Introduction to

Pharmacology

by
Ashwini Somayaji
 Introduction
Pharmacology

• (Greek “Pharmacon” – drug or poison (the active principle), logos-

discourse in)

• “ The science that studies the interaction of the chemical substances

with live organisms, drugs administration for treatment and
prophylaxis of various diseases and pathological processes”.

OR
The science that deals with
• the fate of drugs in the body (pharmacokinetics).
• their actions on the body (pharmacodynamics).
Pharmacology
• Pharmacology is the science of drugs.

• It deals with interaction of exogenously administered chemical

molecules with living systems, or any single chemical

substance which can produce a biological response(‘drug’).

• purpose to understand what drugs do to living organisms, and

more particularly how their effects can be applied to

therapeutics
 Drug

• “ a drug is any substance or product i.e. used or intended to be

used to modify or explore physiological systems or pathological
states for the benefit of the recipient”.
 Sources of Drugs

• Plant : Morphine, Digoxin, Quinine, Atropine

• Animal : Insulin, heparin, etc.
• Mineral : Mg trisilicate, MgSo4, liquid paraffin etc.
• microorganism : pencillin, streptomycin etc.
• Synthetic : NSAIDS, hypnotics, anticancer drugs etc.
• Genetic eng. : Insulin, GH, etc.
• Hybridoma technique : monoclonal antibodies.
• Essential drug : W.H.O has defined essential drugs as “those
chemical compounds that satisfy priority health care needs of the
population”
• Its of utmost importance, basic, indispensable and necessary for the
healthcare needs of the population
• Eg: general anaesthetics, medical gases, opioid analgesics.
• Orphan drug : “Biological products for diagnosis, treatment,
prevention of a rare disease”
• E.g. for Orphan drugs: Haem arginate used to treat acute intermittent
porphyria.
The two main divisions of pharmacology
are
• Pharmacokinetics
“What the body does to the drug”

• Pharmacodynamics
“What the drug does to the body”
Pharmacokinetics
• Examines the movement of a drug over time through the body.
• Pharmacological as well as toxicological actions of drugs are
primarily related to the plasma concentrations of drugs.
• Includes: absorption,distribution,binding/localization/storage,
biotransformation and excretion of the drug.
• First, drug absorption from the site of administration
(Absorption) permits entry of the therapeutic agent (either
directly or indirectly) into plasma.
• Second, the drug may then reversibly leave the bloodstream
and distribute into the interstitial and intracellular fluids
(Distribution).
• Third, the drug may be metabolized by the liver, kidney, or
other tissues (Metabolism).
• Finally, the drug and its metabolites are removed from the body
in urine, bile, or feces (Elimination).

•Knowledge of these four processes

(Absorption, Distribution, Metabolism,
and Elimination) influences the
clinician's decision of the route of administration for a specific
drug, the amount and frequency of each dose, and the dosing
intervals.
Pharmacodynamics
• “ It is the study of biochemical and physiological effects of drug
and their mechanism of action at organ level as well as cellular
level”.
• Drug concentration at site of action & resulting effect
are:
i. Mechanism of action: biochemical or physiological effect
ii. Dose-response relationship
iii. Adverse effect
Example
• Pharmacokinetic
Absorption: Paracetamol is readily absorbed from the
gastrointestinal tract.
Distribution:Paracetamol is distributed into most body tissues
Metabolism:Paracetamol is metabolised extensively in the liver
Excretion: excreted in the urine. The elimination half-life varies
from about 1 to 3 hours
Pharmacodynamics
. Paracetamol is thought to produce analgesia through a central
inhibition of prostaglandin synthesis
PHARMACODYNAMICS
Principles of drug action
•Drugs (except those gene based) do not impart new functions to
any system, organ or cell; they only alter the pace of ongoing
activity.
•However, this alone can have profound medicinal as well as
toxicological impact.
•The basic types of drug action can be broadly classed as:
Stimulation, depression, irritation, replacement and cytotoxic
action.
PRINCIPLE OF MODE EXAMPLE
ACTION
STIMULATION Selective Enhancement of activity of adrenaline stimulates
specialised cells . heart
- Excessive stimulation is often followed by
depression of that function Picrotoxin – CNS stimulant 
convulsions  coma  resp. depression

DEPRESSION Selective Diminution of activity of Barbiturates depress CNS

specialised cells. Quinidine depresses Heart
Certain drugs – stimulate one cell type and Ach – stimulates smooth muscle but
depress others. depresses SA node
IRRITATION Non-selective, often noxious effect – Bitters – salivary and gastric secretion
applied to less specialised cells (epithelium, Counterirritants increase blood flow to a
connective tissue). site
-stimulate associated function . Strong irritant- inflammation

REPLACEMENT Use of natural metabolites, hormones or Levodopa in parkinsonism

their congeners in deficiency states. Iron in anaemia
CYTOTOXIC Selective cytotoxic action for invading penicillin, chloroquine, zidovudine,
ACTION parasites or cancer cells. cyclophosphamide, etc.
Mechanism of drug action
•Physical/ chemical property

• Enzymes

• Ion channels

• Transporters

• Receptors
Physical/ chemical property
•Only a handful of drugs act by virtue of their simple physical or
chemical property
Examples :
•Bulk laxatives (ispaghula)—physical mass
•Activated charcoal—adsorptive property
•Antacids—neutralization of gastric HCl
•Cholestyramine—sequestration of bile acids and cholesterol in
the gut
ENZYMES
 Almost all Biological reactions are carried out under catalytic
influence of enzymes – major drug target.
 Drugs – increases/decreases enzyme mediated reactions.
 Enzyme stimulation is relevant to some natural metabolites
only, e.g. pyridoxine acts as a cofactor and increases
decarboxylase activity.
 Several enzymes are stimulated through receptors and second
messengers, e.g. adrenaline stimulates hepatic glycogen
phosphorylase through b receptors and cyclic AMP.
Enzyme inhibition
•Inhibition of a particular enzyme is a common mode of drug action.
Such inhibition is either competitive or noncompetitive.
Competitive
The drug being structurally similar competes with the normal substrate
for the catalytic binding site of the enzyme so that the product is not
formed or a nonfunctional product is formed.
Enzyme Endogenous substrate Competitive inhibitor
•Cholinesterase Acetylcholine Physostigmine
•Dopa decarboxylase Levodopa Carbidopa
 Noncompetitive

•The inhibitor reacts with an adjacent site and not with the catalytic
site, but alters the enzyme in such a way that it loses its catalytic
property.
Noncompetitive Enzyme inhibitor Enzyme
Aspirin, indomethacin Cyclooxygenase

Lovastatin HMG-CoA reductase

 Ion channels
Proteins which act as ion selective channels participate in
transmembrane signaling and regulate intracellular ionic
composition.
This makes them a common target of drug action.
Drugs can affect ion channels, some of which actually are
receptors, because they are operated by specific signal molecules
either directly and are called ligand gated channels (e.g. Nicotinic
receptor)
Nicotinic receptor

through G-proteins and are termed G-protein regulated

channels (e.g. cardiac β1 adrenergic receptor activated Ca2+
channel
•Drugs can also act on voltage operated channels by directly
binding to the channel and affecting ion movement through it,
• e.g. local anaesthetics which obstruct voltage sensitive Na+
channels

•In addition, certain drugs modulate opening and closing of the

channels,
e.g.: Sulfonylurea hypoglycaemics inhibit pancreatic ATP-
sensitive K+ channels.
 Transporters
Several substrates are translocated across membranes by binding to
specific transporters (carriers) which either facilitate diffusion in
the direction of the concentration gradient or pump the
metabolite/ion against the concentration gradient using metabolic
energy
Amphetamines selectively block dopamine reuptake in brain
neurons by dopamine transporter (DAT).
 Receptors
•The largest number of drugs do not bind directly to the effectors,
viz. enzymes, channels, transporters, structural proteins, template
biomolecules,etc. but act through specific regulatory
macromolecules which control the above listed effectors.
•These regulatory macromolecules or the sites on them which bind
and interact with the drug are called ‘receptors’
Receptor: It is defined as a macromolecule
or binding site located on the surface or
inside the effector cell that serves to
recognize the signal molecule/drug and
initiate the response to it, but itself has
no other function.
• Agonist: An agent which activates a receptor to produce an
effect similar to a that of the physiological signal molecule.
e.g. Adrenaline, Histamine, morphine.
• Antagonist: an agent which prevents the action of an agonist
on a receptor or the subsequent response, but does not have an
effect of its own.
e.g. atropine and muscarine
• Inverse agonist: an agent which activates receptors to produce
an effect in the opposite direction to that of the agonist.
e.g. antihistamine
• Partial agonist: An agent which activates a receptor to produce
submaximal effect relative to full agonist.
e.g. Tramadol.
Major Receptor Families
TYPE 1: LIGAND-GATED ION CHANNELS

•These cell surface receptors, also called ligand gated ion channels,
enclose ion selective channels (for Na+, K+, Ca2+ or Cl¯) within
their molecules
•Agonist binding opens the channel and causes
depolarization/hyperpolarization/ changes in cytosolic ionic
composition, depending on the ion that flows through.

•Response to these receptors is very

rapid, having durations of a few
milliseconds
•In case of nicotinic cholinergic receptor, the molecule (8 nm in
diameter) is composed of 5 subunits (2α +β + γ + δ) enclosing a
transmembrane ion channel within the α subunit.
•Normally the channel is closed (A).
•When two molecules of acetylcholine bind to the two α subunits
(B), all subunits move apart opening the central pore to 0.7 nm,
enough to
•allow passage of partially hydrated Na+ ions.
•Anions are blocked from passage through the channel by positive
charges lining it.
•In other cases, K+, Ca2+ or Cl¯ ions move through the channel
depending on its ion selectivity.
Enzyme-linked receptors

•This class of receptors are utilized primarily by peptide hormones,

and are made up of a large extracellular ligand binding domain
connected through a single transmembrane helical peptide chain to
an intracellular subunit having enzymatic property.
•Binding of a ligand to an extracellular domain activates or inhibits
this cytosolic enzyme activity. Duration of responses to stimulation
of these receptors is on the order of minutes to hours.
•The commonest protein kinases are the ones which phosphorylate
tyrosine residues on the substrate proteins and are called ‘receptor
tyrosine kinases’ (RTKs),
•Typically, upon binding of the ligand to receptor subunits, the
receptor undergoes conformational changes, converting from its
inactive form to an active kinase form. The activated receptor
autophosphorylates, and phosphorylates tyrosine residues on
specific proteins.
Intracellular receptors

•receptor is entirely intracellular and, therefore, the ligand must

diffuse into the cell to interact with the receptor.
•This places constraints on the physical and chemical properties of
the ligand in that it must have sufficient lipid solubility to be able
to move across the target cell membrane.
•For example, steroid hormones exert their action on target cells
via this receptor mechanism.
•Binding of the ligand with its receptor follows a general pattern in
which the receptor becomes activated.
•The activated ligand–receptor complex migrates to the nucleus,
where it binds to specific DNA sequences, resulting in the regulation
of gene expression.
•The time course of activation and response of these receptors is
much longer than that of the other mechanisms described before.
 G-protein coupled receptors (GPCRs)

•These are a large family of cell membrane receptors which are

linked to the effector (enzyme/ channel/carrier protein) through one
or more GTPactivated proteins (G-proteins)
•All such receptors have a common pattern of structural
organization
•The molecule has 7 α-helical membrane spanning hydrophobic
amino acid (AA) segments which run into 3 extracellular and 3
intracellular loops.
•The agonist binding site is located somewhere between the helices
on the extracellular face, while another recognition site formed by
cytosolic segments binds the coupling G-protein.
•The G proteins float in the membrane with
their exposed domain lying in the cytosol,
and are heterotrimeric in composition (α, β
and γ subunits).
In the inactive state GDP is bound to the α
subunit at the exposed domain; activation
through the receptor leads to displacement of
GDP by GTP.
The activated α-subunit carrying GTP
dissociates from the other two subunits and
either activates or inhibits the effector.
A number of G proteins distinguished by their α subunits have
been described.
The important ones with their action on the effector are:
Gs : Adenylyl cyclase activation, Ca2+ channel opening
Gi : Adenylyl cyclase inhibition, K+ channel opening
Go : Ca2+ channel inhibition
Gq : Phospholipase C activation
The important G proteins distinguished by α subunits with
their action on the effector are:

• Gs: Adenylyl cyclase ↑, Ca2+ channel ↑

• Gi: Adenylyl cyclase ↓, K+ channel ↑
• Go: Ca2+ channel ↓,
• Gq: Phospholipase C ↑

Receptor Coupler
• Muscarinic Gi, Go, Gq
• Dopamine D2 Gi, Go
• β -adrenergic Gs, Gi
• α 2-adrenergic Gi, Gs, Go
• GABA β Gi, Go
• 5-HT Gi, Gq, Gs,
 Three major effector pathways through
which GPCR functions

(a) Adenylyl cyclase: cAMP pathway

(b) Phospholipase C: IP3-DAG pathway

(c) Channel regulation

 Second messengers

•Second messengers are small molecules and ions that relay signals
received by cell-surface receptors to effector proteins.
•These second messengers broadcast the initial signal (the “first
message”) that occurs when a ligand binds to a specific cellular
receptor
•The second messenger then diffuses rapidly to protein targets
elsewhere within the cell, altering the activities as a response to the
new information received by the receptor.
•Three classic second messenger pathways are
(1) activation of adenylyl cyclase by G-protein-coupled receptors
(GPCRs) to generate the cyclic nucleotide second messenger 3′-
5′-cyclic adenosine monophosphate (cAMP);
(2) stimulation of phosphoinositide 3-kinase (PI3K) by growth factor
receptors to generate the lipid second messenger
phosphatidylinositol 3,4,5-trisphosphate (PIP3); and
(3) activation of phospholipase C by GPCRs to generate the two
second messengers membrane-bound messenger diacylglycerol
(DAG) and soluble messenger inositol 1,4,5-trisphosphate (IP3),
which binds to receptors on subcellular organelles to release
calcium into the cytosol.
 Receptors regulating gene expression
(Transcription factors, Nuclear receptors)

• In contrast to the above 3 classes of receptors,

these are intracellular (cytoplasmic or nuclear)
soluble proteins which respond to lipid soluble
chemical messengers that penetrate the cell
• Senses signals from the lipid soluble substances
and other hormonal substances to influence the
gene expression
3 categories
• Steroidal hormone receptors: glucocorticoid,
estrogen, progesterone, androgen)- present in
cytosol
• Receptor for thyroid harmones, Vit A and Vit D
• Peroxisome proliferator Activated receptors-lipid
sensor and modulates lipid metabolism
HSP-90: heat shock
protein 90

GR-Glucocorticoid
receptors

GRE-Glucocorticoid
responsive elements

IP-immunophilin
 Transmembrane JAK-STAT binding
receptors

• These receptors differ from RTKs in not having any

intrinsic catalytic domain.
• Agonist induced dimerization alters the intracellular
domain conformation to increase its affinity for a
cytosolic tyrosine protein kinase JAK (Janus Kinase).
• On binding, JAK gets activated and phosphorylates
tyrosine residues of the receptor, which now bind
another free moving protein STAT (signal transducer and
activator of transcription).
 Regulation of receptors

• Receptors exist in a dynamic state; their density

and efficacy to elicit the response is subject to
regulation by the level of on-going activity,
feedback from their own signal output and other
physiopathological influences,
• e.g. estrogens increase the density of oxytocin
receptors on the myometrium.
• The sensitivity of uterus to contractile action of oxytocin
increases progressively during the third trimester of
pregnancy, especially near term
Receptor desensitization
• continued/intense receptor stimulation causes
desensitization : the receptor becomes less efficient in
transducing response to the agonist.
• Eg: At NMJ desensitization caused by a slow conformational
changes in the receptors resulting in tight binding of agonist
without opening of ion channel
 Supersensitization
• In tonically active systems, prolonged deprivation of the
agonist (by denervation or continued use of an
antagonist or a drug which reduces input) results in
supersensitivity of the receptor as well as the effector
system to the agonist.
• This has clinical relevance in clonidine/CNS
depressant/opioid withdrawal syndromes, sudden
discontinuation of propranolol in angina pectoris, etc.
Up and down regulation of receptors

• Down regulation: prolonged exposure to high

concentration of of agonist causes a reduction
in the number of receptors available for
activation
• Due to endocytosis or internalisation of the
receptors from the cell surface
• Eg: In severe asthmatic patients who no longer
responds to beta adrenoceptors
• Prolonged use of tricyclic antidepressants also
causes down regulation of receptors
Up regulation of receptors
• Prolonged occupation of receptors by a blockers
lead to an increase in the number of receptors
with subsequent increase in receptor sensitivity
• Due to externalisation of the receptors
• Some times other hormones like thyroid
hormones causes up regulation of beta
receptors of cardiac muscles leading
tachycardia
Factors modifying drug action
 Factors modifying drug action

The factors modify drug action either:

a) Quantitatively - The plasma
concentration and/ or the action of the
drug is increased or decreased.
b) Qualitatively - The type of response
is altered.
e.g. drug allergy or idiosyncrasy.
 Factors modifying drug action

• Body size
• Age
• Sex
• Species and race
• Genetics
• Route of administration
• Environmental factors and
• time of administration
• Psychological factor
• Pathological states
• Other drugs
• Cumulation
• Tolerance
1. Body size: It influences the concentration of the drug attained at
the site of action.

BW (kg) x average adult dose

Individual dose = ---------------------------------------
70
• Body surface area (BSA) provides a more accurate basis for
dose calculation.

BSA (m2) x average adult dose

Individual dose = ----------------------------------------
1.7
BSA (m2)= BW (Kg) 0.425 x Height (cm) 0.725 x 0.007184
2. Age : The dose of a drug for children is calculated from the adult
dose.
Young's formula:

Age X adult dose

Child dose = ------------------------…...
Age + 12

Dilling's formula:

Age X adult dose

Child dose = ----------------------…....
20
• The newborn has low g.f.r. and tubular transport is immature.
• Glomerular filtration reaches adult rates by 5 month of age and
tubular secretion takes about 7 months to mature.
• Hepatic drug metabolizing system is inadequate in newborns -
chloramphenicol can produce gray baby syndrome.
• Blood brain barrier is more permeable- bilirubin- kernicterus.
• In the elderly, renal function declines.
• Decreased Hepatic drug metabolising activity.
3. Sex:
• Females have smaller body size- lower dose
• Maintenance treatment of heart failure with digoxin ---higher
mortality among women.
• Antihypertensives ( clonidine, methyldopa, β-blockers,
diuretics) interfere with sexual function in males but not in
females.
• Gynaecomastia (of ketoconazole, metoclopramide,
chlorpromazine, digitalis) that can occur only in men.
• Drugs given during pregnancy can affect the foetus.
4. Species and race:

• Rabbits are resistant to atropine.

• Rats and mice are resistant to digitalis.
• Rat is more sensitive to curare than cat.
• Blacks require higher and Mongols require lower concentrations
of atropine to dilate their pupil.
• Indians tolerate thiacetazone better than whites.
• Chloramphenicol in India and Hong Kong, relatively few cases
of aplastic anaemia.
5. Genetics
•The dose of a drug to produce the same effect may vary by 4–6 fold
among different individuals.
•All key determinants of drug response, viz. transporters,
metabolizing enzymes, ion channels, receptors with their couplers and
effectors are controlled genetically.
•Hence, a great deal of individual variability can be traced to the
genetic composition of the subject.
•Pharmacogenetics The study of genetic basis for variability in drug
response is called ‘Pharmacogenetics’.
•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.
•Over expression of P-gp results in tumour resistance to many
cancer chemotherapeutic drugs, because it pumps out the drug from
the tumour cells.
•Codeine fails to produce analgesia in CYP2D6 deficient, because
this enzyme generates morphine from codeine.
6. Route of administration:
• Governs the speed and intensity of drug response.
• Parenteral administration is often resorted to for more rapid,
more pronounced and more predictable drug action.
• A drug may have entirely different uses through different routes.
e.g. Magnesium sulphate---orally causes purgation,
applied on sprained joints---decreases swelling,
intravenously ---CNS depression and hypotension.
7. Environmental factors and time of administration:
• Exposure to insecticides, carcinogens, tobacco smoke etc –
induce drug metabolism.
e.g.
• Food interferes with absorption of ampicillin, but a fatty meal
enhances absorption of griseofulvin.
• Hypnotics taken at night and in quiet, familiar surroundings
may work more easily.
8. Psychological factor:
•Efficacy of a drug can be affected by patient’s beliefs, attitudes
and expectations.
•This is particularly applicable to centrally acting drugs,
•e.g. a nervous and anxious patient requires more general
anaesthetic;

Placebo: “an inert substance which is given in the garb of a

medicine”.
• It works by psychological rather than pharmacological means
and often produces responses equivalent to the active drug.
•However, placebo effects are highly variable even in the same
individual,
•e.g. a placebo may induce sleep on the first night, but not
subsequently.
•Thus, it has a very limited role in practical therapeutics.
•Substances commonly used as placebo are lactose tablets/capsules
and distilled water injection
•Nocebo It is the converse of placebo, and refers to negative
psychodynamic effect evoked by the loss of faith in the medication
and/or the physician. Nocebo effect can oppose the therapeutic
effect of active medication
9. Pathological states :
Not only drugs modify disease processes, several diseases can
influence drug disposition and drug action:
Gastrointestinal diseases : These can alter absorption of orally
administered drugs.
e.g. Achlorhydria decreases aspirin absorption by favouring its
ionization.
• NSAIDs can aggravate peptic ulcer disease. (PG)
Liver diseases:
• Bioavailability of drugs having high first pass metabolism ↑ed
• Serum albumin ↓ed –protein binding of acidic drugs
(diclofenac, warfarin, etc.) ↓ed and more drug is present in the
free form.
• Metabolism & elimination of some drugs- ↓-- dose ↓
• Prodrugs (hepatic metabolism for activation), e.g. prednisone,
bacampicillin- avoided..
Kidney disease:
• Clearance of drugs that are primarily excreted unchanged
(aminoglycosides, digoxin, phenobarbitone) is reduced.

• Plasma proteins, specially albumin decreased –binding of

acidic drug decreased.

• The permeability of BBB ↑ in renal failure.

• e.g. opiates, barbiturates, phenothiazines, benzodiazepines, etc
- more CNS depression.

• Potentially nephrotoxic drugs, e.g. cephalosporins,

aminoglycosides, tetracyclines (except doxycycline),
sulfonamides (crystalluria), vancomycin, cyclosporine,
amphotericin B should be avoided.
10. Other drugs :

• Pharmacokinetic or pharmacodynamic interaction

11. Cumulation:

• Rate of administration is more than the rate of elimination.

• Slowly eliminated drugs are particularly liable to cause

cumulative toxicity.
e.g. Full loading dose of digoxin should not be given if patient has
received it within the past week.
12. Tolerance :
It refers to the requirement of higher dose of a drug to produce a
given response.
Pharmacokinetic Tolerance: increase in the enzyme responsible for
metabolizing drugs.
Eg: Warfarin doses must be increased in patient taking barbiturates
Pharmacodynamic Tolerance:cellular tolerance due to down
regulation of receptors, or down regulation of intracellular
response to drug
Eg:
Tachyphylaxis : (Tachy-fast, phylaxis-protection) –
Acute, sudden decrease in response to a drug after its
administration i.e rapid and short term onset of drug tolerance.
Large dose is required to produce same effect.
This is usually seen with indirectly acting drugs, such as
ephedrine, tyramine, nicotine.
These drugs act by releasing catecholamines in the body,
synthesis of which is unable to match the rate of release:
stores get depleted. Other mechanisms like slow dissociation of
the drug from its receptor, desensitization/internalization or down
regulation of receptor, etc.
Cross tolerance It is the development of tolerance to
pharmacologically related drugs, e.g. alcoholics are relatively
tolerant to barbiturates and general anaesthetics.
Closer the two drugs are, more complete is the cross tolerance
between them,
e.g.— There is partial cross tolerance between morphine and
barbiturates but complete cross tolerance between morphine and
pethidine.
Any questions ???