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Describes the actions of the drug on the body
Influence of drug concentrations on the magnitude of the response
1. A biologic molecule to which a drug binds to bring about a change in function of the biologic
2. It is a specific drug-binding site in a cell or on its surface that mediates drug action.
Nature of drug receptors
1. Regulatory proteins that mediate actions of neurotransmitters, autacoids or hormones
2. Enzymes, e.g. dihydrofolate reductase
3. Transport proteins, e.g. Na+-K+-ATPase
4. Structural proteins, e.g. tubulin
Note: some drugs, e.g. mannitol, do not have a specific receptor.
Major receptor families
Richest sources of therapeutically exploitable pharmacologic receptors are proteins that are
responsible for transducing extracellular signals into intracellular responses. These receptors may
be divided into four families:
1. Ligand-gated ion channels
2. G protein-coupled receptors
3. Enzyme-linked receptors
4. Intracellular receptors
1. Transmembrane ligand-gated ion channels
a) Responsible for the regulation of the flow of ions across cell membranes
b) Activity of these channels regulated by the binding of a ligand to the channel
c) Response is very rapid, enduring for a few milliseconds
d) Receptors mediate diverse functions, including neurotransmission, cardiac
conduction, and muscle contraction
e) For e.g., stimulation of nicotinic receptor by ACh results in sodium influx, generation
of an action potential, and activation of contraction in skeletal muscle
f) Benzodiazepines, on the other hand, enhance stimulation of γ-aminobutyric acid
(GABA) receptor by GABA, resulting in increased chloride influx and
hyperpolarization of the respective cell.
g) Ion-channels such as the voltage-gated sodium channels are important drug receptors
for several drug classes, including local anesthetics.
2. Transmembrane G protein-coupled receptors
a) Consists of G protein-coupled receptors.
Gs β-adrenergic amines
Adenylyl cyclase → ↑ cAMP (2nd messenger) →
vasoconstriction of smooth muscle blood vessels →
Gi α2-adrenergic amines
Adenylyl cyclase → ↑ cAMP (2nd messenger) → open
K+ channels → ↓ heart rate
↑ Ca2+ released from storage vesicles
→ binds with calmodulin → ↑ Ca2+ dependent protein
3. Enzyme-linked receptors
a) Consists of a protein that spans once and may form dimers or multi-subunit
b) Also have cytosolic enzyme activity as an integral component of their structure and
c) Binding of a ligand to an extracellular domain activates or inhibits this cytosolic
d) Duration of responses to the stimulation of these receptors is on the order of minutes
e) Metabolism, growth, and differentiation are important biological functions controlled
by these types of receptors.
4. Intracellular receptors
a) The receptor is entirely intracellular, therefore, the ligand must diffuse into the cell to
interact with the receptor.
b) Ligand must have sufficient lipid solubility to be able to move across the target cell
membrane. Because the receptor ligands are lipid-soluble, they are transported in the
body attached to plasma proteins such as albumin.
c) Primary targets of these ligand-receptor complexes are transcription factors. The
activation or inactivation of these factors causes the transcription of DNA into RNA
and translation of RNA into an array of proteins.
d) For e.g., steroid hormones exert their action on target cells via this receptor
e) The time course of activation and response of these receptors is much longer than that
of the other mechanisms described above.
Regulation of receptors:
1. Down-regulation (desensitization):
in this, number of receptors is decreased.
in this, number of receptors is increased.
When maximal response can be elicited by an agonist at a conc. that does not result in
occupancy of all available receptors, the receptors that are not occupied are called spare
Spare receptors are neither hidden nor unavailable. They are simply not occupied because
maximum response can be achieved by occupying less number of receptors.
Ability of a drug to bind to a receptor.
Ability of the drug to elicit a response after binding to a receptor.
Quantal dose-response relationships
A graph of the fraction of a population that shows a specified response at progressively
When the minimum dose required to produce a specified response is determined in each
member of a population, the quantal dose-response relationship is defined.
EC50, ED50, TD50, etc.:
Median effective (ED50), median toxic (TD50), and (in animals), median lethal (LD50)
In graded dose-response curves, the concentration or dose that causes 50% of the maximal
effect or toxicity. In quantal dose-response curves, the concentration or dose that causes a
specified response in 50% of the population under study
Often called maximal efficacy, is the greatest effect an agonist can produce if the dose is
taken to the highest tolerated level.
Determined mainly by the nature of the drug, and the receptor and its associated effector
Can be measure with a graded dose-response curve but not with a quantal dose-response
Partial agonists have lower maximal efficacy than full agonists.
Denotes amount of drug needed to produce a given effect.
Potency is determined mainly by the affinity of the receptor for the drug and the number of
In graded dose-response measurements, the effect usually chosen is 50% of the maximal
effect and the concentration or dose causing this effect is called EC50 or ED50.
In quantal dose-response measurements, ED50, TD50, and LD50 are also potency variables
(median effective, toxic, and lethal doses, respectively, in 50% of the population studied).
Potency can thus be determined from graded or quantal dose-response curves, but the
numbers obtained are not identical.
A drug that binds to a receptor and produces a biologic response.
Drug capable of fully activating the effector system when it binds to the receptor.
Drugs occupying the receptor can stabilize the receptor in a given conformational state, that
is, in the active or inactive state
For e.g., phenylephrine is an agonist of α1-adrenoreceptors, because it produces the effects
that resemble the action of the endogenous ligand, norepinephrine. Upon binding to α1adrenoreceptors on the membranes of vascular smooth muscle, phenylephrine stabilizes the
receptor in its active state. This leads to mobilization of intracellular Ca2+, causing interaction
of the smooth muscle actin and myosin. Shortening of muscle cells decreases diameter of
arteriole, causing increase in blood pressure. In general, a full agonist has a strong affinity
for its receptor and good efficacy.
A drug that binds to its receptor but produces a smaller effect at full dosage than a full
Partial agonists have efficacies (intrinsic activities) greater than zero but less than that of a
Even if all the receptors are occupied, partial agonists cannot produce an Emax of as great a
magnitude as that of a full agonist.
It may have an affinity which is greater than, less than, or equivalent to that of a full agonist.
Under appropriate conditions, a partial agonist may act as an antagonist of a full agonist.
For e.g., consider what would happen to the Emax of a receptor saturated with a full agonist in
the presence of increasing concentrations of partial agonist. As the number of receptors
occupied by the partial agonist increases, the Emax would decrease until it reached the Emax of
the partial agonist.
The potential of partial agonist to act both as an agonist and antagonist can be fully exploited.
For e.g., aripiprazole, an atypical neuroleptic agent, is a partial agonist at selected dopamine
receptors. As a result, dopaminergic pathways that were overactive tend to be inhibited by
the partial agonist, whereas pathways that were underactive may be stimulated. This might
explain the ability of aripiprazole to improve many symptoms of schizophrenia, with a small
risk of causing extrapyramidal adverse effects.
A drug that binds to the inactive state of receptor molecules and decreases constitutive
activity. (Activity in the absence of a ligand is called constitutive activity.)
Usually, unbound receptors are inactive and require interaction by an agonist to assume an
However, some receptors show spontaneous conversion from inactive to active state in the
absence of agonist. These receptors thus show constitutive activity.
Inverse agonists, unlike full agonists, stabilize the inactive form of the receptors. All of the
constitutively active receptors are forced to remain inactive in the presence of an inverse
This decreases number of activated receptors to below that observed in the absence of a drug.
Thus, inverse agonists reverse the constitutive activity of receptors and exert the opposite
pharmacological effect of receptor agonists.
Drugs that decrease or oppose the actions of another drug or endogenous ligand.
Has no effect if an agonist is not present.
Many antagonists act on the identical receptor macromolecule as the agonist.
Antagonist, however, have no intrinsic activity. They are still able to bind avidly to target
receptors because they possess strong affinity.
A pharmacologic antagonist that can be overcome by increasing the concentration of agonist.
If both antagonist and agonist bind to the same site, they are said to be “competitive”.
The competitive antagonist will prevent the agonist from binding to its receptor and maintain
the receptor in the inactive state.
A pharmacologic antagonist that cannot be overcome by increasing the concentration of the
The effects of competitive antagonists can be overcome by increasing the concentration of
the agonist. In contrast, the effects of irreversible antagonist cannot be overcome with
increasing the agonist concentration.
Competitive antagonists increase ED50, whereas irreversible antagonists do not (unless spare
receptors are present).
The antagonist can bind covalently or with very high affinity to the active site of the receptor
(irreversible antagonist). This irreversibility in binding to the active site reduces the amount
of receptors available to the agonist.
The second type of antagonist binds to a site (“allosteric site”) other than the agonist binding
site. This allosteric antagonist prevents the receptor from being activated even when the
agonist is attached to the active site.
Competitive antagonists reduce agonist potency, whereas noncompetitive antagonists reduce
Functional (physiological) and chemical antagonism
Functional antagonism: a drug that counters the effect of another by binding to a different
receptor and causing opposite effects.
A classic example is the functional antagonism by epinephrine to histamine-induced
bronchoconstriction. Histamine binds to H1 histamine receptor on bronchial smooth muscle,
causing contraction and narrowing of the bronchial tree. Epinephrine is an agonist at β2adrenoceptors on bronchial smooth muscle, which causes the muscles to actively relax.
Chemical antagonism: a drug that counters the effects of another by binding the agonist drug
(not the receptor).
For e.g., protamine sulfate is a chemical antagonist for heparin. It is a basic (positively
charged) protein that binds to the acidic heparin (negatively charged), rapidly preventing its
therapeutic as well as toxic effects.
Allosteric agonist / antagonist
A drug that binds to the receptor molecule without interfering with normal agonist binding but
alters the response to the normal agonist.