DRUG RECEPTOR

Yuandani
LEARNING OBJECTIVES

Will be able to explain:

 Definition of Drug and Receptor

 Theory of Receptor

 Drug-Receptor Interaction

 Concept of agonist and antagonist

SUBTOPICS

 Definition
 Concept of Receptor
 Theory of Receptor
 Drug-Receptor Interaction
 Concept of Agonist and Antagonist
DEFINITION
DRUG

any substance that brings about a change in biologic

function through its chemical actions

RECEPTOR

The component of a cell or organism that interacts with a

drug and initiates the chain of events leading to the drug’s
observed effects.
Sources of Drugs
Natural Sources of Drug

Drugs have been obtained from:

 Plants : alkaloids (morphine, cocaine, atropine, and
quinine)
 Microbes : Antibiotics, isolated Penicillium and
Streptomyces species
 Animal tissues: Hormones
 Minerals :lithium compounds
Synthetic Drugs
 Aspirin,
 barbiturates, and
 local anesthetics (e.g.,procaine)
were among the first drugs to be synthesized in the
laboratory.

To interact chemically with its receptor, a drug molecule

must have:
the appropriate size, electrical charge, shape, and atomic
composition
MACROMOLECULAR NATURE OF DRUG
RECEPTORS

 “orphan” receptors
their ligands are presently unknown, which may prove to
be useful targets for the development of new drugs.

 regulatory proteins
which mediate the actions of endogenous chemical signals
such as neurotransmitters, autacoids, and hormones.
This class of receptors mediates the effects of many of
the most useful therapeutic agents.
 enzymes
which may be inhibited or activated by binding a drug

 transport proteins
eg, Na + /K + -ATPase, the membrane receptor for
cardioactive digitalis glycosides

 structural proteins
tubulin, the receptor for colchicine, an anti-inflammatory
agent
RECEPTOR CONCEPT

 Receptors largely determine the quantitative

relations between dose or concentration of drug
and pharmacologic effects

 Receptors are responsible for selectivity of drug

action

 Receptors mediate the actions of pharmacologic

agonists and antagonists
Type of receptor

A. Intracellular Receptor B. Ligand-gated Ion Channel

Type of receptor

C. G-Protein Coupled Receptor D. Metabophores

Drug-Receptor Theories
 Lock and Key Hypothesis

The drug molecule must fit into the receptor

like a key fits into the lock
Drug-Receptor Theories
 Hypothesis of Clark

The Pharmacologic effect of the drug

depends on the percentage of the receptors
occupied

If receptors are occupied, maximum effect is obtained.

Chemical binding follow the Law of Mass Action.
When a drug (D) combines with a receptor (R), it does so at a rate
which is dependent on the concentration of the drug and the
concentration of the receptor.
drug bound to receptors (B) relates to the concentration of free
(unbound) drug (C)
 Hypothesis of Ariens and Stephenson
Effectiveness of a drug lasts as long as the receptor is
occupied.
Many substance possess different effect ,
some have high affinity for the receptor,
some have low affinity and some are not
effective,
and those ineffective substances block or inhibit
the receptor Occupation Theory
 Hypothesis of Paton
Effectiveness of a drug does not depend on
the actual occupation of the receptor but by
obtaining proper stimulus

Rate Theory
•Agonist or stimulant activity is proportional to the rate of drug-receptor
combination rather than the number of occupied receptors
•Agonist activity is the result of a series of rapid association and
dissociation of the drug and the receptor
•An antagonist has a high association rate but a low rate of dissociation
Drug-Receptor Interactions

 Most of the drugs act by interacting with a cellular

component called receptor.

 Some drugs act through simple physical or chemical

reactions without interacting with any receptor.
 Affinity:
ability of a drug to bind to a receptor
pharmacological
 Efficacy (intrinsic activity): response
ability of a drug to change the receptor
conformation to produce a response.

 Occupancy:
fraction of receptors occupied to the
total number of receptors

So, a pharmacological response

depends on the affinity and efficacy.
Types of Drug-Receptor Interactions
(Concept of Agonist and Antagonist)

Agonist

drugs bind to and activate the receptor

in some fashion, which directly or indirectly
brings about the effect

 Receptor activation involves a change in conformation

Two classes of Agonist
Based on the maximal pharmacologic response that occurs
when all receptors are occupied,
agonists can be divided into two classes:

Full Agonist

AGONIST
Partial Agonist
Full Agonist

 Agonist drugs, when administered at

concentrations sufficient to saturate the
receptor pool, can activate their receptor-
effector systems to the maximum extent of
which the system is capable;
 Full agonist drugs have both high affinity
and high efficacy .
Partial Agonist

 bind to the receptors and activate them in the same way

but do not evoke as great a response, no matter how high
the concentration
 having low intrinsic efficacy
 produce a lower response, at full receptor occupancy
 Partial agonist drugs possess weak efficacy even at 100%
occupancy, producing only submaximal tissue response
 When a partial agonist competes with a full agonist to the
receptor, the partial agonist will act as a competiive
antagonist, because it will decrease the efficacy of the
agonist alone.
Partial and Full Agonist
occupancy of all the receptors by the partial agonist produces a
lower maximal response than does similar occupancy by the full
agonist.
Antagonist

by binding to a receptor, compete with and

prevent binding by other molecules;
do not activate generation of a signal;

 The primary action of antagonists is to prevent agonists (other

drugs or endogenous regulatory molecules) from activating
receptors.
 For example, acetylcholine receptor blockers such as atropine
 Antagonist drugs have appreciable receptor affinity but zero
efficacies
 Two classes of Antagonist

Competitive
Antagonist
Pharmacologic
ANTAGONIST
Irreversible
Antagonists
Competitive Antagonist
 In the presence of a fixed concentration of agonist, increasing
concentrations of a reversible competitive antagonist
progressively inhibit the agonist response; high antagonist
concentrations prevent response completely.
 Conversely, sufficiently high concentrations of agonist can
surmount the effect of a given concentration of the antagonist.
 Because the antagonism is competitive, the presence of
antagonist increases the agonist concentration required for a
given degree of response, and so the agonist
concentrationeffect curve is shifted to the right
 Most antagonistic drugs are competitive
Competitive Antagonist

 The Emax for the

agonist remains the
same for any fixed
concentration of
antagonist
 The presence of
antagonist will
increase the ED50 of
the agonist
Irreversible Antagonist

 Some receptor antagonists bind to the receptor in an

irreversible, either by forming a covalent bond with the
receptor or by binding so tightly that, for practical
purposes, the receptor is unavailable for binding of
agonist.
 After occupancy of some proportion of receptors by
such an antagonist, the number of remaining unoccupied
receptors may be too low for the agonist (even at high
concentrations) to elicit a response comparable to the
previous maximal response
Irreversible Antagonist

 The presence of noncompetitive

antagonist will decrease the Emax of
the agonist
 No change in ED50 of the agonist
 Therapeutic advantages and disadvantages:
 Advantages:
the ability to prevent responses to varying and high
concentrations of agonist
 Disadvantages
If overdose occurs, however, a real problem may arise
 Example:
Phenoxybenzamine (an irreversible α-adrenoceptor antagonist)
Other Mechanisms of Drug Antagonism
 chemical antagonist
by ionic binding that makes the other drug unavailable for
interactions with proteins involved in blood clotting.
example: protamine counteract the effects of heparin

 physiologic antagonism
It occurs between endogenous regulatory pathways
mediated by different receptors
example: glucocorticoid hormone >< insulin
Allosteric

Drugs that bind to the same receptor molecule but do not

prevent binding of the agonist are said to act allosterically
and may enhance or inhibit the action of the agonist
molecule
 Allosteric inhibition is not overcome by increasing the
dose of agonist.
Agonist

Lock and key mechanism

Agonist Receptor

Agonist-Receptor
Interaction
Antagonist

Antagonist Receptor

Antagonist-Receptor
DENIED!
Complex
Competitive and Irreversible Antagonist