling effect and the dose which produces the ceiling effect is
called the ceiling dose.
*May ‘19+ How to calculate the dose for children.

Pediatric dose (PD): Rough calculation of pediatric dose –

 Young's formula: (mostly used)

 PD = Adult dose x Age (in years)

Age + 12

 Clerk's formula: (most accurate):

 PD = Adult dose x Weight (kg)

70

 PD = Adult dose x Weight (lb.)

150

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Body surface area (BSA):
BSA estimates are more accurate for calculation of pediatric doses than body weight
since many physiologic phenomena correlate better to body surface area. The average
body surface area of a 70 Kg human is about 1.8 m². Thus, to calculate the dose for a
child, the following formula may be used:

Approximate PD = Surface area of the patient (m2) x Adult dose

1.8
Response:

It is the effect in the body which is produced by drugs.

Drug + Receptor → Drug-Receptor complex → Response
rd
[T 23 ] Short note: Dose response curve.

Dose-response relationship:
The graphical representation of concentration of drug (at the site of action) & response
is called dose-response relationship.

 Dose is plotted along x axis

 Response is plotted along y axis

Maximum efficacy
(Emax)
Response

Potency (EC50)

Dose (log10 scale)

Figure: Dose-response curve.

Types of dose-response relationship:

1) Graded dose-response relationship

- Represents variability of response according to dose.

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 2) Quantal dose-response relationship / percent-dose relationship / all or none
relationship
- Represents individual variability of response at a fixed dose.
Graded dose-response relationship:
Gradation of response in relation to gradation of dose is called graded dose-response
relationship.

 A slight increase of drug should bring about a small increase in the response in a
graded fashion up to a certain limit.
 The response is directly related to the number of receptor with which the drug
effectively interacts.
 When all receptors are occupied, further increase in dose doesn’t increase
response if it obeys law of mass action.
 Graded dose-response means that the pharmacological effects of the drugs are
expressed in number; such as the heart rate by beat, blood pressure by mmHg.
 Data is obtained from small number of individuals.
Types & shape of curve: 2 types –
1) Arithmetic form: shape is hyperbola.
2) Log scale form: shape is sigmoid.
Information we get from graded dose-response curve:

 Median effective dose (ED50)

 Potency (EC50)
 Efficacy (Emax)
 Affinity
 Selectivity of a drug
 Sensitivity of a drug
 Safety margin of a drug
Advantage:

 Easy to calculate the response.

 Large numbers of figures can be accumulated.
 Maximum portion of the curve remains in the linear way. So, we can compare the
efficacy and potency of one drug with another.
 Short paper is enough.

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Disadvantage:

 Therapeutic index (TI) can’t be measured.

Efficacy
(Emax)

Magnitude of response

Median effective
dose (ED50)

Log10 scale (drug dose)

Figure: Graded dose-response curve.

Quantal dose-response relationship:

Quantal dose-response curve determine the dose of a drug required to produce a
specific magnitude of effect in a large number of individual patient or experimental
animal.

 Obeys all-or-none law.

 There is either maximum response or no response at all.
 For example - to test either presence or absence of hypnosis for a sedative.
 Data is obtained from many individuals.
Shape: Shape is sigmoid.
Information we get from quantal dose-response curve:

 Therapeutic index (TI)

 Median effective dose (ED50)
 Median toxic dose (TD50)
 Median lethal dose (LD50) [in animals]
 Potency
 Selectivity of a drug action
 Variation of drug responsiveness among individuals

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 Therapeutic Toxic
effect effect

Therapeutic
index (TI)
50%

ED50 TD50

Figure: Quantal dose-response curve.

Advantage:

 Prevention of convulsion.
 Prevention of arrhythmia.
 Prevention of death.
 Relief from headache.
Disadvantage:

 Efficacy of drugs can’t be measured.

 Two drugs can’t be compared.
 Very long paper is needed.
Affinity:
The tendency of a drug to bind with its receptor is called affinity.
Potency:
It is the amount of drug required to produce a certain response. It refers to the
concentration (EC50) or dose (ED50) of a drug required to produce 50% of the drugs
maximal effect.
Efficacy (Intrinsic activity):
It is the ability of the drug to elicit a response when it binds to the receptor. It is often
called maximal efficacy (Emax) because it is the greatest effect an agonist can produce if
the dose is taken to a very high level.

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 Emax Drug A is more potent
100
than drug B, but both
show same efficacy.
Response in %

Drug A Drug B Drug C shows lower

50
Drug C potency & lower
efficacy than both
Drug A & Drug B.
0

1 10 100
Log drug concentration (nM/L)
Figure: Typical dose-response curve for drugs showing differences in potency & efficacy.

th th th rd
*May ’19, TS 25 , T 25 , T 24 , T 23 ] Short note: Therapeutic index.

Therapeutic index (TI):

Therapeutic index is usually defined as the ratio of median toxic dose (TD50) to the
median effective dose (ED50).

TD50 & ED50 are determined from quantal dose-response curve.

( )
( )
( )

Information we get from TI / Importance of TI:

1) The therapeutic index represents an estimate of the safety of a drug, because a

very safe drug might be expected to have a very large toxic dose and a much
smaller effective dose. Therefore, the higher the TI, the safer the drug is & vice
versa.
2) If TI of a drug is low, it should be used with caution.
3) For safer therapeutic application of a drug, its TI must be > 1.
4) If TI = 1, the drug acts as a poison; eg - the TI of the poison K6(CN)6, is 1.
5) A drug may have different TI depending upon its clinical use; eg - aspirin.
 In headache: TI is high
 In rheumatoid arthritis: TI is low
6) For application of new drug, TI has greater significance.

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Drugs having low therapeutic index:

 Barbiturate
- Thiopental Na
- Phenobarbitone
 Narcotic analgesic (morphine, pethidine)
 Cardiac glycosides (digoxin)
 Aminoglycoside antibiotics
 Anticoagulants (warfarin)
 Anticonvulsants
 Antihypertensive drugs
 Lithium
 Anticancer drugs
 Oral contraceptives
 Steroids
 Quinidine
 Drugs acting on the CNS.

Drugs having high therapeutic index:

 Antibiotics
- Penicillin
- Sulfonamide
 Benzodiazepines
- Diazepam
- Clonazepam
 NSAIDs (paracetamol)
 Diuretics (thiazide)
 Phenytoin
*May’19+ Define therapeutic window & its clinical importance.

Therapeutic window (TW):

The range between the minimum toxic dose and the minimum therapeutic dose is called
the therapeutic window.

For example - if the average minimum therapeutic plasma concentration of theophylline

is 8 mg/L and toxic effects are observed at 18 mg/L, the therapeutic window is 8-18
mg/L.

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Clinical importance of TW:
1) TW is a more clinically useful index of safety.
2) TW is of greater practical value in choosing the dose for a patient.
3) It can help to avoid most of the potential side effects.
4) It is more reliable than the therapeutic index, since it considers the biological
variation among individuals to a larger extent

Therapeutic
window (TW)

100
Percentage of patients

50

Desired Unwanted
therapeutic adverse
effect effect
0
Log concentration of drug in plasma

Figure: Therapeutic window (TI).

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