Pharmacology – I

PHL-313

By

Majid Ahmad Ganaie M. Pharm., Ph.D. Assistant Professor Department of Pharmacology E mail: majidsays@gmail.com

Chapter 2:

PHARMACDYNAMICS

Learning objectives:

• Principles and mechanism of drug action

• Transducer mechanisms

• Dose-response relationship

• Combined drug effects

HOW DO DRUGS WORK?

• Some antagonize, block or inhibit endogenous proteins

• Some activate endogenous proteins

• A few have unconventional mechanisms of action

Most work by interacting with endogenous proteins:

WHAT DRUG DOES TO THE BODY!

It is the study of biochemical and physiological effects of drug and their mechanism of action at organ level

as well as cellular level.

PRINCIPLES OF DRUG ACTION

- Do NOT impart new functions on any system, organ or cell

- Only alter the PACE of ongoing activity

• STIMULATION

• DEPRESSION

• IRRITATION

• REPLACEMENT

• CYTOTOXIC ACTION

PRINCIPLE OF

ACTION

MODE EXAMPLE

STIMULATION Selective Enhancement of level of activity

of specialised cells

- Excessive stimulation is often followed by

depression of that function

Pilocarpine stimulates salivary

glands

Picrotoxin – CNS stimulant

convulsions coma death

DEPRESSION Selective Diminution of activity of

specialised cells

Certain drugs – stimulate one cell type and

depress others

Barbiturates depress CNS

Quinidine depresses Heart

Ach – stimulates smooth muscle

but depresses SA node

IRRITATION Non-selective often noxious effect –

applied to less specialised cells

(epithelium, connective tissue)

-stimulate associated function

Bitters – salivary and gastric

secretion

Counterirritants increase blood

flow to a site

REPLACEMENT Use of natural metabolites, hormones or

their congeners in deficiency states

Levodopa in parkinsonism

Iron in anaemia

CYTOTOXIC

ACTION

Selective cytotoxic action for invading

parasites or cancer cells – for attenuating

them without affecting the host cells

Penicillin, chloroquine

MECHANISM OF DRUG ACTION

MECHANISM OF DRUG ACTION

• MAJORITY OF DRUGS INTERACT WITH TARGET

BIOMOLECULES:

Usually a Protein

1. ENZYMES

2. ION CHANNELS

3. TRANSPORTERS

4. RECEPTORS

1. Enzymes – drug targets

• All Biological reactions are carried out under catalytic influence of enzymes – major drug target

• Drugs – increases/decreases enzyme mediated reactions

• In physiological system enzyme activities are optimally set

• Enzyme stimulation is less common by drugs – common by endogenous substrates – Pyridoxine (cofactor in decarboxylase activity)

– Adrenaline stimulates hepatic glycogen phosphorylase (hyperglycaemia)

• Enzyme inhibition – common mode of drug action

Enzymes – contd.

• Nonspecific inhibition: Denaturation of proteins –

strong acids, heavy metals, alkalies, alcohol, phenols

etc.

• Specific Inhibition:

Competitive Noncompetitive

What is specific enzyme inhibition?

• A drug may inhibit a

particular enzyme

without affecting

others and influence

that particular

substrate-enzyme reaction ultimately to

influence in the

product formation

Normal

Drug + Enzyme

Competitive Inhibition

Enzyme Inhibition - Examples

• Equilibrium: – Physostigmine Vs Acetylcholine (cholinesterase)

– Sulfonamides Vs PABA (folate synthetase)

– Moclobemide Vs Catecholamines (MAO-A)

– Captopril Vs Angiotensin 1 (ACE)

• Nonequilibrium: – Orgnophosphorous compounds/Nerve gases (cholinesterase)

• Non-competitive: – Acetazolamide (carbonic anhydrase), Omeprazole (HKATPase) ,

Aspirin (cyclooxygenase)

Effects of enzyme inhibition:

Normal Competitive (equilibrium)

2. Ion Channnel

• Proteins take part in transmembrane

signaling and regulates ionic composition

• Drugs also target these channels:

– Ligand gated channels

– G-protein operated channels

– Direct action on channels

• Examples

+ +

- -

+ +

--

- -

+ + + +

- -

Na+

+ + + +

- - - -

Resting (Closed**)

Open

(brief)

inactivated

Very slow repolarization in presence of LA

LA receptor

LA have highest affinity for the inactivated form

Refractory period

LA acting on Na+ receptors

3. Transporters

• Substrates are translocated across membrane by

binding to specific transporters (carriers) – Solute Carrier

Proteins (SLC)

• Pump the metabolites/ions I the direction of

concentration gradient or against it

• Drugs interact with these transport system

• Examples: Probenecid (penicillin and uric acid),

Furosmide (Na+K+2Cl- cotransport), Hemicholinium

(choline uptake) and Vesamicol (active transport of Ach

to vesicles)

4. Receptors

• Drugs usually do not bind directly with enzymes,

channels, transporters or structural proteins, but act

through specific macromolecules – RECEPTORS

• Definition: It is defined as a macromolecule or binding

site located on cell 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, e.g. G-

protein coupled receptor

Receptors – contd.

• Two essential functions:

– Recognition of specific ligand molecule

– Transduction of signal into response

• Two Domains:

– Ligand binding domain

– Effectors Domain – undergoes functional

conformational change

Some Definitions

• Agonist: An agent which activates a receptor to produce an effect

similar to a that of the physiological signal molecule, e.g. Muscarine

and Nicotine)

• 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. DMCM

• Partial agonist: An agent which activates a receptor to produce

submaximal effect but antagonizes the action of a full agonist, e.g.

pentazocine

• Ligand: any molecule which attaches selectively to particular

receptors or sites (only binding or affinity)

Some Definitions – contd.

• Affinity: Ability of a substrate to bind with

receptor

• Intrinsic activity (IA): Capacity to induce

functional change in the receptor

If explained in terms of affinity and IA:

• Agonist: Affinity + IA (1)

• Antagonist: Affinity + IA (0)

• Partial agonist: Affinity + IA (0-1)

• Inverse agonist: Affinity + IA (0 to -1)

D + R DR Complex

Affinity – Measure of propensity of a drug to bind

receptor; the attractiveness of drug and receptor

– Covalent bonds are stable and essentially irreversible

– Electrostatic bonds may be strong or weak, but are usually

reversible

Drug - Receptor Binding Affinity

Drug Receptor Interaction

DR Complex Effect (E)

Efficacy (or Intrinsic Activity) – ability of a bound drug

to change the receptor in a way that produces an

effect; some drugs possess affinity but NOT efficacy

Drug Receptor Interactions, The two-state model of receptor activation

(Resting state)

(Active state)

(Activated state)

The receptor is in two conformational states, ‗resting‘ (R) and ‗active‘ (R*), which exist in

equilibrium

Normally, when no ligand is present, the equilibrium lies far to the left, and a few receptors are

found in the R* state

For constitutively active receptors, an appreciable proportion of receptors adopt the R*

conformation in the absence of any ligand

Agonists have higher affinity for R* than for R and thus shift the equilibrium from the resting

state (R) to the active (R*) state and hence, produce a response

Drug Receptor Interactions, Inverse agonist

Inverse agonist ―An agent which binds to the same receptor

binding-site as an agonist for that receptor but

exerts the opposite pharmacological effect‖

Difference from Antagonist: Antagonist binds to the

receptor, but does not reduce basal activity

Agonist positive efficacy

Antagonist zero efficacy

Inverse agonist negative efficacy

Inverse agonists are effective against certain types

of receptors (e.g. certain histamine receptors and

GABA receptors) which have constitutive activity

Example 1: the agonist action of benzodiazepines on the benzodiazepine

receptor in the CNS produces sedation, muscle relaxation, and controls

convulsions. b-carbolines (inverse agonists) which also bind to the same receptor

cause stimulation, anxiety, increased muscle tone and convulsions

Example 2: the histamine H2 receptor has constitutive activity, which can be

inhibited by the inverse agonist cimetidine. On the other hand, burimamide acts

as a neutral antagonist

Drug Receptor Interactions, The two-state model of receptor activation & Inverse Agonist

Inverse Agonist Antagonist

(Resting state)

(Active state)

(Activated state)

An inverse agonist has higher affinity for R than for R* and thus will shift the

equilibrium from the active (R*) to resting state (R) state

A neutral antagonist has equal affinity for R and R* so does not by itself affect the

conformational equilibrium but reduces by competition the binding of other

ligands

In the presence of an agonist, partial agonist or inverse agonist, the

antagonist restores the system towards the constitutive level of activity

Drug Receptor Interactions, The two-state model of receptor activation & Inverse Agonist, contd.

An inverse agonist has higher affinity for R than for R* and thus will shift the

equilibrium from the active (R*) to resting state (R) state

A neutral antagonist has equal affinity for R and R* so does not by itself affect the

conformational equilibrium but reduces by competition the binding of other

ligands

In the presence of an agonist, partial agonist or inverse agonist, the

antagonist restores the system towards the constitutive level of activity

Drug-Receptor Bonds 1. Covalent Bond

-Very strong

-Not reversible under biologic conditions

unusual in therapeutic drugs

Example: phenoxybenzamine at a adrenergic

receptors

The rest of pharmacology is concerned with weak, reversible, electrostatic attractions:

2. Ionic bond

-Weak, electrostatic attraction between positive

and negative forces

-Easily made and destroyed

3. Dipole - dipole interaction

-A stronger form of dispersion forces formed by the

instantaneous dipole formed as a result of

electrons being biased towards a particular atom

in a molecule (an electronegative atom).

-Example: Hydrogen bonds

Drug-Receptor Bonds, contd.

4. Hydrophobic interactions

―The tendency of hydrocarbons (or of lipophilic

hydrocarbon-like groups in solutes) to form

intermolecular aggregates or intramolecular

interactions in an aqueous medium‖

-usually quite weak

-important in the interactions of highly lipid-

soluble drugs with the lipids of cell membranes

and perhaps in the interaction of drugs with the

internal walls of receptor ―pockets‖

5. Dispersion (Van der Waal) forces

-Attractive forces that arise between particles as

a result of momentary imbalances in the

distribution of electrons in the particles.

-These imbalances produce fluctuating dipoles

that can induce similar dipoles in nearby

particles, generating a net attractive force.

Drug-Receptor Bonds and Selectivity

Drugs which bind through weak bonds to their receptors are generally more

selective than drugs which bind through very strong bonds

This is because weak bonds require a very precise fit of the drug to its

receptor if an interaction is to occur

Only a few receptor types are likely to provide such a precise fit for a

particular drug structure

To design a highly selective short acting drug for a particular receptor, we

would avoid highly reactive molecules that form covalent bonds and instead

choose molecules that form weaker bonds

Selectivity:

Preferential binding to a certain receptor subtype leads to a greater effect at

that subtype than others

-e.g. salbutamol binds at β2 receptors (lungs) rather than at β1 receptors

(heart)

Lack of selectivity can lead to unwanted drug effects.

-e.g. salbutamol (b2-selective agonist ) vs isoprenaline (non-specific b-agonist) for

patients with asthma. Isoprenaline more cardiac side effects (e.g.,

tachycardia)

Receptors – contd.

• Cell surface receptors remain floated in cell membrane lipids

• Functions are determined by the interaction of lipophillic or hydrophillic domains of the peptide chain with the drug molecule

• Non-polar hydrophobic portion of the amino acid remain buried in membrane while polar hydrophilic remain on cell surface

• Hydrophilic drugs cannot cross the membrane and has to bind with the polar hydrophilic portion of the peptide chain

• Binding of polar drugs in ligand binding domain induces conformational changes (alter distribution of charges and transmitted to coupling domain to be transmitted to effector domain

Receptors – contd.

• Drugs act on Physiological receptors and

mediate responses of transmitters,

hormones, autacoids and others –

cholinergic, adrenergic or histaminergic

etc.

• Drugs may act on true drug receptors -

Benzodiazepine receptors

The Transducer mechanism

• Most transmembrane signaling is accomplished by a small number of different molecular mechanisms (transducer mechanisms)

• Large number of receptors share these handful of transducer mechanisms to generate an integrated response

• Mainly 4 (four) major categories: 1. GPCR

2. Receptors with intrinsic ion channel

3. Enzyme linked receptors

4. Transcription factors (receptors for gene expression)

Receptor Family Summary and Examples

1- Ligand-gated Ion Channels

They incorporate a ligand-binding (a receptor) site, usually in the

extracellular domain and they are activated by binding of a ligand (agonist)

to the receptor on the channel molecule.

Binding of the agonist causes a conformational change in the receptor

which leads to ion channel opening.

Involved in fast synaptic transmission

They control the fastest synaptic events in the nervous system, in which

neurotransmitter acts on the postsynaptic membrane of a nerve or muscle cell

and transiently increases its permeability to particular ions

Example: nACh

receptor

2. G-protein-Coupled Receptors (GPCRs)

The largest family: G-protein (guanine nucleotide binding regulatory

proteins) families: Gs ,Gi and Gq

Examples: mAChR, adrenoceptors, glutamate receptors, GABAB receptors

Actions: fast (seconds)

Structure:

GPCR consists of seven transmembrane a-helices

G-protein consists of 3 subunits, a, b, g.

Guanine nucleotides bind to the a-subunit which has enzymatic activity (GTP GDP)

The b and g subunits remain together as b, g-complex

2. G-protein-Coupled Receptors

―The activation of the effector tends to be self-limiting‖?? ------GTPase

Amplification?

Mechanism: binding of the agonist to the

GPCR activation of the GPCR G-

protein activation (G-GDP G-GTP) :

activation of enzyme with subsequent

generation of second messengers (e.g.

cAMP, IP3) → biological effect or

opening or closing of an ion channel

(Inactive) (Active)

Opposite functional effects may be produced at the same cell type by GPCRs (e.g.,

mAChR and b-adrenoceptors in cardiac cells)

2. G-protein-Coupled Receptors, Effectors

PIP2:

phosphatidylinositol-

4,5-bisphosphate

IP3:

inositol-1,4,5-

trisphosphate

DAG:

1,2-diacylglycerol

PIP2

Gq

G-proteins and Effectors

• Large number can be distinguished by

their α-subunits

G protein Effector pathway Substrates

Gs Adenylyl cyclase Beta-receptors, H2, D1

Gi Adenylyl cyclase Muscarinic M2

D2, alpha-2

Gq Phospholipase C Alph-1, H1, M1, M3

Go Ca++ channel Potassium channel in heart,

smooth muscle

Common intracellular signaling proteins

b) Protein kinases: modulate the activity or the binding

properties of substrate proteins by phosphorylating

serine, threonine, or tyrosine residues.

The phosphorylated form of some proteins is

active, whereas the dephosphorylated form of

other proteins is active.

The combined action of kinases and

phosphatases can cycle proteins between active

and inactive states.

(a) GTP-binding proteins with GTPase activity function

as molecular switches.

When bound to GTP they are active; when

bound to GDP, they are inactive.

They fall into two categories, trimeric G proteins

and Ras-like proteins.

c) Adapter proteins contain various protein-binding

motifs that promote the formation of multiprotein

signaling complexes.

3. Kinase-linked Receptors, General structure &

activation of receptor tyrosine kinases

Tyrosine-kinase (called receptor tyrosine kinase, more common) and guanylate cyclase-

linked (much less common) receptors

Actions: take minutes

Examples: Growth factors, hormones (e.g.

insulin) and cytokines

Receptors for various hormones (e.g., insulin)

and growth factors possess tyrosine kinase

activity in their intracellular domain.

The intracellular domain incorporates both ATP-

and substrate binding sites

Cytokine receptors do not usually have intrinsic

kinase activity, but associate, when activated by

ligand binding, with kinases known as Jaks,

which is the first step in the kinase cascade

Kinase-linked Receptors, General structure and activation of receptor tyrosine kinases

The ligands for some RTKs, such as the receptor for

EGF, are monomeric; ligand binding induces a

conformational change in receptor monomers that

promotes their dimerization.

The ligands for other RTKs are dimeric; their binding

brings two receptor monomers together directly.

In either case, upon ligand binding, a tyrosine kinase

activity is ―switched on‖ at the intracellular portion.

the kinase activity of each subunit of the dimeric

receptor initially phosphorylates tyrosine residues

near the catalytic site in the other subunit.

Subsequently, tyrosine residues in other parts of the

cytosolic domain are autophosphorylated.

Protein phosphorylation leads to altered cell function

via the assembly of other signal proteins

Kinase-linked Receptors, Activation of Ras following binding of a

hormone (e.g., EGF) to an RTK.

1. The adapter protein GRB2 binds to a specific

phosphotyrosine on the activated RTK and to

Sos, which in turn interacts with the inactive

Ras·GDP.

2. The guanine nucleotide – exchange factor

(GEF) activity of Sos then promotes formation

of active Ras·GTP.

Note that Ras is tethered to the membrane by a farnesyl anchor

Kinase-linked Receptors, Kinase cascade that transmits signals

downstream from activated Ras protein

1. Activated Ras binds to the N-terminal domain of

Raf, a serine/threonine kinase.

2. Raf binds to and phosphorylates MEK, a dual-

specificity protein kinase that phosphorylates

both tyrosine and serine residues.

3. MEK phosphorylates and activates MAP

kinase, another serine/threonine kinase.

4. MAP kinase phosphorylates many different

proteins, including nuclear transcription factors,

that mediate cellular responses.

3. Kinase-linked Receptors, Growth Factor Receptors

Activation of Ras

GDP/GTP Exchange

Activation

Binding of SH2-domain protein (Grb2)

Tyrosine

residue

Conformation

change

Dimerisation

Tyrosine

autophosphrylation

Phosphorylation

of Grb2

Raf

Mek

MAP kinase

Various transcription factors

GTP

NUCLEUS

Gene Transcription

Agonist binding leads to dimerisation and autophosphorylation of the intracellular domain of each receptor

SH2 domain proteins, Grb2, then bind to the phosphorylated receptor and are themselves phosphorylated

Ras, which is a proto-oncogene product, functions like a G-protein, and conveys the signal (by GDP/GTP exchange) Grb

Activation of Ras in turn activates Raf, which is the first of a sequence of three kinases, each of which phosphorylates, and activates, the next in line

The last of these, mitogen-activated protein (MAP) kinase, phosphorylates one or more transcription factors that initiate gene expression, resulting in a variety of cellular responses, including cell division

Ras

Grb2

Grb2

MEMBRANE

Cytokine binding leads to receptor

dimerisation, and this attracts a cytosolic

tyrosine kinase unit (Jak) to associate with,

and phosphorylate, the receptor dimer

Among the targets for phosphorylation by Jak

are a family of transcription factors (Stats)

which bind to the phosphotyrosine groups on

the receptor-Jak complex, and are

themselves phosphorylate

Thus activated, Stat migrates to the nucleus

and activates gene expression

3. Kinase-linked Receptors, Cytokine Receptors

NUCLEUS

Gene Transcription

Stat

Stat Stat

Jak Jak Jak Jak

Binding &

phosphorylation

of SH2-domain

protein (Stat)

MEMBRANE

4. Intracellular Receptors

These receptors could be cytosolic or nuclear

Several biologic signals are sufficiently lipid-soluble to cross the plasma

membrane and act on intracellular receptors.

One of these is a gas, nitric oxide (NO), that acts by stimulating an intracellular

enzyme, guanylyl cyclase, which produces cyclic guanosine monophosphate

(cGMP), which stimulates a cGMP-dependent protein kinase.

Another class of ligands—including corticosteroids, mineralocorticoids, sex

steroids, vitamin D, and thyroid hormone—stimulates the transcription of genes

in the nucleus by

binding to nuclear receptors

This binding of hormone exposes a normally hidden domain of the receptor

protein, thereby permitting the latter to bind to a particular nucleotide sequence

on a gene and to regulate its transcription.

End result is an alteration in gene transcription and therefore protein synthesis

Actions: slow-acting (hours), long lasting

Nuclear Receptors, an example

Mechanism of glucocorticoid

action.

A heat-shock protein, hsp90,

binds to the glucocorticoid

receptor polypeptide in the

absence of hormone and

prevents folding into the active

conformation of the receptor.

Binding of a hormone ligand

(steroid) causes dissociation of

the hsp90 stabilizer and permits

conversion of glucocorticoid

receptor to the active

configuration.

The active glucocorticoid receptor binds to a particular nucleotide

sequence on a gene altered

transcription of certain genes

Dose-Response Relationship

• Dose-plasma concentration

• Plasma concentration (dose)-response

relationship

Dose-Response Curve

dose Log dose

% r

esponse

% r

esponse

100% 50%

100% 50%

Dose-Response Curve

• Advantages:

– A wide range of drug doses can easily be

displayed on a graph

– Potency and efficacy can be compared

– Comparison of study of agonists and

antagonists become easier

Potency and efficacy

• Potency: It is the amount of drug required to produce a

certain response

• Efficacy: Maximal response that can be elicited by a drug

Response

Drug in log conc.

1 2 3 4

Therapeutic index (TI)

• Therapeutic Index = Median Lethal Dose (LD50) Median Effective dose (ED50)

Idea of margin of safety Margin of Safety

Therapeutic index (TI)

• It is defined as the gap between therapeutic effect DRC

and adverse effect DRC (also called margin of safety)

Therapeutic Index, contd.

Why don’t we use a

drug with a T.I. <1?

ED50 > TD50 = Very Bad!

• High therapeutic index

– NSAIDs

• Aspirin

• Tylenol

• Ibuprofen

– Most antibiotics

– Beta-blockers

• Low therapeutic index

– Lithium

– Neuroleptics

• Phenytoin

• Phenobarbital

– Digoxin

– Immunosuppressives

Therapeutic Index (T.I.)

Combined Effects of Drugs

• Drug Synergism – Additive effect (1 + 1 = 2)

• Aspirin+paracetamol, amlodipine+atenolol

– Supraadditive effect (1 + 1 = 4) • Sulfamethoxazole+trimethoprim, levodopa+carbidopa,

acetylcholine+physostigmine

• Drug Abntagonism: 1. Physical: Charcoal

2. Chemical: KMNO4, Chelating agents

3. Physiological antagonism: Histamine and adrenaline in bronchial asthma, Glucagons and Insulin

4. Receptor antagonism

Antagonists, Overview

Definition

―An antagonist is a substance that does

not provoke a biological response itself,

but blocks or reduces agonist-mediated

responses‖

Antagonists have affinity but no

efficacy for their cognate receptors

Binding of antagonist to a receptor will

inhibit the function of a partial agonist,

an agonist or inverse agonist at that

receptor

Antagonists mediate their effects by binding to the active site or to allosteric

sites on receptors or they may interact at unique binding sites not normally

involved in the biological regulation of the receptor's activity.

Antagonist activity may be reversible or irreversible depending on the longevity

of the antagonist–receptor complex which in turn depends on the nature of

antagonist receptor binding.

• Receptor antagonism:

1. Competitive antagonism (equilibrium)

2. Competitive (non equilibrium)

3. Non-competitive antagonism

Drug antagonism DRC

Drug antagonism DRC – non-

competitive antagonism Response

Shift to the right and lowered response

Drug in log conc.

Agonist Agonist + CA (NE)

Antagonists, 1-Competitive reversible antagonist

It binds to same site on receptor as agonist

inhibition can be overcome by increasing

agonist concentration (i.e., inhibition is

reversible)

No significant depression in maximal response

(Emax ??)

The agonist dose-response curve will be

shifted to the right (without a change in the

slope of the curve)

Maximal response occurs at a higher agonist

concentration than in the absence of the

antagonist

It primarily affects agonist potency

Clinically useful

Example: Prazosin at a adrenergic receptors

Agonist Antagonist +

Agonist

EC50A EC50B

Antagonists, 1-Competitive reversible antagonist

It binds to same site on receptor as agonist

inhibition can be overcome by increasing

agonist concentration (i.e., inhibition is

reversible)

No significant depression in maximal response

(Emax ??)

The agonist dose-response curve will be

shifted to the right (without a change in the

slope of the curve)

Maximal response occurs at a higher agonist

concentration than in the absence of the

antagonist

It primarily affects agonist potency

Clinically useful

Example: Prazosin at a adrenergic receptors

Antagonists, 2- Competitive irreversible antagonist

It binds to same site on receptor as agonist

The antagonist possesses reactive group

which forms covalent bond with the receptor

the antagonist dissociates very slowly, or

not at all

inhibition cannot be overcome by increasing

agonist concentration (i.e., inhibition is

irreversible)

Maximal response is depressed (i.e., Emax is

decreased)

The agonist dose-response curve will be shifted

to the right (the slope of the curve will be

reduced)

Agonist potency may or may not be affected

The only mechanism the body has for overcoming the block is to synthesize new receptors

Experimental tools for investigating receptor functions

Example: phenoxybenzamine at a adrenergic receptors

Competitive reversible antagonist vs Competitive irreversible antagonist

Antagonists, contd.

Antagonist Receptor

Antagonist-Receptor

Complex

DENIED!

Competitive Antagonists, In Motion

Antagonists, 3- Non-competitive antagonist It does not bind to the same receptor sites as

the agonist. It would either:

bind to a distinctly separate binding site from the

agonist decreased affinity of the receptor for the

agonist, ―allosteric inhibition‖, So, it prevents conformational changes in the

receptor required for receptor activation after the

agonist binds ―allosteric inhibition‖,

or alternatively block at some point the chain of

events that leads to the production of a response by

the agonist

Inhibition cannot be overcome by increasing

agonist concentration (irreversible)

Agonist maximal response will be depressed

Agonist dose-response curve will be shifted to

the right (the slope of the curve will be reduced)

Agonist potency may or may not be affected

Agonist

Antagonist

+ Agonist

Example: the noncompetitive antagonist action of crystal violet (CrV) on nicotinic

acetylcholine receptors is explained by an allosteric mechanism in which the binding

of CrV to the extracellular mouth of the resting receptor leads to an inhibition of

channel opening

Agonist Receptor

Antagonist

‘Inhibited’-Receptor DENIED!

Non-competitive Antagonist, In Motion

Antagonists, contd.

4. Physiologic (functional) antagonist

Physiologic antagonism occurs when the actions of two agonists working at

two different receptor types have opposing (antagonizing) actions

Example 1: Histamine acts at H1 receptors on bronchial smooth muscle to cause

bronchoconstriction, whereas adrenaline is an agonist at the β2 receptors bronchial

smooth muscle, which causes bronchodilation.

Example 2: histamine acts on receptors of the parietal cells of the gastric mucosa to

stimulate acid secretion, while omeprazole blocks this effect by inhibiting the proton

pump

5. Chemical antagonist

Chemical antagonism occurs when two substances combine in solution

the active drug is lost

Example : Chelating agents (e.g., dimercaprol) that bind heavy metals, and thus

reduce their toxicity

6. Pharmacokinetic antagonist

Pharmacokinetic antagonist effectively reduces the concentration of the

active drug at its site of action

Example: phenobarbital accelerates the rate of metabolic degradation of warfarin