Drug Receptors intercaction and Drug antagonism : Dr Rahul Kunkulol's Power point preparations

RECEPTORS AND RECEPTOR

SUPERFAMILIES

Dr.Rahul Kunkulol Asso. Professor dept. of Pharmacology

RMC,LONI

Receptor

DRUG

INTRODUCTION

“Corpora non agunt nisi fixate”.P. Ehrlich (1908)

Paul Ehrlich described drug-receptor binding:(“Agents do not act unless they are bound”)

Receptor

DRUG

DrugsDrugs can be defined as agents that uniquely interact with specific target molecules in the body, thereby producing a biological effect.

Drugs can be

stimulatory or

inhibitory

Drugs

Drugs interact with biological systems in ways that mimic, resemble or otherwise affect the natural chemicals of the body.

• - or -Drugs can produce effects by virtue of :• Acidic or basic properties (e.g. Antacids,

protamine)• Surfactant properties (amphotericin)• Ability to denature proteins (astringents)• Osmotic properties (laxatives, diuretics)• Physicochemical interactions with membrane

lipids (general and local anesthetics).

DRUG SPECIFICITY Specificity is reciprocal: Individual classes of drug bind only to certain targets, and individual targets recognized only certain classes of drug.No drugs are completely specific in their action. In many cases increasing the dose of a drug will cause it affect target other than the principle one, and this can lead to side effects. E.g. TCA

Targets for drug action

•Receptor

•Ion channels

•Enzymes

•Carrier molecules

Four kinds of

regulatory protein involved

as primary

drug targets.

Targets for drug action

ION CHANNELSLigand gated ion channels –incorporate a receptor and open or close only when the receptor is occupied by an agonist. Ex.- Local anesthetics (direct) Voltage gated ion channels-drugs binds on accessory sites on the channel protein and affect channel gating.Ex.- dihydropyridines (indirect)

ENZYMESMany drugs target enzymes. Often the drug molecule is a substrate analogue that act as a competitive inhibitor of the enzyme ,either reversibly or irreversibly. Examples:- Enzymes Inhibitors Acetylcholinesterase Neostigmine Cyclooxygenase Aspirin

CARRIER MOLECULE The transport across cell

membranes of ions and organic molecules generally requires a carrier protein . Ex. 1.Transport of glucose,a.a. into the cell. 2.Transport of ions, organic molecule into the tubule.

RECEPTOR Receptor are the sensing elements in the

system of chemical communications that coordinates the function of all the different cells in the body.

Chemical messengers : Hormones

Drugs Transmitters Other mediators

Drug and receptorDrugs, as well as hormones, neurotransmitter, autacoids and toxins can make possible the transfer of information to cells by interaction with specific receptive molecules called “receptors”.

Receptor

DRUG

DRUG RECEPTOR INTERACTION

Receptor mediated response

Binding Activation

Occupation of receptor by a drug molecule may or may not result in activation of the receptor.

Drug-Receptor Interactions

Drug-receptor interactions serve as signals to trigger a cascade of events. This cascade or signaling pathway, is a collection of many cellular responses which serve to amplify the signal and produce a final effect.

Effectors are thus the molecules that translate the drug-receptor interaction into changes in cellular activity.

+ EFFECT

DRUG DRUG + RECEPTOR DRUG + RECEPTOR EFFECTOR EFFECTOR INTERACTION COMPLEX SYSTEM

STIMULUS BINDING ACTIVATION TRANSDUCTION AMPLIFICATION RESPONSE

SIGNALLING PATHWAY

Classification of Receptors

IUPHAR (International Union of Pharmacological Science)Pharmacological

Mediator (i.e. Insulin, Norepinephrine, estrogen)

Biochemical and BiophysicalSecond messenger system (i,.e. cAMP,

PLC, PLA) Molecular or Structural

Subunit composition (i.e. 5HT1A )Anatomical

Tissue (i.e muscle vs ganglionic nAChRs)

Cellular (i.e. Membrane bound vs Intracellular)

RECEPTOR SUPERFAMILIES

LIGAND- GATED ION CHANNELS G-PROTEIN COUPLED RECEPTORS KINASE LINKED RECEPTORS NUCLEAR RECEPTORS

Type- Ionotropic receptors

Location-cell membrane

Effector-ion channel

Coupling-direct Examples-Fast neurotransmitters :

Nicotinic Ach Glutamate GABAA,

LIGAND GATED ION CHANNELS

LIGAND GATED ION CHANNELS

GATING MECHANISM

Neurotransmitter

Post synaptic membrane inotropic receptor (LGIC)

Increased permeability of ions

Depolarization

Action potential

STRUCTURE OF ACH NICOTINIC RECEPTOR

GABAA RECEPTOR

GABAA RECEPTOR

GABA

metabolites

Succinic Semialdehyde

GT: GABA transaminase SSD: Succinic semialdehyde dehydrogenase

GT

SSD

Cl-

G – PROTEIN COUPLED RECEPTORS

Type: Metabotropic Location: Cell membrane Coupling: G-protein

Exampels- Muscarinic, Adrenergic, Opioid, Dopamine, 5HT,Peptides,Purines

SIGNAL TRANSDUCTION

CLASSES OF G-PROTEINS Gs Gi Gq Go

Amplification………..?

Receptor Signaling Pathways

Adenylate Cyclase (AC)

Guadenylyl Cyclase (GC)

Phospholipase C (PLC)

Phospholipase A (PLA2)

Nitric oxide Synthase

Ions

cAMP cGMP DAG and IP3 Arachidonic acid NO and CO Na+, Ca2+, K+, Cl-

SECOND MESSENGER

EFFECTOR

Adenylate Cyclase ATP cAMP Activation of PK

Phosphorylation

of cell proteins 5AMP Enzymes involved in energy metabolism, cell division, cell differentiation, ion channels, and contractile proteins in smooth muscles

REGULATION OF ENERGY BY CAMP

PHOSPHOLIPASE C

ION CHANNELLS AS TARGET FOR G- PROTEINS GPCR controls ion channels directly

by mechanism that they do not involve second messengers like cAMP or IP3.

Either alpha or beta and gamma subunits of G protein acts as second messenger

Ex-m ACH receptor enhances K+ permeability

KINASE LINKED RECEPTORS

Mediate the actions of wide variety of proteins mediators including growth factors, cytokines & hormones such as insulin.

Receptor for various hormones (insulin) & growth factor incorporate tyrosine kinase activity in their intracellular domain.

Cytokine receptors have intracellular domain that activates cytosolic kinases when the receptor is occupied.

SIGNAL TRANSDUCTION

Receptor Ligand binding

Dimerisation of receptor

Autophosporylation of tyrosine residue

Binding of intracellular proteins

Gene transcription

NUCLEAR RECEPTORS Nuclear receptors regulate gene

transcription. Nuclear receptor-a misnomer as

they are located in the cytosol and migrate to nucleus when ligand is present.

Examples: Steroid hormones, thyroid hormones retinoic acid and vit. D.

SteroidReceptor

Confomational change

Dimer

Move to nucleus and bind to hormone – responsive elements

Increase RNA Polymerase activity

Production of specific m RNA

NUCLEAR RECEPTORS

RECEPTOR SUPERFAMILIES

RECEPTOR SUPERFAMILIES

DESENSITISATION & TACHYPHYLAXIS

Definition: TACHYPHYLAXIS The effect of a drug gradually diminishes

when it is given continuously or repeatedly, which often develops in the course of minutes.

Tolerance is conventionally used to describe a more gradual decrease in responsiveness to a drug, taking days or weeks to develop.

The distinction is not sharp. Refractoriness is used to indicate loss of

therapeutic efficacy. Drug resistance is used to indicate loss of

effectiveness of antimicrobial or anti tumor drugs.

MECHANISMS Loss or change in receptors Exhaustion of mediators metabolic degradation Physiological adaptation Active extrusion of drug from cell

Drug-Receptor InteractionsTheory and assumptions of drug-receptor

interactions. Drug Receptor interaction follows simple Law

mass-action relationships,

The magnitude of the response is proportional to the fraction of total receptor sites occupied by drug molecules.

Combination or binding to receptor causes some event which leads to a response.

Response to a drug is graded or dose-dependent.

Dose response curve…...

Agonism and Antagonism

Cont..AGONIST: Binding + ActivationAgonists facilitate receptor response

ANTAGONIST: If a drug binds to the receptor without causing activation and thereby prevents the agonists from binding, is termed as Antagonist.

Tendency of a drug to bind the receptor is governed by its affinity, where as tendency of it, ones bound, to activate the receptor is denoted by its efficacy.

PARTIAL AGONISTS: Drugs with intermediate levels of efficacy, such that even if 100% of receptors are occupied the tissue response is sub maximal.

PARTIAL & FULL AGONIST

Partial Agonists Full agonists

max response Full response @

~20% occupancy Partial agonists

sub maximal response

100% occupancy ~40% response

Comparison of Affinity & Efficacy of Ligands

Ligand Affinity Efficacy

Agonist ++++ ++++

Antagonist ++++ -

Partial agonist ++++ ++

TWO STATE MODEL The receptor shows the two

conformational stage resting (R) and activated (R*) which exist in equilibrium.

R R* Normally when no ligand is present,

the equilibrium lies far to the left.

In the presence of ligand (A) equilibrium will depend on

equilibrium constant i.e. /. For pure antagonist it is zero. For agonist it is a finite value. For drug X / is small – partial

agonist For drug Y / is large – agonist Therefore constant / is measure of

efficacy

R+D=

DRUG ANTAGONISM The effect of one drug is diminished or

completely abolished in the presence of another.

CLASSIFICATION Chemical antagonism Pharmacokinetic antagonism Antagonism by receptor block Noncompetitive antagonism, i.e. block of

receptor – effector linkage Physiological antagonism

Cont…

CHEMICAL ANTAGONISM

Two substances combine in solution and effect of active drug is lost, e.g. Dimercaprol bind to heavy metals

PHARMACOKINETIC ANTAGONISM

In this antagonist effectively reduces the concentration of the active drug at its site of action. This can happen various ways by increased metabolic degradation, decreased absorption or increased excretion.

REVERSIBLE COMPETITIVE ANTAGONISM

• Antagonist binds receptor but does not activates it.

• Incr’d [agonist] restores tissue response to agonist

• Antagonism “surmountable

• In the presence of antagonist, the agonist log concentration effect curve is sifted to the right without change in slope or maximum.

Antagonism-Competitive

IRREVERSIBLE COMPETITIVE ANTAGONISM

• In this antagonist dissociates very slowly or not at all resulting in no change in antagonist occupancy when agonist is applied. Covalently bind receptors

Irreversible, insurmountable antagonism

↓ number of available receptors -- ↓ agonist max response

IRREVERSIBLE COMPETITIVE ANTAGONISM

NONCOMPETITIVE ANTAGONISM Antagonists blocks at some points chain of

events that lead to production of response by agonist.

Effect will be slope and maximum of the agonist log concentration response curve.

PHYSIOLOGICAL ANTAGONISM In this there is interaction of two drugs

whose opposing action in the body tend to cancel each other example – Histamine and Omeprazole on parietal cell of gastric mucosa.