Preface

Agam is a group of budding medicos, who are currently doing their under graduation in
various Medical Colleges across Tamil Nadu and Pondicherry. The group was initiated on 18th
November 2017, in the vision of uniting medicos for various social and professional causes.

We feel delighted to present you Agam pharmacology notes prepared by Agam Divide and
Rule 2019 Team to guide our fellow medicos to prepare for university examinations.

This is a reference work of 2nd year medical students from various colleges. The team took
effort to refer many books and make them into simple notes. We are not the authors of the
following work. The images used in the documents are not copyrighted by us and is obtained from
various sources.

Dear readers, we request you to use this material as a reference note, or revision note, or
recall notes. Please do not learn the topics for the 1st time from this material, as this contain just the
required points, for revision.
Acknowledgement

On behalf of the team, Agam would like to thank all the doctors who taught us Pharmacology.
Agam would like to whole heartedly appreciate and thank everyone who contributed towards the
making of this material. A special thanks to Kareeshmaa H C, who took the responsibility of leading
the team. The following are the name list of the team who worked together, to bring out the
material in good form.

• Amritesh K Purushothaman
• Ananthapriya G
• Anusha Lakshmi Cheetiyar A
• Bala Diwakar T
• Jason Thetravalan T
• Jeyabarathi T A
• Kareeshmaa H C
• Manasa Sundar
• Mustansir Aziz Kitabi
• Nandhinee A
• Pavithra J
• Ragha Dharshini K
• Ramachandiran N
• Rishikkesh Ramana G
• Riya Kant
• Shreevardhan G M
• Sri Vishnu Prasath T
• Taher Hussain
 INDEX

Chapter 1: Routes of Drug Administration

Essay
1. Routes of Drug Administration………………………. 1

Short Notes
2. Transdermal Drug Delivery System………………… 8

Short Answers
3. Pharmacodynamics……………………………………… 10
4. Pharmacokinetics…………………………………………. 10
5. Drug…………………………………………………………….. 10
6. Pharmacotherapeutics………………………………… 10
7. Clinical Pharmacology………………………………….. 10
8. Toxicology……………………………………………………. 11
9. Essential Drugs…………………………………………….. 11
10. Orphan Drugs………………………………………………. 11
11. Drug Delivery by Transdermal Patches…………. 12
 1

1. Routes of Drug Administration:

Most of drugs can be administered by a variety of routes. The choice of
appropriate route in a given situation depends both on drug as well as
patient related factors.

Local Routes:
These routes can only be used for localized lesions at accessible sites and for
drugs whose systemic absorption is minimal from these sites.

➢ Systemic side effects are consequently absent or minimal

1. Topical
o External application of the drug to the surface for localized action
Drugs can be efficiently delivered to the localized lesions on skin, nasal mucosa,
eyes, ear canal, anal canal, vagina in the form of lotion, ointment, cream, powder,
paints, drops, pessaries.
Ex: Anti-fungal pessaries in vaginal candidiasis.

ADVANTAGES:

It is more convenient and encouraging to the patient.

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2. Deeper Tissues:
Certain deep areas can be approached using a syringe or needle but the drug
should be in a form such that systemic absorption is slow.
Ex: Intra-articular Injection (Hydrocortisone acetate in knee joint)

3. Arterial Supply:
▪ Close intra-arterial injection is used for contrast media in angiography.
▪ Anti-cancer drugs can be infused in femoral or brachial artery to localise
the effect for limb malignancies.

SYSTEMIC ROUTES:
The drug administered through systemic routes is intended to be absorbed into
the blood stream.

1. Oral:
Oral ingestion is the oldest and commonest mode of drug administration.

ADVANTAGES: DISADVANTAGES:

Safer. Action of drugs is slower. Therefore, not suitable for

More convenient. emergency.
Does not need assistance. May cause nausea and vomiting.
Non-invasive. Unpalatable drugs are difficult to administer.
Painless. Certain drugs such as penicillin G, Insulin are
Need not to be sterile. destroyed by digestive juices.
Cheaper. Cannot be used for un co-operative/unconscious
patients

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2. Rectal:
Certain irritant and unpleasant drugs can be put into rectum as suppositories or
retention enema for systemic effect.
Ex: Diazepam, Indomethacin, Paracetamol, Ergotamine.

ADVANTAGES: DISADVANTAGES:
When the patient is unconscious Inconvenient
and is having recurrent vomiting. Embarrassing
Liver is Bypassed. Absorption is slow
Rectal irritation may occur

3. Sublingual:
• The Tablet or pellet containing the Drug is placed under the tongue or
crushed in the mouth and spread over the buccal mucosa.
• Only lipid soluble and non-irritating drugs can be administered.
Ex: Glyceryl Trinitrate, Buprenorphine, Nifedipine, Desamino-oxytocin

ADVANTAGES: DISADVANTAGES:
Absorption is rapid - within minutes drug Buccal ulceration can occur
reaches the circulation. Lipid insoluble drugs cannot be given.
First pass metabolism is avoided.
After the desired effect is obtained, the
drug can be spat out to avoid unwanted
effects.

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4. Cutaneous:
• Highly lipid soluble drugs can be applied over skin for slow and prolonged
absorption.
• The drug can be incorporated in an ointment and applied over the specific
area of skin. Usually chest, abdomen, upper arm, lower back are utilized.
• Transdermal Therapeutic Systems (TTS).
• These are adhesive patches of various shapes and sizes. The drug is held in
a reservoir between an outer layer and a porous membrane.
Ex: Glyceryl Trinitrate, Fentanyl, Estradiol.

ADVANTAGES: DISADVANTAGES:
Action is very rapid. Irritant gases may increase secretion.
First pass metabolism is avoided. May induce cough.

5. Inhalation:
• Volatile liquids and gases are given by inhalation.
• Absorption takes place from the vast surface of alveoli.
Ex: General Anaesthetics.

6. Nasal:
• Drugs can be administered through nasal route as mucous membrane of
the nose can readily absorb certain drugs.
Ex: GnRH Agonists and Desmopressin have been used by this route.
Oxymetazoline drops for allergic rhinitis.

ADVANTAGES: DISADVANTAGES:
Duration of action is prolonged. Can cause irritation to skin.
Provide constant plasma drug levels. Expensive.
Patient compliance is good. Large Doses cannot be given.

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7. Parenteral:

o Parenteral refers to administration by injection which takes the drug directly

into the tissue fluid or blood without having to cross enteral mucosa.

ADVANTAGES: DISADVANTAGES:
Drug action is faster. Preparation has to be sterilised.
Gastric irritation and vomiting is Costlier.
prevented. Technique is painful and invasive.
Can be employed in unconscious un co- Assistance of another person is needed.
operative or vomiting patient. Chances of local tissue injury.
Liver is bypassed

A. Subcutaneous:
o The drug is deposited in the loose subcutaneous tissue which is richly
supplied by nerves but is less vascular.
Ex: DOCA, Testosterone.

ADVANTAGES: DISADVANTAGES:
Less painful Self-injection is not possible because deep
Absorption is rapid penetration is needed.
Soluble substances, Can cause local infection and tissue necrosis.
suspensions, colloids can be Should be avoided in anticoagulant treated patients
given by this route. because it can produce local haematoma.
Irritant solutions can damage the nerve if injected
nearer a nerve.

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B. Intra-Muscular:
o The drug is injected in one of the large skeletal muscles - Deltoid, Triceps,
Gluteus Maximus.
o Muscle is less richly supplied with sensory nerves and is more vascular.

ADVANTAGES: DISADVANTAGES:
Self-injection is possible because deep Absorption is slower.
penetration is not needed. Irritant drugs cannot be injected.
Should be avoided in shock patient who
are vasoconstricted.

C. Intra-Venous:
• The drug is injected into one of the superficial veins so that it reaches the
circulations. It can be given as BOLUS – lump.
• Slow injection – over 15 to 20 minutes.
• Slow infusion - When constant plasma concentration are required. About 1
L of solution is infused over 3 to 4 hours.
Ex: Oxytocin, Aminophylline, Heparin.

ADVANTAGES: DISADVANTAGES:
Most useful route in emergencies Once injected, the drug cannot be
because drug is immediately available withdrawn.
for action. Thrombophlebitis of the injected vein.
Large volumes of solution can be given. Extravasation of the drug may cause
Provides predictable blood necrosis of the adjoining tissues.
concentration with 100% bioavailability. Self-medication is difficult.
If unwanted effects occur infusion can Only aqueous solution can be given but not
be stopped; If higher levels are required suspensions, oily solutions and depot
infusion rate can be increased. preparations.
Irritants can be given by this route as Chances of causing air embolism is another
they get quickly diluted in the blood. risk.
Is the riskiest route – vital organs like
Heart, Brain are exposed to high
concentration of the drug.

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D. Intra-Dermal
The drug is injected into the skin raising a bleb or scarring of the epidermis
through a drop of the drug is done.
Ex: Smallpox vaccine, BCG Vaccine, Sensitivity Testing.

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2. Transdermal Drug Delivery System:

➢ Transdermal therapeutic systems (TTS) are devices in the form of adhesive
patches of various shapes and sizes (5-20 cm2) which deliver the contained drug
at constant rate into systemic circulation via stratum corneum.

➢ This is a cutaneous type of drug delivery system. High lipid soluble drugs can be
applied over the skin for slow and prolonged absorption.

➢ The drug (in solution or bound to polymer) is held in a reservoir between an

occlusive backing film and a rate controlling micropore membrane.

➢ The under surface of the micropore membrane is smeared with an adhesive

impregnated with the priming dose of the drug which is protective by another
film that is to be peeled off just before application.

➢ The drug is delivered at the skin surface by diffusion for percutaneous absorption
into circulation and the micropore membrane is such that rate of drug delivery to
skin surface is less than the slowest rate of absorption from the skin.

➢ Usually chest, abdomen, upper arm, lower back, buttock or mastoid region are
utilized and the drug is delivered at a constant rate irrespective of the site of
application.

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➢ TTS have designed to last for 1-3 days and they provide smooth plasma
concentrations without fluctuations; minimize inter-individual variations.

Examples:

1. Scopolamine patch for sialorrhoea and motion sickness

2. Nitroglycerin patch or ointment for prophylaxis of angina
3. Estrogen patch for Hormone Replacement Therapy (HRT)
4. Clonidinde patch for Hypertension
5. Fentanyl patch for chronic pain
6. Nicotine patch for de-addiction

ADVANTAGES: DISADVANTAGES:
Self-administration is possible Expensive
Patient compliance is better Local irritation may cause dermatitis and
Duration of action is prolonged itching
Systemic side effects are reduced Erythema
Provides a constant plasma Patch may fall off unnoticed
concentration of the drug
First-pass metabolism is bypassed

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3. Pharmacodynamics:
• The actions of the drug on the body are termed pharmacodynamics.
• Most drugs must bind to a receptor to bring about an effect.
• Pharmacodynamics include physiological and biochemical effects of drugs and
their mechanism of action at organ system, subcellular and macromolecular
levels.

4. Pharmacokinetics:
• The actions of the body on the drug are called pharmacokinetics.
• Pharmacokinetic processes govern the absorption, distribution, binding /
localization / storage, biotransformation and elimination of drugs.
• It has great practical importance in the choice and administration of a
particular drug for a particular patient.

5. Drug:
The WHO in 1966 defined “Drug is any substance or product that is used or is
intended to be used to modify or explore physiological systems or pathological
states for the benefit of the recipient.”

6. Pharmacotherapeutics:
• It is the application of pharmacological information together with knowledge
of the disease for its prevention, mitigation or cure.
• Selection of the most appropriate drug, dosage and duration of treatment
taking into account the specific features of a patient are a part of
pharmacotherapeutics.

7. Clinical pharmacology:
• It is the scientific study of drugs (both old and new) in man.
• It includes pharmacodynamic and pharmacokinetic investigation in healthy
volunteers and in patients; evaluation of efficacy and safety of drugs and
compare with other forms of treatment, surveillance of patterns of drug use,
adverse effects, etc.
• The aim of clinical pharmacology is to generate data for optimum use of drugs
and the practice of ‘evidence based medicine’.

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8. Toxicology:
It is the study of poisonous effect of drugs and other chemicals (household,
environmental pollutant, industrial, agricultural, homicidal) with emphasis on
detection, prevention and treatment of poisonings. It also includes the study of
adverse effects of drugs, since the same substance can be a drug or a poison,
depending on the dose.

9. Essential drugs:
I. The WHO has defined Essential drugs as “those that satisfy the priority
healthcare needs of the population.”
II. Essential medicines are meant to be available
a. within the context of functioning health systems,
b. at all times,
c. in adequate amounts,
d. in appropriate dosage forms,
e. with assured quality and adequate information,
f. and at a price the individual and the community can afford.
III. Last revised essential drug list was released in 2017 (20th list first being in
1977) which had 433 medicines with dosage forms and strength.

10. Orphan drugs:

a. These are drugs or biological products for diagnosis, treatment, prevention of
a rare disease or condition, for which there is no reasonable expectation that
the cost of development and marketing, will be recovered from the sale of the
drug.
b. Governments in developed countries offer tax benefits and incentives for
developing such drugs.
Ex: Fomepizole, Digoxin antibody, liothyronine, Colchicine, Azacitidine.

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11. Drugs delivered by transdermal patches:

Nitro-glycerine, nicotine, scopolamine,

clonidine, lidocaine, oxybutynin,
fentanyl, estradiol, testosterone,

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Chapter 2: Pharmacokinetics 1

Short Notes
1. Specialized Transport Mechanism………………… 13
2. Prolongation of Drug Action…………………………. 17
3. Plasma Protein Binding…………………………………. 19

Short Answers
4. Passive Diffusion….……………………………………… 21
5. Filtration…………..…………………………………………. 21
6. Bioavailability.…………………………………………….. 21
7. Bioequivalence……………………………………………. 22
8. Blood Brain Barrier….………………………………….. 22
 13

1. SPECIALISED TRANSPORT MECHANISMS

SPECIALISED TRANSPORT ARE BROADLY CLASSIFIED INTO

CARRIER TRANSPORT

VESICULAR TRANSPORT

CARRIER TRANSPORT
1. Facilitated diffusion
It is the movement of large or charged molecules via membrane proteins
(e.g. ions, sucrose, etc.)

2. Active transport mechanisms:

In this electrochemical process, the solute is transported against
electrochemical gradient with the use of energy, in the form of ATP.

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BROADLY CLASSIFIED INTO

• PRIMARY
• SECONDARY

PRIMARY ACTIVE TRANSPORT:

I. Na+K+ATPase:
Na+K+ ATPase is present in all eukaryotic cells. This is an antiport that pumps K+ into
the cell and Na+ outside of the cell. This maintains high K+ concentration inside the
cell.

Functions:
• Cytosolic ion concentration: High K+ and low Na+ inside the cell
• Cell volume: By maintaining ion concentration.
• Protein Synthesis: They maintain high K+ required for protein synthesis.
• Resting membrane potential
• Hormone actions: mediates actions of hormones like thyroxine, aldosterone
and insulin.
CLINICAL: Inhibition of Na+K+ pump by cardiac glycosides: Ouabain, digitalis
Increased intracellular Na+ leads to increased Calcium ion concentration in
myocardial cells thereby increasing their contractility.

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II. Ca++ ATPase: Present in sarcoplasmic reticulum of muscle cells and

endoplasmic reticulum of other cells. They function by removing calcium from
cytoplasm thereby decreasing contractility of muscles.

III. H+ K+ ATPase or Proton ATPase:

Present in parietal cells of stomach and intercalated cells of the distal
nephrons.
• In stomach it is involved in HCl secretion
• In kidney it is involved in secretion of H+ in urine and reabsorption of K+ ions.
They acidify the urine.

IV. ABC Transporters:

ATP-binding cassette proteins. They are 12 membrane binding domains.
CFTR Protein, cystic fibrosis transmembrane protein is an ABC Protein.
They are related to drug resistance in cancer cells.

SECONDARY ACTIVE TRANSPORT

The electrochemical gradient produced by the primary active transport

enables transport of substances across the membrane.
Ex: SGLUT transports glucose simultaneously with Na.

VESICULAR TRANSPORT
Proteins involved:

• Clathrin: Fibrillar protein helps in transportation from Golgi apparatus to

lysosome (AP-1 Clathrin) and from Golgi apparatus to endosomes (AP-2
Clathrin)

• Coating proteins: They help in transportation of vesicles between endoplasmic

apparatus and Golgi apparatus.

• Dynamin: Helps in formation of vesicles.

• Docking proteins: They help in the attachment of vesicles to membrane.

V snare protein and T snare protein.

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Transport mechanisms:

1. Endocytosis

Types:
• Phagocytosis
• Receptor mediated endocytosis
• Pinocytosis: cell drinking or fluid drinking. Mechanism by which cells take in
extracellular fluid.

2. Exocytosis:
Two major pathways
• Constitutive exocytosis: Proteins are continuously secreted by the cells.
Ex: Secretion of mucus by goblet cells.
• Regulated Exocytosis: Macromolecules that are stored in the vesicles get
released on specific stimuli. This is also called as Non constitutive exocytosis.
Ex: Hormone release.

3. Transcytosis:
When vesicles are used for intracellular transport purposes. It is also
called as cytopemisis.

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2. PROLONGATION OF DRUG ACTION

Prolongation of drugs is useful in the following ways:
• Frequency of administration is reduced, therefore more convenient
• Patient compliance is improved
• Large fluctuations in plasma concentration are avoided
o side effects related to high peak plasma level just after a dose (e.g.
nifedipine) would be minimized;
o better round-the-clock control of blood sugar, etc.
• Drug effect could be maintained overnight without disturbing sleep, e.g.
antiasthmatics, anticonvulsants, etc.

Methods utilized for prolonging drug action.

1. By prolonging absorption from site of administration
a. Oral
i. Sustained release tablets, capsules, etc.;
ii. drug particles are coated with resigns, plastic materials or other
substances which temporally disperse release of the active
ingredient in the GIT.
iii. Controlled release tablet/capsule utilizes a semipermeable
membrane to control the release of drug from the dosage form.
Such preparations prolong the action by 4 to 8 hours and no more,
because in that time drug particles reach the colon.
iv. Also, the drug release pattern and consequently the attained blood
levels of the drug may be more variable than the regular tablet of
the same drug

b. Parenteral
i. The s.c. and i.m. injection of drug in insoluble form (benzathine
penicillin, lente insulin) or as oily solution (depot progestins); pellet
implantation, silastic and biodegradable implants can provide for
its absorption over a couple of days to several months or even
years.
ii. Inclusion of a vasoconstrictor with the drug also delays absorption
(adrenaline+ local anaesthetics)

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c. Transdermal drug delivery systems

i. The drug impregnated in adhesive patches/strips/ointment applied
on skin prolongs drug action.
ii. Eg. GTN
2. By increasing plasma protein binding
a. Drug congeners are highly bound to plasma protein and are slowly
released in the free active form,
b. Eg. sulfadoxine.

3. By retarding rate of metabolism

a. Small chemical modification can markedly affect the rate of metabolism
without affecting the biological action, e.g. addition of ethinyl group to
estradiol makes it longer acting and suitable for use as oral contraceptive.
b. Inhibition of specific enzyme by one drug can prolong the action of
another drug,
i. e.g. allopurinol inhibits the degradation of 6-mercaptopurine,
ii. ritonavir boosts the levels of indinavir,
iii. cilastatin protects imipenem from degradation in kidney.

4. By retarding renal excretion

a. This is done by suppressing he tubular secretion of drug.
b. Being an active process, it can be suppressed by a competing substance.
c. e.g. probenecid prolongs duration of action of penicillin and ampicillin.

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3. PLASMA PROTEIN BINDING

• Most drugs possess physicochemical affinity for plasma proteins and get
reversibly bound to these.
o Acidic drugs bind to plasma albumin & is quantitatively more important.
Eg. Barbiturates, Benzodiazepines, NSAIDs Valproic acid, Phenytoin,
Penicillins, Sulfonamides, Tetracyclines, Tolbutamide, Warfarin
o Basic drugs to α1 acid glycoprotein Eg. β-blockers Bupivacaine,
Lidocaine, Disopyramide, Imipramine Methadone Prazosin Quinidine,
Verapamil
• Extent of binding depends on the individual compound; no generalization for a
pharmacological or chemical class can be made (even small chemical change can
markedly alter protein binding),

• Saturation of binding sites:

o Increasing concentrations of the drug can progressively saturate the

binding sites:
o fractional binding may be lower when large amounts of the drug are
given. The generally expressed percentage binding refers to the usual
therapeutic plasma concentrations of a drug.
o The clinically significant implications of plasma:
1. Highly plasma protein bound drugs are largely restricted to the
vascular compartment because protein bound drug does not cross
membranes (except through large paracellular spaces, suchas in
capillaries).
2. The bound fraction is not available for action. However, it is in
equilibrium with the free drug in plasma and dissociates when the
concentration of the latter is reduced due to elimination. Plasma
protein binding thus tantamounts to temporary storage of the
drug.
3. High degree of protein binding generally makes the drug long
acting, as bound fraction is not available for metabolism or
excretion, unless it is actively extracted by liver or by kidney
tubules.

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❖ Glomerular filtration does not reduce the concentration of the

free form in the efferent vessels, because water is also filtered.
❖ Active tubular secretion, however, removes the drug without
the attendant solvent → concentration of free drug falls →
bound drug dissociates and is eliminated resulting in a higher
renal clearance value of the drug than the total renal blood flow
(The same is true of active transport of highly extracted drugs in
liver.
❖ () Plasma protein binding here, acts as a carrier mechanism and
hastens drug elimination, e.g. excretion of penicillin (elimination
t½ is 30 min); metabolism of lidocaine. Highly protein bound
drugs are not removed by haemodialysis and need special
techniques for treatment of poisoning.
4. The generally expressed plasma concentrations of the drug refer to
bound as well as free drug. Degree of protein binding is taken into
account while relating these to concentrations of the drug that are
active in vitro, e.g. MIC of an antimicrobial.
5. Displacement Interactions:
❖ This occurs between many drugs bound to the same site. The
drug bound with higher affinity will displace that bound with
lower affinity.
❖ If just 1% of a drug that is 99% bound is displaced, the
concentration of free form will be doubled.
❖ Drug interactions are minimal. clinical significance being
attained only in case of highly bound drugs with limited volume
of ddistribution.
❖ Clinically important displacement interactions are:
• Aspirin displaces sulfonylureas.
• Indomethacin, phenytoin displaces warfarin
6. Alter drug binding
❖ In hypoalbuminemia, binding may be reduced and high
concentrations of free drug may be attained, e.g. phenytoin and
furosemide.
❖ Other diseases may also alter drug binding, e.g. phenytoin and
pethidine binding is reduced in uraemia; propranolol binding is
increased in pregnant women and in patients with inflammatory
disease (acute phase reactant α1 acid-glycoprotein increases).

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4. Passive diffusion
It is the most important mechanism for majority of the drug; the membrane
plays no active role.
➢ It is bidirectional
➢ Energy independent
➢ Along the concentration gradient
➢ Depends directly to the lipid: water partition coefficient of the
drug

5. Filtration:
Filtration is the passage of the drugs through aqueous pores in the membrane or
through the paracellular spaces.
Occurs at capillaries, glomeruli etc. (have large pores)
Accelerated by the rate of blood flow (hydrodynamic pressure) rather than on
lipid solubility or pH of medium.

6. Bioavailibility:
Bioavailability refers to the rate and extent of absorption of a drug from a dosage
form administered by any route, as determined by concentration-time curve in blood
or by its excretion in urine.
➢ It is the measure of the fraction of the administered dose of the drug
that reaches systemic circulation in unchanged form.
➢ Used particularly for oral route.
➢ Factor affecting: Intestine / liver metabolism (first pass effect)
Excretion in bile.

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7. Bioequivalence:
Two preparations of drug are said to be bioequivalent when the rate and
extent of bioavailability of the active metabolite (drug) from them is not significantly
different under suitable test conditions.

8. Blood brain barrier:

The capillary boundary that is present between the blood and brain is called
blood brain barrier.
• Endothelial cells are joined by tight junctions in the brain capillaries.
• Only lipid soluble and unionised form of drugs can pause through BBB
EG: barbiturates, diazepam, volatile anaesthetics etc.
• Pathological states like meningitis and encephalitis increase the
permeability of BBB.

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 INDEX

Chapter 3: Pharmacokinetics 2

Essay
1. Biotransformation ……………………………………….. 23

Short Notes
2. Microsomal Enzyme Induction……………………… 27
3. First Pass Metabolism…………………………………… 29
4. Kinetics of Elimination………………………………….. 31
5. Prolongation of Drug Action…………………………. 36
6. Newer Drug Delivery System………………………… 38
7. Therapeutic Drug Monitoring……………………….. 39

Short Answers
8. Clearance……………………………………………………... 40
9. Plateau Principle…………………………………………... 40
10. Loading Dose…………………………………….………….. 41
11. Maintenance Dose………………………………………… 41
12. Plasma Half-life…………………………………….……….. 41
13. Hoffman Elimination………………..……………………. 41
14. D/B Microsomal & Non-Microsomal Enzyme…. 42
 23

1. BIOTRANSFORMATION
Biotransformation means the chemical alteration of the drug in the body. It is
needed to render non polar compounds to polar so that they are excreted in the
renal tubules.

Biotransformation of the drug may lead to:

1. Inactivation ex: ibuprofen, paracetamol, lidocaine etc.
2. Active metabolite from an active drug ex: active drug - morphine active
metabolite - morphine-6-glucuronide
3. Activation of an inactive drug ex: levodopa to dopamine

Biotransformation reactions are classified into:

• Phase I (Nonsynthetic) (Functionalization)
• Phase II (Synthetic) (Conjugation)

Phase I
I. Oxidation:
• This reaction involves addition of oxygen or removal of hydrogen. Oxidative
reactions are mostly carried out by a group of monooxygenases in the liver,
which in final step involve cytochrome P-450 hemoprotein, NADPH,
cytochrome P-450.
• The CYP isoenzymes are important for drug metabolism in humans. Ex: CYP2E1
helps in metabolism of paracetamol, alcohol and Halothane. CYP2C19 helps in
metabolism of omeprazole, lansoprazole, phenytoin, diazepam etc

II. Reduction:
• Converse of oxidation and involves working of CYP-450 in opposite direction.
Alcohols aldehydes quinones are reduced. Drugs primarily reduced are
chloramphenicol, halothene, warfarin etc.

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III. Hydrolysis:
• Cleavage of drug molecule by taking up a molecule of water.
esterase
Example: Ester + water -------› Acid + Alcohol

Drugs that undergo hydrolysis are lidocaine, pethidine, oxytocin etc.

IV. Cyclization:
• Formation of ring structure from a straight chain compound ex: cycloguanil
from proguanil.

V. Decyclization:
• Opening up of ring structures of cyclic drug molecule such as barbiturates and
phenytoin.

Phase II
Glucuronide conjugation:
• It is carried out by a group of UDP glucuronosyl transferases.
• Compounds with hydroxyl or carboxylic acid group are easily conjugated.
ex: Chloramphenicol, aspirin etc.

Acetylation:
• Compounds having amino or hydrazine residues are conjugated with the help
of acetyl coenzyme A, ex: sulfonamides, isoniazid, clonazepam etc.

Methylation:
• Amines and phenols are Methylated by methyl transferases, methionine and
cystin.
• ex: adrenaline, histamine, methyl dopa et.

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Sulfate conjugation:
• The phenolic compounds and steroids are sulfated by sulfotransferases. ex:
chloramphenicol, methyl dopa, sex steroids etc.

Glycine conjugation:
• Salicylates, nicotinic acid and other drugs having carboxylic acid are conjugated
with Glycine.

Glutathione conjugation:
• This is done by glutathione S transferases forming mercapturate.
• ex: paracetamol

Ribonucleoside/nucleotide synthesis:
• This pathway is important for activation of purines and pyrimidines and are
used in cancer chemotherapy.

➢ The drug metabolising enzymes are divided into microsomal enzymes and non-
microsomal enzymes
Microsomal enzymes:
▪ These are located in Smooth ER of the liver. They catalyse most of the
oxidation, reduction, hydrolysis, and glucronide conjugation.

Non microsomal enzymes:

▪ These are present in the cytoplasm and mitochondria of hepatic cell. Some
oxidation and reduction, many hydrolytic reactions and all conjugation except
Glucuronidation.

▪ These enzymes are deficit in new born especially in premature.

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Hofmann elimination
❖ This refers to Inactivation of the drugs in the body fluids by spontaneous
molecular rearrangement without the agency of any enzyme.
❖ ex: Atracurium.

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2. MICROSOMAL ENZYME INDUCTION

• Many drugs interact with DNA and increase the synthesis of microsomal
enzyme protein like cytochrome P 450 and UGTs.
• As a result of rate of metabolism of inducing drug itself (auto induction), some
other co administered drugs is accelerated.

Microsomal Enzymes Drugs Inducing them:

CYP3A Anticonvulsants, rifampicin, glucocorticoids
CYP2D6 & CYP2C8/9 Phenobarbitone and Rifampicin
CYP2C19 & CYP1A1/2 Carbamazepine and Rifampicin
CYP2E1 Isoniazids and chronic alcohol consumption
CYP1A Omeprazole, 3-methylcholanthrene, benzopyrene, charcoal
broiled meat, industrial pollutants.
Miscellaneous Nevirapine, griseofulvin, DDT, Chronic alcohol consumption

• Every inducer increases the biotransformation of certain drugs but not that of
others.
• Example: Phenobarbitone affects large number of drugs, because
Phenobarbitone→ Induces→ CYP3A and CYP2D6→ Metabolizes many drugs
Polycyclic hydrocarbons affect drugs like theophylline and warfarin. Because,
Polycyclic hydrocarbons→Induces→CYP1A→ metabolizes few drugs

MECHANISM OF ACTION:

• Induction involves microsomal enzymes in liver and other organs.

↓
• Increases the rate of metabolism 2-4 fold
↓
• Peak at 4-14 days
↓
• When withdrawn, return to their original levels by 1-3 weeks.

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CONSEQUENCES:

• ↓ Intensity and/or duration of action of drugs. Eg. Failure of contraception

with oral contraceptives.
• ↑ Intensity and/or duration of action of drugs. Eg. Acute paracetamol toxicity.
• Tolerance – Due to auto induction. Eg. Rifampin, Nevirapine, Carbamazepine
dose to be doubled after 2 weeks.
• Faster metabolization of steroids, bilirubin.
• Precipitation of acute intermittent porphyria by depressing δ aminolevulinic
acid Synthetase.
• Intermittent use may interfere dose of another regularly prescribed drug. Eg.
Oral Anticoagulants, oral hypoglycemic, antiepileptic, anti hypertensives.
• Interference with chronic toxicity testing in animals.

POSSIBLE USE OF ENZYME INDUCTION

• Congenital nonhaemolytic jaundice: Due to deficient glucuronidation of
bilirubin, Phenobarbitone hastens clearance of jaundice.
• Cushing’ Syndrome: Phenytoin→ degrades adrenal steroids → reduces the
manifestations
• Chronic poisonings: By faster metabolism
• Liver Disease

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3. FIRST PASS METABOLISM

Definition:
First pass metabolism refers to the metabolism of drug during its passage from
the site of absorption into the systemic circulation. It is an important determinant of
oral bioavailability.

Mechanism:
Orally administered drugs
↓
Metabolizes in intestinal wall and liver
↓
A fraction of the drug is lost.

Prevention: By sublingual, transdermal or parenteral routes.

Hepatic extraction ratio (ER Liver):

It is the fraction of drug prevented by the liver from reaching the systemic
circulation.
ER Liver = CL liver
Hepatic blood flow

Systemic bioavailability (F) = Fractional absorption × (I ― ER)

When a drug with high first pass metabolism is given orally with high dose, the
plasma concentration of its metabolites will be higher and if they contribute to the
adverse effects, oral dosing will be less safe.

Attributes of drugs with high first pass metabolism:

• Oral dose is higher than parentral or sublingual dose.
• Individual variation in the oral dose due to differences in the extent of first
pass metabolism.
• Oral bioavailability increases in patients with severe liver disease.
• Oral bioavailability of a drug increases when another drug competes with it in
first pass metabolism. Eg. Chlorpromazine and propanolol.

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LOW INTERMEDIATE HIGH ( NOT HIGH ORAL

ORAL) DOSE
Phenobarbitone Aspirin Isoprenaline Propanolol
Phenylbutazone Quinidine Lidocaine Alprenolol
Tolbutamide Desipramine Hydrocortisone Verapamil
Theophylline Nortriptyline Testosterone Salbutamol
Pindolol Chlorpromazine Glyceryl
trinitrate
Diazepam Pentazocine Morphine
Isosorbide Meteprolol Pethidine
mononitrate

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4. KINETICS OF ELIMINATION:

Importance:
To devise rational dosage regimens and to modify them according to individual
needs.

Clearance (CL):
The clearance of a drug is the theoretical volume of plasma from which the
drug is completely removed in unit time.

CL = Rate of elimination/C, C- plasma concentration

Drugs follow one of the following orders of kinetics.

First Order Kinetics:

• Rate of elimination α Drug concentration
• CL remains constant
• A constant fraction of the drug present in the body is eliminated in unit time.
• Majority of the drugs fall into this category.
•
Zero order kinetics:
• Rate of elimination is constant

• CL α 1
Drug concentration
• A constant amount of drug is eliminated in unit time, irrespective of drug
concentration. e.g., ethyl alcohol
• Also called capacity limited elimination or Michaelis- Menten elimination.

Non-linear elimination:
• For some drugs, kinetics change from first to zero order at higher doses.
• E.g. Phenytoin, Tolbutamide, Theophylline, warfarin
• The dose-rate-plasma concentration plot is curved.

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Blood flow dependent elimination:

• For few drugs the elimination capacity of an organ of elimination far exceeds
the amount of drug normally presented to it by blood circulation.
• So these drugs are almost completely eliminated in a single passage through
the organ of elimination.
•
Plasma half-life:
• The plasma half-life t ½ of a drug is the time taken for its plasma concentration
to be reduced to half of its original value.
• Semilog plasma concentration – time plot has two slopes.

Initial rapid declining α phase- due to distribution

Later less declining β phase- due to elimination
• So two half-lives can be calculated.
• Half-life derived from β slope is called half-life of the drug.
• T ½ = In2 , In2 is the log 2=0.693, k- elimination constant

K
• But, k = CL
V
• So, t ½ = 0.693 × V
CL
• Complete drug elimination occurs in 4 or 5 half-lives.
• For first order kinetics, t ½ remains constant
• Eg.

Aspirin 4 hrs
Penicillin -G 30
min
Doxycycline 20 hrs

• For zero order kinetics, t ½ gets prolonged with dose. T ½ is meaningless for
these drugs, because it is not fixed.

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Repeated drug administration:

• When a drug is given repeatedly within a short time, it gets accumulated until
elimination balances it. Till hen a steady state plasma concentration is
attained.
• Cpss= dose rate
CL
• Cpss α dose rate.
• Dose rate = target Cpss × CL
• After oral administration, Dose rate = target Cpss × CL
F
• This relationship is linear only when the drug follows first order kinetics.
• In case of drugs following, Michaelis-Menten elimination,
• Rate of drug elimination = (Vmax) (C)
Km + C

Plateau Principle:
• When a constant dose of drug is repeated before the expiry of 4t ½, it would
achieve higher peak concentration because some remnant of the previous
dose will be present.
• This continues until the elimination mechanism balances it out.
• Plasma concentrations plateaus and fluctuates. This is known as plateau
principle of drug accumulation.
• The amplitude of fluctuations depends on the dose interval relative to t ½.
• Dose intervals are based on the clinical acceptance of amplitude of
fluctuations.
• When dose rate is changed, new Cpss is obtained.
• When drug is given orally, Cpss is 1/3 of the way between minimal and
maximal levels.

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Target level strategy:

• For drugs whose effects are not easily quantifiable, it is best to achieve a
certain plasma concentration which has been defined to be in the therapeutic
range. E.g. anticonvulsants, antidepressants, lithium etc.
• Drugs with short half-life administered at conventional intervals achieve the
target levels only intermittently and fluctuate markedly.
• Drugs with longer t ½, if administered repeatedly will accumulate according to
plateau principle and produce toxicity later.
• So these drugs are given in two phases- Loading dose and Maintenance dose.
• Loading Dose: This is a single or few quickly repeated doses given in the
beginning to attain target concentration rapidly.
Loading dose = target Cp × V
F
This is governed only by V.
• Maintenance dose: This dose had to repeat at specified intervals after
attainment of target Cpss.
It is governed by CL of the drug.
Dose rate = target Cpss × CL
F
• Advantage:
The two phases provide rapid therapeutic effect with long term safety.
E.g. Digoxin, chloroquine, long-acting sulfonamides, doxyclyclines,
amiadarone.
• This is valid for short acting drugs and i.v. administration e.g. Lidocaine
• Monitoring of plasma concentration of drugs: The Cpss depends on its F, V
and CL. Each of these parameters varies considerably. Measurement of plasma
drug concentration can give an estimate of the pharmacokinetic variables in
that patient and the deviation from the average patient so that the dose can
be altered.
• Revised dose rate = Previous dose rate × Target Cpss
Measured Cpss

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Therapeutic drug monitoring (TDM) is useful in following situations

1. Drugs with low safety margin – Digoxin, anticonvulsants, antiarrhythmics,
antibiotics, lithium
2. If individual variations are large as in antidepressants, lithium.
3. Poisoning
4. Potentially toxic drugs used in the presence of renal failure as in vancomycin,
aminoglycoside
5. In case of failure of response without any apparent reason – antimicrobials
6. To check patient compliance – psycho pharmacological agents.

Monitoring of plasma concentration is of no value for

1. Drugs whose response is easily measurable, e.g. antihypertensives,
hypoglycemics, diuretics, oral anticoagulants
2. Drugs activated in the body, e.g. Levodopa
3. Hit and run drugs, e.g. reserpine, guanethidine, Omeprazole, MAO inhibitors.
4. Drugs with irreversible action e.g. organophosphate anticholinesterases,
phenoxybenzamine

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5. Prolongation of drug action:

Methods:

• By prolonging absorption from site of administration:

1. Oral:
Drug particles are coated with resin or substance which
temporarily disperse release of active ingredient in G.I.T.
2. Parentral:
i) Subcutaneous and intramuscular injection of drug in
insoluble form or as oily solution prolongs the
absorption.
ii) Also inclusion of a vasoconstrictor with drugs also
delays absorption. Eg: local anesthetics.
3. Transdermal drug delivery system:
Drug impregnated in adhesive patches, strips etc. and
applied on skin. Eg: GTN

• By increasing the plasma protein binding:

Drug congeners are highly bound to plasma and release slowly.
Eg: sulfadoxine.

• By decreasing the rate of metabolism:

1. Small chemical modification:
Eg. Addition of ethinyl group to estradiol > makes it long
active.
2. Inhibition of specific enzyme by one drug prolongs action of
another drug.
Eg. Allopurinol inhibits the degeneration of 6-
mercaptopurine.

• By retarding renal excretion:

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The tubular secretion which is a active process can be suppressed

by some competing substance.
Eg: Probenecid prolongs duration of action of penicillin, ampicillin and
amoxicillin.

Uses of prolongation of drug action:

1) frequency of administration is reduced.
2) Avoiding large fluctuation in plasma concentration.
3) Drug effect could be maintained overnight without disturbing sleep
.
4) Reduces the changes of breaking the treatment schedule. So that
more convenient.
• Used for drugs with t1/2 ≤ 4 hrs

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6. New drug delivery system:

To localize and prolong the delivery of the drug to specific target organ.
Eg:
• Liposomes:
>Unilamellar or bilamellar nano vesicles produced by Sonication of
biodegradable phospholipids like lecithin.
Used in:
• Liposomal IV: selectively taken up by reticuloendothelial cells
and malignant cells: therefore, the drug gets delivered
selectively to these cells.
• Liposomal Amphotericin B: in Kala-azar and systemic mycosis.

• Drug releasing implants:

The implants are coated with drug and placed in target organ.
Therefore, to prolong delivery of minute quantities of drug by slow
release.
Eg: i) Progestin (IUCD): gives protection upto 5 yrs.
ii) Antimicrobial drug coated stent: to prevent re-stenosis and in
failure of angioplasty.

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7. Therapeutic drug monitoring:

• To verify the attainment of target level in patient and to adjust the

dose rate accordingly.
• Used to give an estimate of the pharmacokinetic variable in that
patient.
• Selection of correct interval of drug dosing for the patient.

Useful in case of:

1) Drug with low safety margins. Eg: anticonvulsant.
2) If there is large individual variations, Eg: Li,
antidepressant….
3) In case of poisoning and toxic drugs.
4) In case of failure of response Eg: antimicrobials.
5) To check patient’s compliance.

Not needed in case of:

1) If the drug is activated only inside body.
2) Drugs with irreversible action.
3) Whose response is easily measurable.
4) Hit and run drugs.

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8. CLEARANCE (CL):
The clearance of a drug is the theoretical volume of plasma from which the drug
is completely removed in unit time.
CL=Rate of elimination / C
Where C is the plasma concentration.

First order clearance:

The rate of elimination is directly proportional to the drug concentration; CL
remains constant or a constant fraction of the drug present in the body is eliminated
in unit time.

Zero order clearance:

The rate of elimination remains constant irrespective of drug concentration, CL
decreases with increase in concentration or a constant amount of the drug is
eliminated in unit time. e.g.: ethyl alcohol. This is also called Capacity limited
elimination or Michaelis-Menten elimination.

9. PLATEAU PRINCIPLE:
When constant dose of a drug is repeated, it would achieve higher peak
concentration, because some remnant of the previous dose will be present in the
body. This continues with every dose until progressively increasing rate of elimination
balances the amount administered over the dose interval.
Subsequently plasma concentration plateaus and fluctuates about an average
steady state level. This is known as plateau principle of drug accumulation.

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10. LOADING DOSE:

This is a single or few quickly repeated does given in the beginning to attain
target concentration rapidly.
Loading dose = target Cp×V /F
Loading dose is governed only by V and not by CL or t1/2.

11. MAINTENANCE DOSE:

This dose is one that is to be repeated at specified intervals after the
attainment of target Cpss so as to maintain the same by balancing elimination.
Maintenance dose = target Cpss ×CL / F
It is governed by CL or t1/2.

12. PLASMA HALF LIFE:

 The plasma Half-Life (t ½) of a drug is the time taken for its plasma
concentration to be reduced to half of its original value.
 since first order kinetics is an exponential process, mathematically, the
elimination t ½ is
 t ½ = ln2 / k
 where ln2 is the natural logarithm of 2
 k is the elimination rate constant of the drug therefore,
t ½ = 0.693 × V / CL ( k = CL/V)

13. HOFMANN ELIMINATION:

This refers to inactivation of the drug in the body fluids by spontaneous molecular
rearrangement without the agency of any enzyme
E.g.: Atracurium

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14. DIFFERENCE BETWEEN MICROSOMAL AND NON

MICROSOMAL ENZYMES:

MICROSOMAL ENZYMES NON MICROSOMAL ENZYMES

 Located on smooth endoplasmic reticulum primarily  Present in the cytoplasm and mitochondria of
in liver also in kidney, intestinal mucosa and lungs hepatic cells and other tissues like plasma

 The monooxygenases, cytochrome P450, UGTs,  The esterases, aliases, some flavoprotein oxidases
episode hydrolases are microsomal enzymes and most conjugases are non-microsomal

 They catalase most of the oxidations, reductions,  Some oxidation and reductions, many hydrolytic
hydrolysis and glucuronide conjugation. reactions and all conjugations except
glucuronidation

 They are inducible by drugs, certain dietary

constituents  They are not inducible

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 INDEX

Chapter 4: Pharmacodynamics

Essay
1. Transducer Mechanisms………………………...…….. 43
2. G-Protein Coupled Receptors………………………… 46

Short Notes
3. Enzyme Inhibition………………………………………… 49
4. Affinity and Intrinsic Activity…………......……..… 51
5. Nuclear Receptors……………………………………….. 52
6. Dose – Response Relationship……..………………. 53
7. Drug Synergism and Antagonism………..………… 54

Short Answers
8. Types of Drug action……………………..……………... 56
9. Receptor………….…………………………………………... 56
10. Agonist……….…………………………………….………….. 56
11. Inverse Agonist…..………………………………………… 56
12. Partial Agonist.…………………………………….……….. 56
13. Antagonist…………………………………………………….. 57
14. Ligand……………………………………..……………………. 57
15. Two State Recptor Model………………………….…. 57
16. Orphan Receptors………………………………………… 58
 INDEX

17. Spare Receptors……………………………………………. 58

18. Silent Receptors……………………………………………. 58
19. Function of Receptors………………………………….. 58
20. Potency………………………………………………………… 58
21. Efficacy…………………………………………………………. 59
22. Drug Action…………………………………………………… 59
23. Therapeutic Index…………………………………………. 59
24. Therapeutic Range………………………………………… 59
 43

1. Transducers mechanisms:

Introduction:
• The drug given has to cross restrictive barriers to reach its target within the
body and produce the required therapeutic effects.

They cross the restrictive barrier by

1. Active transport
2. Passive transport
3. Facilitated diffusion

• The drug effect is attained by its interaction with the macromolecular

component i.e. the drug receptor
• Drug receptor (also known as drug target)
It is the cellular macromolecule with which the drug interacts to elicit a cellular or
systemic response.
They serve as receptors for endogenous regulatory ligands and are expressed on
surface of Cells.

The various transducer mechanisms are

1. Ion channels
a. Voltage gated channels

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b. Ligand gated channels

They respond to neurotransmitters

such as acetylcholine, GABA, glycine,
etc.

They do not possess ion selectivity;

activation of receptor allows passage
of both Na+ and K+ ions.

c. Transient receptor potential channel

Involved in various sensation like temperature, touch, pain, etc

2. Transmembrane receptors linked to intracellular enzymes

a. Receptor tyrosine kinase

inactive tyrosine kinase dimerisation (ACTIVATED) phosphorylation transcription

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b. JAK-STAT Receptor pathway

c. Receptor Serine-Threonine kinase
d. Toll like Receptors
e. TNF-α Receptors

3. Nuclear receptor

4. G –Protein coupled receptors

a. Adenyl cyclase pathway
▪ Cyclic AMP Pathway
▪ Cyclic GMP pathway
b. Phospolipase C: IP3 – DAG Pathway
c. Channel regulation.

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2. G-Protein Coupled Receptors:

• Large family of cell membrane receptors which are linked to the effector
through one or more GTP activated protein for response effectuation.
• All such receptor has a common pattern of structural organization.
• The molecule has 7 alpha helical membrane spanning hydrophobic amino
acid segments which run into 3 extracellular and 3 intercellular loops.
• The agonist binding site is located somewhere between the helices on the
extracellular face, while another recognition site formed by cytosolic
segments bunds the coupling G protein.
• The G proteins float in the membrane with their exposed domain lying in
the cytosolic and are heterobiomeric in composition (alpha,beta,gama
subunits).
• In its inactive state GDP is bound to the subunit alpha at the exposed
domain.
• Activation through the receptor leads to displacement of GDP BY GTP.
• The activated alpha subunit carrying GTP dissociates from the other two
subunits and either activates or inhibits the effector. The beta Gama dimer
also has shown to activate receptor potassium channels.

➢ Ga – adenylyl cyclase activation, Ca2+ channel opening

➢ Gi – adenylyl cyclase inhibition, k+ channel opening
➢ Go - ca2+ channel inhibition
➢ Gq – phospholipase C activation.

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• A limited number of G proteins are shared between different receptors and

one receptor can utilize more than one G protein.

Receptor Coupler
Muscarinic M2 G1, Go
Muscarinic M1,M2 Gq
Dopamine, D2 Gi, Go
Beta adrenergic Gs
Alpha 1 adrenergic Gq
Alpha 2 adrenergic Gi, Go
GABA b Gi, Go
Serotonin ,5HT 1 Gi, Go
Serotonin ,5HT 2 Gq
Prostanoid Gs, Gq, Gi

• The alpha subunit has GTPase activity, the bound GTP is slowly hydrolyzed
into GDP. The alpha subunit then dissociates from the effector to rejoin it’s
other subunits.
• There are three major effector pathways through which GPCRs function
I. Adenylyl cyclase: CAMP pathway
II. Phospholipase C: IP3 DAG pathway
III. Channel regulations
Adenylyl cyclase pathway:
• Activation of adenylyl cyclase results in intracellular accumulation of
second messenger CAMP which functions mainly through cAMP dependent
protein kinase.
• The Pka phosphorylates and alters the function of many enzymes, ion
channels to manifest as increased contractility, relaxation, glycogenolysis.

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• Activation of cAMP is terminated intracellularly by the

phosphodiesterase which hydrolyzed it to 5 AMP.

Phospholipase C pathway:
• Activation of phospholipase Cbeta by the activates GTP and generates
second messenger inositol,1,4,5 triphosphate and diacylglycerol. The TP3
mobilizes the calcium from ER. The DAG recruiters protein kinase and
activates it. They activate intracellular proteins and mediate various
response s such a as contractions, secretions, neurinal excitation.

Channel regulations:
• Activates G protein can also open or inhibiting ionic channels specific
for Ca2+ and K + without any second messenger such acAMO or IP3.
• They bring about hyperpolarization change la to intracellular
Ca2+channels.
• Physiological responses like changes in transmitter release, neuronal
action, inotropy.

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3. Enzyme inhibition:

Selective inhibitor of a particular enzyme is a common mode of drug action.

Enzyme inhibition
It is further classified into
1. Non selective
2. Selective
• Competitive
• Non competitive

A. Non selective mode of enzyme inhibition.

Chemicals denature proteins and inhibits all enzymes non selectively
E.g.: heavy metal salts, strong acids, alkalis, formaldehyde, phenols, etc.

B. Selective mode of enzyme inhibition.

The common mode of drug action.
i) Competitive type
Equilibrium type.
• The drug is structurally similarly to normal substrate.
• Thus competes for catalytic binding site of enzyme
• As a result, the product is either not formed or a non-functional
product is formed.
• New equilibrium is attained in the presence of drug.
• Km increases
• V-max remains unchanged
• High substrate concentration required to achieve ½ maximal
concentration
Increase in substrate concentration increase can displace the
inhibitor

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Non equilibrium type.

• Occurs when drug react with catalytic site bit either from
covalent bond or have high affinity for the enzyme.
• Km increases.
• V-max reduced.
• Even increase in concentration can't displace the inhibitor.
• E.g.: ■ Organophosphates and enzyme cholinesterase.
■ Methotrexate have high affinity for dihydrofolate reductase
than DHEA (normal substrate).

ii) Non competitive

• These inhibitors or drugs react with an adjacent (allosteric) site
and not with the catalytic site.
• They alter the enzyme to loose its catalytic property.
• Km unchanged
• V-max reduced.
• E.g.: ■ Digoxin – Na+ K+ ATPase pump.
■ Aspirin, Indomethacin – cyclooxygenase.
■ Acetazolamide – carbonic anhydrase.

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4. Affinity and Intrinsic Activity

Affinity: the ability to bind with the receptor is known as affinity.

Intrinsic Activity: the capacity to induce a functional change in the receptor is

designed as affinity.

Agonist: they have both affinity and maximal intrinsic activity (IA=1).
Ex: adrenaline, histamines

Competitive antagonist: they have affinity but no intrinsic activity(IA=0).

Ex: propanolol, naloxone

Partial agonist: have affinity and submaximal intrinsic activity.

(IA between 0-1) .
Ex: dichloroisoproterenol (no beta receptor).

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5. Nuclear receptors

• These are class of proteins responsible for sensing steroid and thyroid
hormones.
• They directly bind to DNA and regulate expression of adjacent genes thereby
controlling development, homeostasis and metabolism.
• It is activated by its Ligand, binding to them results in conformational change
resulting in up or down regulation of gene expression.
• They can directly interact and control the expression of genomic DNA.
• They play key roles in both EMBRYONIC DEVELOPMENT and ADULT
HOMEOSTASIS.

MECHANISM OF ACTION

Hormone binds to nuclear receptor

dissociation of heat shock proteins

dimerisation and translocation to nucleus

triggering the DNA

DNA is transcripted to mRNA

Protein synthesis occurs in ribosome

modification of cellular function

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6. Dose response relationship:

When a drug is administered systemically the dose response relationship

has two components.
• Dose plasma concentration relationship – determined by
pharmacokinetic consideration.
• Plasma concentration response relationship- can be studied in vitro
o The intensity of the response increases with increase in dose
o The dose response curve is rectangular hyperbola
o It obeys law of Mass action,
E = E-max ×[D]
KD + [D]
E – observed effect at the dose [D] of the drug
E-max- maximal response.
KD – dissociation constant of the dose receptor complex.
Dose of the drug at which half maximal response is produced.

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7. Drug Synergism and Antagonism

• Greek syn – together ergon -work

• When the action of one drug is facilitated or increased by the other, they
are said to be synergistic.
• In a synergistic pair, both the drugs can have the action on the same
direction or given alone one may be inactive but still enhance the action of
the other when given together.
• Synergism can be 2 types
✓ Additive
✓ Supra additive
Additive: the effect of the two drugs is in the same direction and simply adds
up
Effect of drug A and B = effect of drug A + effect of drug B
Ex: aspirin +paracetomol (analgesic)
Nitrous oxide + halothane (as general anaesthetic)

Supra additive: the effect of combination is greater than the individual effect of
the components.
Effect of drug A+B > effect of drug A + effyof drug B
Ex: acetylcholine + physostigmine (inhibition of breakdown)
Enalapril + hydrochlorothiazide (tackling two contributory factors)

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•Antagonism: when one drug decrease or abolishes the action of another, they
are said to be antagonistic.
Effect of drug A+B <effect of drug A + effect of drug B
In an antagonistic pair one drug is inactive and decrease the effect of the
another.
Antagonism is classified as
a) Physical antagonism: based on physical properties of the drug
Eg : charcoal absorbs alkaloids, prevents alkaloidal poisoning
b) Chemical antagonism: 2 drug chemically react and produce an inactive
product
Eg: tannins + alkaloids = insoluble alkaloidal tannant
c) Physiological or functional antagonism: have pharmacological effects in
opposite direction
Eg: histamine and adrenaline in BP
d) Receptor antagonism: one drug blocks the receptor action of another
drug
Two types – competitive and non-competitive.

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8. Types of drug action.

The basic types of drug action are
• Stimulation
• Depression
• Irritation
• Replacement
• Cytotoxic action

9. Receptor
It is defined as a macromolecule or binding site located on the surface or
inside the effectors’ cell that serves to recognize the signal molecule or drug and
initiate the response to it, but itself has no other function.

10. Agonist
An agent which activates a receptor to produce an effect similar to that of
the physiological signal molecule.

11. Inverse agonist

An agent which activates a receptor to produce an effect in opposite
direction to that of the agonist.

12. Partial agonist

An agent which activates a receptor to produce submaximal effect but
antagonizes the action of a full agonist.

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13. Antagonist
An agent which prevents the action of an agonist on a receptor or the
subsequent response but does not have any effect of its own.

14. Ligand
Any molecule which attaches selectively to particular receptors or sites.

15. Two state receptor model

Where,
Ra – active state of receptor
Ri – inactive state of receptor

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16. Orphan receptors

Receptors for which no endogenous mediators or ligands is at present
known.

17. Spare receptors

The maximal response elicited by an agonist at a concentration that does
not require full occupancy of the available receptors. The unused receptors are
known as spare receptors or receptor reserve.

18. Silent receptors

Also known as drug acceptors or sites of loss.
These are sites which bind specific drugs but no pharmacological response is
elicited.

19. Function of receptors

• To propagate regulatory signals from outside to inside the effectors’ cells,

when the molecular species carrying the signal cannot itself penetrate the cell
membrane
• To amplify signals
• To integrate various intracellular and extracellular regulatory signals.
• To regulate and maintain homeostasis

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20. Drug action

It is the initial combination of drug with its receptor resulting in confirmatory
change or preventing the conformational change.

21. Potency
The amount of drug needed to produce a response.

22. Efficacy
It is the maximal response that can be elicited by the drug.

23. Therapeutic index

It is the gap between dose which produces specific effect on 50% of
individuals and the dose which kills 50% of recipients.

Median lethal dose (LD50)

Therapeutic index =
Median effective dose(ED50)

24. Therapeutic range

It is the difference between the dose which produces minimal therapeutic
effect and the dose which produces maximal acceptable adverse effect.

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Chapter 5: Aspects of Pharmacology, Clinical

Pharmacology and Drug Development

Essay
1. Clinical Trial………………….……………………...…….. 60

Short Notes
2. Fixed Dose Combination……………………………… 63
3. Factors Affecting Drug Action………......……..…. 64

Short Answers
4. Dose……………………………………………..……………... 71
5. Pharmacogenetics………………………………………... 71
6. Pharmacogenomics………………………………………. 71
7. Placebo Effect………………………………………………. 72
8. Nocebo Effect………………………………………………. 72
9. Cross Tolerance……………………………………………. 73
10. Tachyphylaxis………………………………………………. 73
11. Evidence Based Medicine…………………………….. 74
12. Drug Response in Elderly……………………………… 75
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1. Clinical trial, Various phases of clinical trials:

Clinical trial
It is the prospective ethically designed investigation in human subjects to
objectively discover or verify or compare the results of two or more therapeutic
measures (drug).

Phase 0: Microdosing study

Carried out by clinical pharmacologist

• A new strategy being developed to reduce the cost and time of the
drug development process which are neither established nor
mandatory.

• 𝒅𝒓𝒖𝒈 𝒂𝒅𝒎𝒊𝒏𝒊𝒔𝒕𝒆𝒓𝒆𝒅 𝒊𝒏 𝒉𝒆𝒂𝒍𝒕𝒉𝒚 𝒗𝒐𝒍𝒖𝒏𝒕𝒆𝒆𝒓𝒔 =

𝟏
𝒕𝒉 𝒐𝒇𝒆𝒔𝒕𝒊𝒎𝒂𝒕𝒆𝒅 𝒅𝒐𝒔𝒆
𝟏𝟎𝟎
𝟏𝟎𝟎 𝒎𝒈 𝒐𝒇 𝒕𝒐𝒕𝒂𝒍 𝒅𝒐𝒔𝒆

The pharmacokinetics is worked out in accelerator mass spectrometry

or LC Tandem mass spectrometry.

ADVANTAGES: DISADVANTAGES:
No therapeutic or toxic effects, but Microdose pharmacokinetics may be
yield pharmacokinetic information. quite different from pharmacological
dose.

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Phase 1: Human pharmacology and safety

Carried out by clinical pharmacologist/ trained physicians.

• Subjects are exposed from low estimated dose to increasing stepwise

to achieve the effective dose.
• Emphasis is on safety, tolerability, to detect dangerous effects on
vitals i.e. ↑ or ↓ in BP, HR, Arrhythmia, etc.
• Side effects are noted and pharmacodynamics are observed.
• Human pharmacokinetic parameters of drug are measured.
• No blinding, study is open label.

Phase 2: Therapeutic exploration and dose ranging

Carried out by clinical investigators (trained physicians).

• 100 – 500 patients are selected according to inclusion and exclusion
criteria.
• The primary aim is to establish therapeutic efficacy, dose range and
ceiling effect.
• Tolerability and pharmacokinetics are studied as extension of phase 1.
• Carried in 2 – 4 centres.
• The candidate drug gets dropped if desired clinical efficacy is not
obtained.
• It may be blinded or open label.

Phase 3: Therapeutic confirmation.

Carried out by specialist in treating the target disease.

• 500 – 3000 patients are studied in many centres.

• The aim is to establish the value of the drug in relation to existing
therapy.
• Safety and tolerability is assessed on a wider scale.

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• Indications are finalized and guidelines for therapeutic use are

formulated.
• ‘New drug application’ is submitted to licensing authority ( like FDA)
for the marketing permission.
• Restricted marketing permission for use only in hospitals with specific
monitoring facilities, or only by specially trained physicians may be
granted in case of toxic drugs which are found useful in serious or
otherwise incurable diseases.

Phase 4: Post marketing surveillance.

• Idiosyncratic adverse effects or those that occur only after long term
use or unexpected drug interaction are noted this stage.
• Therapeutic trials involving children, elderly, pregnant or lactating
women are included in this stage.
• Acceptability and ADR of the released drug is collected from practicing
physicians.
• Modified release dosage forms, additional routes of administration,
fixed dose drug combinations may be explored.

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2. FIXED DOSE COMBINATION OF DRUGS

DEFINITION: A large number of pharmaceutical preparations contain two or more
drugs in a fixed dose ratio. These are called fixed dose combination of drugs.

ADVANTAGES:
1. Convenience and better patient compliance: All the components needed for
the patient are present in the drugs. So it may be cost saving.
2. Synergistic combinations: E.g. sulfamethoxazole + trimethoprim, levodopa +
carbidopa, combination oral contraceptives.
3. Therapeutic effect may add up while side effects may not. e.g. amlodipine +
atenolol as antihypertensive.
4. Side effects may be counteracted by other. E.g. thiazide + a potassium sparing
diuretic.
5. Single drug will not be administered. In TB and HIV-AIDS.
DISADVANTAGES:
1. Patient may not need all the drugs. Additional side effects and expense are
common.
2. Dose needs to be adjusted and personalised.
3. Time course of action of the components may be different.
4. Altered renal or hepatic function of the patient may affect the
pharmacokinetics.
5. Adverse effect cannot be ascribed to one drug.
6. Contradiction to one component contradicts the whole preparation.
7. Confusion of therapeutic aims and false sense of superiority of two drugs over
one is fostered. Steroids should never be combined with drugs meant for
internal dose.

Caution: The physician must be careful with the neediness of the ingredients of
the preparation.
It can never be justified that a drug given to a patient who does not need it in
order to provide him another one that he needs.

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3. FACTORS MODIFYING DRUG ACTION:

Variation in response to the same dose of a drug between different patients and even
in same patients on different occasions is a rule than exception.

Why?
1. Difference in pharmacokinetic handling of drugs: varying plasma/target site.
2. Variations in number or state of receptors
3. Variations in neurogenic/hormonal tone or concentrations of specific
constituents
A number of host and external factors influence drug response. They fall into two
categories-genetic and non-genetic
The factors modify drug action either:
➢ Quantitatively – This can be dealt with by adjustment of drug dosage.
➢ Qualitatively – e.g. drug allergy or idiosyncrasy. This precludes further use
of that drug.
1. Body Size: It influences the concentration of the drug attained at the site of
action
Individual dose = BW (kg) × average adult dose
70
Body surface area provides a more accurate basis for calculation.
Individual Dose = BSA (m2) × average adult dose
1.7
BSA can be calculated from Dubois formula
BSA (m2) = BW (kg) 0.425 × Height (cm) 0.725 × 0.007184
2. Age:
• The dose of the drug for children is calculated from adult dose.
• For many drugs dosage recommendations are on mg/kg basis.
• However, infants and children are not small adults. They have
important physiological differences from adults.
• The newborn has low GFR and tubular transport is immature.
• Hepatic drug metabolizing system is inadequate in newborns —
chloramphenicol can produce gray baby syndrome.

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• Blood-brain barrier is more permeable—drugs attain higher

concentration in the CNS (accumulation of unconjugated
Bilirubin causes kernicterus).
• Drug absorption may also be altered in infants because of lower gastric
acidity and slower intestinal transit.
• Transdermal absorption however, is faster because their skin is thin
and more permeable.
• Rectal absorption is fast and more predictable in infants and young
children.
• After the first year of life, drug metabolism is often faster than in
adults, e.g. theophylline, phenytoin, carbamazepine t½ is shorter in
children.
• Also, higher per kg dose is needed for drugs which are primarily
excreted unchanged by kidney, e.g. daily dose of digoxin is about 8–12
μg/kg compared to adult dose of 3–5 μg/kg.
• Elderly: In the elderly, renal function progressively declines (intact
nephron loss) so that GFR is ~ 75% at 50 years and ~ 50% at 75 years
age compared to young adults.
• Due to lower renal as well as metabolic clearance, the elderly are prone
to develop cumulative toxicity while receiving prolonged medication.
• slower absorption due to reduced gut motility as well as blood flow to
intestines,
• lesser plasma protein binding due to lower plasma albumin,
• Increased or decreased volume of distribution of lipophilic and
hydrophilic drugs respectively.
• In general, the incidence of adverse drug reactions is much higher in
the elderly.
3. Sex:
• Females have smaller body size and require doses that are on the
lower side of the range.
• A number of antihypertensive have potential to interfere with sexual
function in males but not in females.
• Ketoconazole causes loss of libido in men but not in women.
• There are marked and progressive physiological changes during
pregnancy, especially in the third trimester, which can alter drug
disposition.
• Gastrointestinal motility is reduced
• Plasma and extracellular fluid volume expands.

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• While plasma albumin level falls, that of α1 acid glycoprotein

increases.
• Renal blood flow increases markedly.
• Hepatic microsomal enzymes undergo induction—many drugs are
metabolized faster.
• Thus, the overall effect on drug disposition is complex and often
difficult to predict.

4. Species and Race:

• There are many differences in responsiveness to drugs among
different species.
• These are important when extrapolating differences from
experimental animals.
• Among human beings, blacks require high and Mongols require low
concentration of atropine and ephedrine to dilate their pupil.
• β-blockers are less effective in Afro- Carribeans.
• Despite extensive use in India, there is no reported case of
quiniodochlor related cases of sub-acute myelooptic neuropathy
(SMON).
5. Genetics:
• The dose of the drug to produce the same effect may vary 4-6 times
among different individuals.
• All the determinants of drug response are controlled genetically.
• Pharmacogenetics: The study of genetic basis for variability in drug
response is called Pharmacogenetics.
• It deals with genetic influences on drug action as well as on drug
handling by the body.
• Pharmacogenomics: Is the use of genetic information to guide the
choice of drug and dose on an individual basis.
• It intends to identify individuals who are either more likely or less
likely to respond to a drug, as well as those who require altered dose
of certain drugs.
• The goal is personalized medicine.
• There are some specific genetic defects which lead to discontinuous
variation in drug responses, e.g.
• 1. Atypical pseudocholinesterase result prolonged succinylcholine
apnoea.
• 2. The low activity CYP2C9 variants metabolize warfarin at a slow rate
and are at higher risk of bleeding.

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• 3. Severe 5-fluorouracil toxicity occurs in patients with

dihydropyrimidine dehydrogenase (DPD) deficiency.
• 4. Irinotecan induced neutropenia and diarrhoea is more in patients
with UGT1A1 *28 allele of glucuronyl transferase.
• 5. Thiopurine methyl transferase (TPMT) deficiency increases risk of
severe bone marrow toxicity of 6-mercaptopurine and azathioprine.
6. Route of Administration:
• Route of administration governs the speed and intensity of drug
response.
7. Environmental factors and time of administration:
• Exposure to charcoal, carcinogens, insecticides, tobacco smoking and
consumption of charcoal broiled meat are well known to induce drug
metabolism.
• Meals and type of diet can alter drug absorption. E.g. food interferes
with the absorption of ampicillin while fatty meal enhances
griseofulvin absorption.
• Subjective effects may be influenced by the setup in which it is taken.
E.g. Statins cause greater inhibition in late evening.
8. Psychological Factor:
• Efficacy of drug can be affected by the patient’s beliefs, attitudes and
expectations.
• This is particularly applicable to centrally acting drugs. E.g. a nervous
and anxious patient requires more general anesthetic.
• Placebo (meaning- I shall please): This is an inert substance which is
given in the garb of a medicine. It works by psychodynamic means.
• Placebos are used in two situations:
• As a control device in clinical trial of drugs
• To treat a patient who, in the opinion of the physician, does not
require an active drug.
• Placebos induce physiological responses.
• When an active drug is administered, it produces effect due to both
pharmacodynamic and psychodynamic actions.
• Placebo effects are highly variable. Thus it has a very limited role in
practical purposes.
• Common placebos are lactose tablets/capsules and distilled water
injection, multivitamin preparations.
9. Pathological states:
• Several diseases can influence drug disposition and drug action.
• Gastrointestinal diseases: Certain diseases can change absorption of
orally administered drugs. e.g. Amoxicillin absorption is decreased

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while cephalexin and cotrimoxazole is increased in celiac disease. Thus

malabsorption syndrome does not necessarily reduce absorption of all
drugs.
• NSAIDs can aggravate peptic ulcer disease.
• Liver disease: Liver disease can influence drug disposition.
• Bioavailability of drugs having high first pass metabolism is introduced
to due to loss of hepatocellular function and portocaval shunting.
• Serum albumin is reduced—protein binding of acidic drugs (diclofenac,
warfarin, etc.) is reduced.
• Metabolism and elimination of some drugs is decreased- their dose
should be reduced. Alternative drugs that do not depend on hepatic
metabolism should be preferred.
• Prodrug needing hepatic metabolism for activation should be avoided.
E.g. bacampicillin.
• Liver disease can influence action of drugs.
• In cirrhotics, brain sensitivity to morphine and barbiturates is
increased can lead to coma.
• Brisk diuresis can precipitate mental changes in patients with
impending hepatic encephalopathy.
• Oral anti-coagulants can prolong prothrombin time.
• Fluid retaining action of NSAIDs and lactic acidosis due to metformin
are accentuated.
• Kidney disease: It markedly affects pharmacokinetics of many drugs.
• Clearance of drugs that are primarily excreted unchanged
(aminoglycosides, digoxin, phenobarbitone) is reduced parallel to
decrease in creatinine clearance (CLcr).
• Loading dose of such a drug is not altered (unless edema is present),
but maintenance doses should be reduced.
• Albumin is reduced so is binding of acidic drugs.
• BBB permeability is increased so does CNS depression when
barbiturates, opiates are administered.
• Pethidine is contraindicated due to the seizures.
• Antihypertensive drugs produce greater postural hypertension.
• Tetracyclines accentuate uremia.
• NSAIDs cause more fluid retention.
• Nephrotoxic drugs like aminoglycosides, tetracyclines should be
avoided.
• Thiazide can precipitate uremia so furosemide should be used.

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• Potassium sparing diuretics should be spared because they cause

cardiac depression due to hyperkalemia.
• Congestive cardiac failure: It alter drug kinetics by
• Decreasing drug absorption from g.i.t due to mucosal edema and
vasoconstriction.
• Altering volume of distribution.
• Retarding drug elimination as a result of decreased perfusion and
congestion of liver.
• The decompensated heart is more sensitive to digitalis action.
• Thyroid disease:
• Hypothyroid patients are more sensitive to digoxin, morphine and CNS
depressants.
• Hyperthyroid patients are resistant to digoxin, but prone to
arrhythmogenic action.
• The clearance of digoxin is roughly proportional to thyroid function.
• Other conditions:
• Schizophrenics tolerate large doses of phenothiazines.
• MI patients are more prone to adrenaline and digitalis induces cardiac
arrhythmias.
• Myasthenia gravis patients are very sensitive to curare.
• Cotrimoxazole produces higher incidence of adverse reactions in AIDS
patients.
10.Other Drugs: Drugs can modify the response to each other by
pharmacokinetic or pharmacodynamic interaction between them.
11.Cumulation:
• Any drug will cumulate in the body if rate of administration is more
than the rate of elimination.
• However, slowly eliminated drugs are particularly liable to cause
cumulative toxicity, e.g. prolonged use of chloroquine causes retinal
damage.
• Full loading dose of digoxin should not be given if patient has received
it within the past week.
• A course of emetine should not be repeated within 6 weeks.
12.Tolerance: It refers to the requirement of higher dose of a drug to produce a
given response.
• Tolerance is a widely occurring adaptive biological phenomenon.
• Loss of therapeutic efficacy after prolonged/intensive use o a drug is
generally called refractoriness.

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• Natural: The species/individual is inherently less sensitive to the drug,

e.g. rabbits are tolerant to atropine; black races are tolerant to
mydriatics. Some are hyporesponders to certain drugs.
• Acquired: It is acquired by repeated administration of drugs. It is easily
recognized in the case of CNS depressants. Tolerance develops to the
sedative action of chlorpromazine but not to its antipsychotic action.
Tolerance occurs to the sedative action of phenobarbitone but not as
much to its anti-epileptic action. Tolerance occurs to analgesic and
euphoric action of morphine, but not as much to its constipating and
miotic actions.
• Cross Tolerance: It is the development of tolerance to
pharmacologically related drugs. E.g. alcoholics are relatively tolerant
to barbiturates and general anesthetics. There is partial cross
tolerance between morphine and barbiturates but complete cross
tolerance between morphine and pethidine.

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4. Dose
It is the appropriate amount of drug needed to produce a certain
degree of response in a given patient.
Ex: the dose of aspirin for headache is 0.3-0.6g.
Antiplatelet dose is 60-150mg/day

5. Pharmacogenetics
• It is the study of genetic basis of variability in drug response.
• It deals with the genetic influences on drug action as well as
drug handling by the body.

6. Pharmacogenomics
• It is the use of genetic information to guide the choice of drug
and dose on an individual basis.
• It intends to identify the individual who are either more likely or
likely to respond to a drug, as well as those who require
alternate doses of certain drugs.
• Attempt is made to define the genetic basis of an individual's
profile of drug and to predict the best treatment for him or her.

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7. Placebo Effect:
Placebo is a Latin word meaning “I shall please”.
This is an inert substance given in the grab of a medicine.
This works by psychodynamic rather than pharmacodynamics means.
Placebo is used in 2 situations
1. As a control in clinical trial of drugs
2. To treat the patient who, in the opinion of physician doesn’t require
drugs.
• Placebo doesn’t induce physiological response.
• Commonly used placebo are lactose tablets /
Capsule and distilled water injection.

8. Nocebo Effect:
• It is the converse of placebo and refers to negative
psychodynamic effect evoked by the pessimistic activity of the
patient or by loss of faith in the medicine.
• Nocebo effect can oppose the therapeutic effect of the patient.

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9. Cross Tolerence
It is defined as the development of tolerance to pharmacologically
related drugs.
Eg: Alcoholics are relatively tolerant to barbiturates and genera anaesthetics

Mechanism
• Pharmacokinetic/Drug disposition tolerance: The effective
concentration of the drug at the action site is reduced due to
enhancement of drug elimination on chronic use
Eg: Renal excretion of Amphetamine is increased on chronic use
• Pharmacodynamic/cellular tolerance: Drug action is lessened because
the cells become less responsive. This is due to desensitization or down
regulation of receptors or weakening of response effectuation.

10. TACHPHYLAXIS
• It refers to rapid development of tolerance when doses of a drug
repeated in quick succession result in marked reduction in response.

• Usually seen in indirectly acting drugs (Ephedrine, Tyramine, Nicotine

which act by releasing catecholamines; synthesis of which is unable to
match the rate of release and stores get depleted)

• Other mechanisms –
I. Slow dissociation of drug from its receptor
II. Desensitization/Internalisation/Down regulation of receptor
III. Compensatory homeostatic adaptation

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11. EVIDENCE BASED MEDICINE

• It is the process of systematically finding evaluating and using contemporary
research finding as the basis of clinical decisions.
• Results of well-designed multicentric interventional trails are forming the basis
of constantly evolving guidelines for disease management.
• Therapeutic evaluation of drug includes:
I. Quantitation of benefit afforded by it
II. The best way (dosage, duration, patient selection) to use it
III. How it compares with other available drugs
IV. Surveillance of ADR produced by it
• Clinical studies are of three types:
i. Clinical trials
ii. Cohort studies
iii. Case control studies

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12. DRUG RESPONSE IN ELDERLY

• Elderly people are more prone to develop cumulative toxicity due to following
reasons
a) Renal function progressively declines due to nephron loss and
thus GFR decreases (75% at 50yrs and 50% at 75 yrs.)
b) Reduction in hepatic microsomal drug metabolizing activity
and hepatic blood flow
c) Thus oral bioavailability of drugs with high hepatic extraction
is increased
d) Slow absorption due to reduced gut motility as well as blood
flow to the intestines
e) Lesser plasma protein binding due to lower plasma albumin
f) Increased/Decreased volume of distribution of lipophilic and
hydrophilic drugs respectively
EG: Streptomycin Adult dose - 1g/day
50yrs - 0.75g/day
75yrs - 0.5g/day

• Aged are relatively intolerant to Digitalis due to reduced responsiveness of ß

adrenergic receptors to both agonists and antagonists
• Due to prostatism in elderly males, mild anticholinergic activity can accentuate
bladder voiding difficulty
• They are likely to be on multiple drug therapy for hypertension, ischaemic
heart disease, diabetes, arthritis which increase many fold drug interactions.

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Chapter 6: Adverse Drug Reactions

Short Notes
1. General Detoxification…..……………………………… 76

Short Answers
2. Pharmacovigilance………………………..……………... 77
3. Treatment for Hypersensitivity……………………… 78
4. Drug Dependance…………………………………………. 79
5. Drug Withdrawal Reaction……………………………. 79
6. Teratogenicity………………………………………………. 80
7. Intolerance……………………………………………………. 81
8. Idiosyncrasy………………………………………………….. 82
9. Mutagenicity…………………………………………………. 83
10. Carcinogenicity……………………………………………… 83
11. Rational Prescribing………………………………………. 83
12. Post Marketing Surveillance………………………….. 84
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1. GENERAL DETOXIFICATION AND SUPPORTIVE MEASURES:

A. Resuscitation and maintenance of vital functions:

• Ensure patent airway, adequate ventilation, give artificial respiration.
• Severe poisoning often makes the patient comatose.
• maintain blood pressure and heart beat by fluid and crystalloid
infusion, pressure agents, cardiac stimulants, pacing, defibrillation.
• Prevent and manage seizures.
• Maintain body temperature.
• Maintain blood sugar level.

B. Termination of exposure(decontamination):
• It is done by removing the patient to fresh air, removing
contaminated clothing and washing the skin and eyes, induction of
emesis with syrup ipecac or gastric lavage.
• Contraindicated in corrosive and CNS stimulant poisoning.

C. Prevention of absorption of ingested poisons:

• Suspension of 20 -40g of activated charcoal, which has large surface
area and can adsorb many chemicals, should be administered in
200ml of water.
• Contraindicated in paralytic ileus or intestinal obstruction.

D. Hastening elimination:
• By inducing dieresis or altering urinary PH.
• Excretion of many poisons, especially those which are eliminated
mainly by hepatic metabolism, is not enhanced by forced dieresis.

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2. PHARMACOVIGILANCE

• It is related to collection, detection, assessment, monitoring & prevention of

adverse effect of drugs

Started in 2010
(NATIONAL COORDINATING CENTER) INDIAN PHARMACOPEA

COMMISSION IN UP

• AVOID INAPPROPRIATE USE IF DRUGS

• USE APPROPRIATE DOSE, ROUTE AND FREQUENCY OF DRUGS
• HISTORY OF DRUG REACTION
• HISTORY OF ALLERGIC DIAEASE
• SEE POSSIBILITY OF DRUG INTERACTIONS
• LABORATORY MONITORING

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3. TREATMENT OF HYPERSENSITIVITY

• THE OFFENDING DRUGS MUST BE IMMEDIATELY STOPPED

• CHECK THE PASSAGE OF AIRWAYS, ENSURE REDUCING RESPIRATORY STRESS
• ASSES THE LEVEL OF CONSICIOUSSNESS

IN CASE OF ANAPHILATIC SHOCK:

1. PUT THE PATIENT IN RECLINING POSITION, ADMINISTRATE

THE HIGH FLOW OF OXYGEN.

4. INTRAVENOUS
GLUCOCORTICOID TREATMENT 2. INJECT ADREALINE

3. ADMINISTRATION OF A H1 ANTIHISTAMINE

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4. DRUG DEPENDANCE
• It is altered physiological state produced by repeated administration of a drug
which necessitates the continued presence of the drug to maintain
physiological equilibrium.
• Discontinuation of the drug results in a characteristic Withdrawal syndrome.
• It is previously called Neuroadaptation of Drug
Eg: Opioids, Barbiturates, Alcohol and Benzodiazepines.

5. DRUG WITHDRAWAL REACTIONS

Sudden interruption of therapy with certain drugs can produce conditions which may
worsen the prevailing disease such as
i) Acute alcohol insufficiency may be precipitated by abrupt cessation of
corticosteroid therapy.
ii) Severe hypertension, restlessness and sympathetic over activity may
occur shortly after discontinuing clonidine.
iii) Worsening of angina pectoris, precipitation of myocardial infarction
may result from stoppage of ß blockers.
iv) Frequency of seizures may increase on sudden withdrawal of an
antiepileptic.

• These changes can be avoided by GRADUAL withdrawal of Drug.

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6. TERATOGENICITY
• It is the capacity of a drug to cause Foetal abnormalities when administered to
the pregnant mother.
• The embryo is the most dynamic biological systems and in contrast to adults,
drug effects are often irreversible.
• Drugs can affect the foetus at 3 stages:
i) Fertilization and implantation-(conception to 17 days) Failure of
pregnancy which often unnoticed.
ii) Organogenesis-(18-55days): Most vulnerable period
iii) Growth and Development (56 days onwards)
• The type of malformation depends on the drug as well as the stage at which
exposure to the teratogen occurred.
• Foetal exposure depends on the blood level and duration of which the drug
remains in the maternal circulation.
EG: Thalinomide – Phocomelia
Alcohol – Foetal alcohol syndrome
ACE inhibitors – Hypoplasia of organs
NSAIDs- premature closure of ductus arteriosus
Valproate – Spina bifida

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7. INTOLERANCE

CHRACTERISTIC TOXIC EFFECTS OF A DRUG AT THERAPEUTIC DOSE

INTOLERANCE

CONVERSE OF TOLERANCE INDICATES A LOW THERSHOLD

EXAMPLE:
• TRIFLUPROMAZINE
• CARBAZEPINE
• CHLOROQUINE

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8. IDIOSYNCRASY

GENETICALLY DETERMINED ABNORMAL ACTIVITY TO A CHEMICHAL

IDIOSYNCRASY

NON GENETICALLY DEFINED ABNORMAL DRUG INTERACTION WITH

UNUSAUAL DRUG EFFECT GENETIC OR NON GENETIC PECULARITY
OF AN INDIVISUAL

EXAMPLE:
• BARBITURATES
• QUININE
• CHLOROMPHENICOL

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9. Mutagenicity:
Ability of the drug to induce genetic damage is assessed in bacteria (Ames test),
mammalian cell cultures and in intact rodents.

10. Carcinogenicity:
Drug is given for long-term, even the whole life of the subject and are under
observation for development
of tumours

11. Rational prescribing:

Rational prescribing implies the choice of correct drugs for diseases, the
appropriateness of the whole therapeutic set up along with follow up of the outcome.
The criteria to evaluate rational prescribing are:
• Appropriate indication: the reason to prescribe the medicine is based on sound
medical considerations.
• Appropriate drug in efficacy, tolerability, safety, and suitability for the patient.
• Appropriate dose, route and duration according to specific features of the
patient.
• Appropriate patient: no contraindications exist drug acceptable to the patient;
likelihood of adverse effect is minimal and less than the expected benefit.
• Correct dispensing with appropriate information/instruction to the patient.
• Adequate monitoring of patients adherence to medication, as well as of
anticipated beneficial and untoward effects of the medication.
Factors influencing prescribing
• Knowledge of the prescriber.
• Role models: one tends to follow prescribing
• Practices of one’s teachers or senior/popular Physicians.
• Patient load: heavy load tends to foster routinized Symptom based prescribing.
• Attitude to afford prompt symptomatic relief at all Cost.
• Imprecise diagnosis: medication is given to cover All possible causes of the illness.
• Drug promotion and unrealistic claims by manufacturers.
• Unethical inducements (gifts, dinner parties, Conference delegation, etc.)
• Patient’s demands: many patients are not satisfied unless medication is
prescribed; misconceptions, Unrealistic expectations, ‘pill for every ill belief.

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12. Post Marketing Surveillance:

• It is the phase 4 of clinical trials.

• is carried out to obtain additional data about benefit and risk of use of drug in a
larger number of patients following long-term use.
• It provides information on adverse reactions, drug interactions, new indications
and evaluation of different formulations.
• helps to estimate incidence of adverse reactions, detect previously unknown
adverse reactions and identify risk factors for the adverse reactions.

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