IntroductionAt molecular level drug must be

bound to particular constituents of cells and tissue in order to produce an effect.

P. Ehrlich (German physician, biologist, chemist) summed it “a drug will not work unless it is bound”.

The critical binding sites are often referred to as drug targets. Receptor is one of the common drug target.

Receptor

Drug

Receptors

Macromolecular structure protein in nature, situated usually on the cell surface which has specific “chemorecognition” property which when combine with appropriate chemical substance results in a series of biochemical events that may lead to a response.

Receptor Functions : Two essential functions 1. Recognization of specific ligand molecule (Ligand binding

domain) (exogenous: drug and endogenous: hormone, neurotransmitter, autacoids)

2. Transduction of signal into response (Effector domain) (Initiation of a biochemical event that leads to characteristic change in the physiological function of the cell i.e. the response.)

Ligand binding domain

Transduction of signal into response

TermsAffinity: The tendency of a drug to

bind to receptor is governed by its affinity.Affinity: A > B

Efficacy: It is the capacity of a drug receptor complex to dissociate and elicit response.Efficacy: A > B

Potency: The quantity of a drug requires to produce desired response.Potency: A > B

Formula

[ D ] + [ R ] [ D ][ R ] Response + D + R

Affinity = K1 and K2

Efficacy = K3

This reaction can be explained in terms of Law of Mass action.

(The rate of chemical reaction is directly proportional to concentration of reacting molecule.)

K1

K2

K3

AgonismIt describes the process of binding of

a drug to its specific receptor, activate it and produce some molecular and cellular response.

Agonist are the chemical substances or drugs that can interact (combine) with a receptor (affinity) and thereby initiate a cellular reaction or response (efficacy) are termed by agonist.

It must have affinity and efficacy.

Efficacy maximum = 1e.g. Adrenaline in cardiac arrest stimulate β1 receptor – increase force of contraction and heart rate.

Partial AgonistProcess of binding of a drug

with its receptor and produce relatively insufficient response.

Partial agonist have some antagonistic effect.

Efficacy = 0 – 1e.g. Nalorphine Pantazosine Pindplol

Inverse AgonistBinding of a drug with a receptor

and produce opposite effect.

Affinity present

Efficacy = -1 e.g Benzodiazepines produces

CNS depression. β Carbolines produce excitation, anxiety and convulsion.

D-D combination

Summation :-Two drugs eliciting same response, but with different mechanism and their combined effect is equal to their summation. (1+1=2)

Aspirin Codiene

PG - Opiods receptor +

Analgesic+ Analgesic+

++

D-D combination

Additive: combined effect of two drugs acting by same mechanism

Aspirin glucocorticoids

PG PG

Analgesic+ Analgesic+

+ +

Synergism (Supra additive):- (1+1=3)

The combined effect of two drug effect is higher than either individual effect.

Ex:-1.Sulfamethaxazole+ Trimethoprim2. Levodopa + Carbidopa.

Antagonism

It is a phenomenon which describes binding of a drug to its receptor but cannot activate it and will prevent action of an agonist. Affinity more than agonist.Efficacy = 0;

e.g: Atenolol –Block b1 receptor of

heart Naloxane – Block Opioid receptor

Types of AntagonismChemical

Physiological

Pharmacological

Physiological antagonism

Two antagonists, acting at different sites, counter balance each other by producing opposite effect on same physiological system.

Histamine –acts on H1 R- Vasoconstriction Nor epinephrine –acts on beta 2R -Vasodilatation

Chemical antagonism – When a drug antagonizes the effect of another drug by

simple chemical reaction without action on the receptor.Chelating agents – e.g. desferioxamine in iron

overload, EDTA in increased Ca++ level. Charge neutralization – e.g. Heparin strongly

electronegative neutralizes protamine sulfate.Acid neutralization – e.g. HCL + Antacid.

Pharmacological AntagonismCompetitive

Reversible antagonism where agonist & antagonist compete for same receptor

Antagonism can be overcome by increased concentration of agonist.

Parallel shifting of dose – response curve

Non-CompetitiveIrreversible binding of

receptorAgonist cannot compete

with antagonistThere will be resynthesis of

R and action will be regain.

Therapeutic index:Is the ratio of median toxic dose

to median effective dose.If a drug having TD50 is 100mg

& ED 5mg,then TI is 100/5=20 .

TI should be more than one

50

50

ED

TDindex c Therapeuti =

MARGIN OF SAFETY = LD1 / ED99 The ratio of the dosage required to kill 1% of population,

compared to the dosage that is effective in 99% of population. The higher the margin of safety, the better.

Drugs with high therapeutic index – Paracetamol, thiazide, diazepam, clonazepam.

Drugs with low therapeutic index – Digitalis, anticoagulant, hypoglycemic agents, antiepilaetics, antiarrhythmic.

:Therapeutic window:Optimal therapeutic range of plasma concentrations at which most o the patients experience the desired effect.Therapeutic range Therapeutic window

Sub optim

a l

optimal

Dose response relationship /curveThe pharmacological effect of a drug depends on its

concentration at the site of action, which in turn is determined by the dose of the drug administered. such a relation is called the D-R relation ship.

The extent to which the desired response alters as the dose is change.

Dose is plotted on the horizontal axis Response on the vertical axis.

Graded Dose response curve:In this relationship as the dose of drug increased the

effect or the response of the drug is also increase.

Hyperbolic curve Sigmoid curve

→ Dose → log Dose

→ R

espo

nse

%

→ R

espo

nse

%

→Dose- Response curve → Log Dose Response curve

Quantal Dose Response curve:It determines the dose of a drug

required to produce specific] magnitude of effect in a large

number of individual patients or experimental animals (e.g. releif of headache), or for preservation of safety of experimental subjects (eg, using low doses of a cardiac stimulant and specifying an increase in heart rate of 20 beats/min as the quantal effect), or it may be an inherently quantal event (eg, death of an experimental animal).

Quantal dose-effect plots. Shaded boxes (and the accompanying black curves) indicate the frequency distribution of doses of drug required to produce a specified effect; that is, the percentage of animals that required a particular dose to exhibit the effect. The open boxes (and the corresponding colored curves) indicate the cumulative frequency distribution of responses, which are lognormally distributed.

Clinical importance:Both curves provides information regarding the

potency & selectivity of drugs.Graded dose response curve indicates the maximal

efficacy of drug.The quantal dose response curve indicates the

potential variability of responsiveness among individuals & TI.

Dose-response curves for two hypothetical drugs. DrugX: the dose that brings about the maximum wanted effect is lessthan the lowest dose that produces the unwanted effect. The ratioED50 (unwanted effect)/ED50 (wanted effect) indicates that drugX has a large therapeutic index: it is thus highly selective in itswanted action. Drug Y causes unwanted effects at doses wellbelow those which produce its maximum benefit.The ratio ED50(unwanted effect)/ED50 (wanted effect) indicates that the drug hasa small therapeutic index: it is thus nonselective

Q. write down the therapeutic implication of pharmacological antagonism?

Questions?

Questions?

Questions?

Questions??

Questions?

Thank you for your attention