Pharmacodynamics

Mechanisms of Action of Drugs

DRUG TARGET SITES
RECEPTORS

• Are the specific molecules in a biologic

• system with which drugs interact to produce changes in
the function of the system.

• Must be selective in their ligand-binding characteristics

• must also be modifiable when they bind a drug molecule

The receptor site (the recognition site) for a drug

is the specific binding region of the receptor
macromolecule and has a relatively high and selective
affinity for the drug molecule.

• Many drugs are classified on the basis of their primary

receptor affinity.
• EFFECTORS are molecules that translate the
drug–receptor interaction into a change in
cellular activity.

OR
• Component of a system that accomplishes
the biologic effect after the receptor is
activated by an agonist; often a channel or
enzyme molecule

• The best examples of effectors are enzymes

such as adenylyl cyclase.
RECEPTORS SITES FOR DRUGS/LIGANDS BINDING
 EFFICACY or Emax

• Often called maximal efficacy—is the

greatest effect (Emax) an agonist can
produce if the dose is taken to very high
levels.

• Partial agonists have lower maximal

efficacy than full agonists .
 POTENCY

• OR
• The amount of drug needed to produce a
given effect.

• The effect/response usually chosen is 50%

of the maximal effect and the dose causing
this effect is called the EC50
 GRADED DOSE-RESPONSE
RELATIONSHIPS
• A graph of increasing response to increasing drug concentration or dose

• When the response of a particular receptor-effector system is measured

against increasing concentrations of a drug, the graph of the response
versus the drug concentration or dose is called a graded dose-response
curve

• The efficacy (Emax ) and potency (EC50 or ED50 ) parameters are

derived from these data..

• The smaller the EC50 (or ED50 ), the greater the potency of the drug.
GRADED DOSE-RESPONSE RELATIONSHIPS
 QUANTAL DOSE-RESPONSE
RELATIONSHIPS
• A graph of the fraction of a population that shows a specified response at
progressively increasing doses

• 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

• The median effective (ED50), median toxic (TD 50), and (in animals) median
lethal (LD50) doses are derived from experiments carried out in this manner.

• Quantal dose-response data provide information about the variation in sensitivity

to the drug in a given population, and if the variation is small, the curve is steep.
In Quantal dose-response measurements,

ED50 (median effective dose), TD 50 (median toxic dose) and

LD50 (median lethal dose )are also potency variables, in 50%
of the population studied.

• Unlike the graded dose-response determination, no attempt

is made to determine the maximal effect of the drug.

• Thus, potency can be determined from either Graded or

Quantal dose-response curves, but the numbers obtained
are not identical.
QUANTAL DOSE-RESPONSE RELATIONSHIPS
 Therapeutic index (TI) of a Drug
•is the ratio of the dose that produces toxicity in half the population (TD50) to the dose
that produces a clinically desired or effective response (ED50) in half the population

• TI = TD 50

ED50

•Represents an estimate of the safety of a drug, because a very safe drug might be
expected to have a very large toxic dose and a much smaller effective dose.

Therapeutic window:

• A more clinically useful index of safety

•Describes the dosage range between the minimum effective therapeutic concentration /
dose, and the minimum toxic concentration/ dose.
 ANTAGONISTS
Competitive Pharmacologic Antagonists
• are the drugs that bind to, or very close to, the agonist receptor site in
a reversible way without activating the effector system for that
receptor.

• In the presence of a competitive antagonist, the log dose-response

curve for an agonist is shifted to higher doses (ie, horizontally to the
right on the dose axis), but the same maximal effect is reached .

• The agonist, if given in a high enough concentration, can displace the

antagonist and fully activate the receptors.

• Unlike the effects of a competitive antagonist, the effects of an

irreversible antagonist cannot be overcome by adding more agonist.
 Allosteric antagonists

• Do not bind to the agonist receptor site, they bind to some other
region of the receptor molecule that results in inhibition of the
response to agonists .

• They do not prevent binding of the agonist.

• In contrast, pharmacologic antagonists bind to the agonist site and

prevent access of the agonist.

• High concentrations of agonist displace or prevent the binding of a

pharmacologic antagonist but not an allosteric antagonist.

• A noncompetitive antagonist that acts at an allosteric site of the

receptor may bind reversibly or irreversibly; a noncompetitive
antagonist that acts at the receptor site binds irreversibly.
 Physiologic Antagonists
• Binds to a different receptor molecule, producing
an effect opposite to that produced by the drug it
antagonizes.

Example of a physiologic antagonist

• The antagonism of the bronchoconstrictor action

of histamine (mediated at histamine receptors)
by epinephrine's bronchodilator action (mediated
at adrenoceptors).
 Chemical Antagonists
• Interacts directly with the drug being antagonized to
remove it or to prevent it from binding to its target.
• A chemical antagonist does not depend on interaction with
the agonist's receptor (although such interaction may
occur).

Examples of a chemical antagonist

• Dimercaprol, a chelator of lead and some other toxic

metals.

• Pralidoxime, which combines avidly with the phosphorus

in organophosphate cholinesterase inhibitors(insecticides).
 Signaling Mechanisms and receptors
These are the molecular mechanisms by which a drug acts and represent the classic
drug–receptor interactions and involve signaling across the membrane.

Types of transmembrane-signaling mechanisms for receptor-effector systems

(1)Intracellular Receptors for Lipid-Soluble Agents

(2)Membrane-spanning receptor- effector enzymes

(3)Receptors Located on Membrane-Spanning Molecules That Bind Separate

Intracellular Tyrosine Kinase Molecules (Janus kinases; JAKs)
(4)Receptors Located on Membrane Ion Channels
OR
Ligand-activated or modulated membrane ion channels

(5)Receptors Linked to Effectors via G Proteins

 Intracellular Receptors for Lipid-Soluble Agents (often steroid
receptor-like)

• Some drugs, especially more lipid-soluble or

diffusible agents (eg, steroid hormones, nitric oxide),

• may cross the membrane and combine with an

intracellular receptor that affects an intracellular
effector molecule.

• The receptor and effector may or may not be the

same molecule, but no specialized trans-membrane
signaling device is required.
Receptors That Are Intracellular
Membrane-spanning receptor- effector enzymes

• A transmembrane receptor that binds and stimulates a protein tyrosine kinase

• Drugs that affect membrane-spanning enzymes combine with a receptor site

on the extracellular portion of the molecule and modify its intracellular activity.

• For example,
Insulin acts on a tyrosine kinase that is located in the membrane.
The insulin receptor site faces the extracellular environment, and the effector
enzyme catalytic site is on the cytoplasmic side.

When activated, such receptors dimerize and phosphorylate specific intracellular

protein substrates.
Receptors Located on Membrane-
Spanning Enzymes,eg.Insulin receptor
Receptors Located on Membrane-Spanning Molecules
That Bind Separate Intracellular Tyrosine Kinase
Molecules (Janus kinases; JAKs)
• Also known as cytokine receptors, these receptors have
and intracellular domains and form dimers.

• However, after receptor activation by an appropriate drug

(often a cytokine) at the extracellular receptor site,
associated but separate tyrosine kinase molecules (Janus
kinases; JAKs) are activated,

• resulting in phosphorylation of STAT molecules (signal

transducers and activators of transcription).

• STAT dimers (the effectors) then travel to the nucleus,

where they regulate transcription.
 Receptors Located on Membrane Ion Channels
OR
Ligand-activated or modulated membrane ion channels

• Receptors that regulate membrane ion channels may

directly cause the opening of the channel (eg,
acetylcholine at the nicotinic receptor)
or
• Modify the ion channel's response to other agents (eg,
benzodiazepines at the GABA activated chloride
channel).

• The channel molecule acts as both receptor and effector,

and the result is a change in transmembrane electrical
potential.
 Receptors Linked to Effectors via G Proteins

Activation of these receptor by the drug results in activation of separate

coupling G proteins (located in the intracellular face of the membrane),

• which either stimulate or inhibit the cyclase. Thus, the receptor and
effector are linked through the G-coupling protein.

• The best-defined examples of this group are the sympathomimetic drugs

• which activate or inhibit adenylyl cyclase (formerly called adenylate
cyclase) by a multistep process

• Many types of G proteins have been identified; 3 of the most important

are :
• Gs,
• Gi and
• Gq
Gq LINKED Phosholipase C activation
 RECEPTOR REGULATION

• Receptors are dynamically

regulated in number, location,
and interaction with other
molecules.

• Tachyphylaxis.
• Frequent or continuous
exposure to agonists often
results in short-term diminution
of the response, sometimes
called tachyphylaxis.
• Example is continuous use of
nitroglycerin results in loss of
response
 RECEPTOR REGULATION

• Down regulation of receptors:

• Long-term reductions in receptor number may
occur in response to continuous exposure to
agonists.

• Up-regulation of receptors:
• When receptor activation is blocked for
prolonged periods (usually several days) by
pharmacologic antagonists or by denervation.