• Specific molecules in a biologic system with which drugs
interact to produce changes in the function of the system.
• Receptors must be selective in their ligand-binding
• Receptors also must be modified as a result of binding an
agonist molecule (so as to bring about the functional change).
• Many receptors have been identified, purified, chemically
characterized, and cloned.
• The majority of the receptors characterized to date are
proteins; a few are other macromolecules such as DNA.
• The receptor site or recognition site for a drug is the specific
binding region of the macromolecule and has a high and
selective affinity for the drug molecule.
• The interaction of a drug with its receptor is the fundamental
event that initiates the action of the drug.
• Effectors are molecules that translate the drug-receptor
interaction into a change in cellular activity.
• The best examples of effectors are enzymes such as adenylyl
• Some receptors are also effectors in that a single molecule
may incorporate both the drug binding site and the effector
mechanism, eg, the tyrosine kinase effector of the insulin
receptor, or the sodium-potassium channel of the nicotinic
Graded Dose-Response Relationships:
• 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.
• Plotting the same data on semilogarithmic axes usually
results in a sigmoid curve, which simplifies the
mathematical manipulation of the dose-response data .
• The efficacy (Emax) and potency (ECs0) parameters are
derived from these data.
• The smaller the EC50, the greater the potency of the drug.
Quantal Dose-Response Relationships:
• 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.
• When plotted as the fraction of the population that responds
at each dose versus the log of the dose administered, a
cumulative quantal dose-response curve usually sigmoid in
shape, is obtained.
• The median effective (ED50), median toxic (TD50), and
median lethal doses (LD50) are extracted from experiments
carried out in this manner.
• Efficacy, often called maximal efficacy, is the maximal effect
(Emax) an agonist can produce if the dose is taken to very high
• Efficacy is determined mainly by the nature of the receptor
and its associated effector system.
• It can be measured with a graded dose-response curve but
not with a quantal dose-response curve.
• By definition, partial agonists have lower maximal efficacy
than full agonists.
• The amount of a drug needed to produce a given effect.
• In graded dose-response measurements, the effect usually chosen
is 50% of the maximal effect and the dose causing this effect is
called the EC50.
• Potency is determined mainly by the affinity of the receptor for the
• In quantal dose-response measurements ED50., TD50., and LD50
are typical potency variables (median effective, toxic, and lethal
doses, respectively, in 50% of the population studied).
• Thus. potency can be determined from either graded or quantal
dose-response curves, but the numbers obtained are not identical.
• Spare receptors are said to exist if the maximal drug response
is obtained at less than maximal occupation of the receptors.
• In practice, the determination is usually made by comparing
the concentration for 50% of maximal effect (EC50) with the
concentration for 50% of maximal binding (Kd).
• If the EC50 is less than the Kd, spare receptors are said to
• This might result from one of several mechanisms.
• First, the effect of the drug-receptor interaction may persist
for a much longer time than the interaction itself.
• Second, the actual number of receptors may exceed the
number of effector molecules available. The presence of spare
receptors increases sensitivity to the agonist because the
likelihood of a drug-receptor interaction increases in
proportion to the number of receptors available.
Inert Binding Sites:
• Inert binding sites are components of endogenous molecules
that bind a drug without initiating events leading to any of the
• In some compartments of the body (eg, the plasma), inert
binding sites play an important role in buffering the
concentration of a drug because bound drug does not
contribute directly to the concentration gradient that drives
• The two most important plasma proteins with significant
binding capacity are albumin and orosomucoid (a1-acid
Agonists and Partial Agonists:
• An agonist is a drug capable of fully activating the effector
system when it binds to the receptor.
• A partial agonist produces less than the full effect, even when
it has saturated the receptors.
• In the presence of a full agonist, a partial agonist acts as an
Competitive and Irreversible Pharmacologic
• Competitive antagonists are drugs that bind to the receptor in
a reversible way without activating the effector system for
• In the presence of a competitive antagonist, the log dose-
response curve is shifted to higher doses (ie, horizontally to
the right on the dose axis) but the same maximal effect is
• In contrast, an irreversible antagonist causes a downward shift
of the maximum, with no shift of the curve on the dose axis
unless spare receptors are present.
• The effects of competitive antagonists can be overcome by
adding more agonist.
• Irreversible antagonists cannot be overcome by adding more
• Competitive antagonists increase the ED50; irreversible
antagonists do not (unless spare receptors are present).
• A physiologic antagonist is a drug that binds to a different
receptor, producing an effect opposite to that produced
by the drug it is antagonizing.
• Thus it differs from a pharmacologic antagonist, which
interacts with the same receptor as the drug it is
• A common example is the antagonism of the
bronchoconstrictor action of histamine (mediated at
histamine receptors) by epinephrine's bronchodilator
action (mediated at beta adrenoceptors).
• A chemical antagonist is a drug that interacts directly with the
drug being antagonized to remove it or to prevent it from
reaching its target.
• A chemical antagonist does not depend on interaction with
the agonist's receptor (although such interaction may occur).
• A common example of a chemical antagonist is dimercaprol, a
chelator of lead and some other toxic metals.
• Pralidoxime, which combines avidly with the phosphorus in
organophosphate cholinesterase inhibitors, is another type of
Cholinesterase generator Enzyme active site
Therapeutic Index, Therapeutic Window:
• The therapeutic index is the ratio of the TD50 (or LD50) to the
ED50, determined from quantal dose-response curves.
• The therapeutic index represents an estimate of the safety of a
drug, since a very safe drug might be expected to have a very large
toxic dose and a small effective dose.
• Unfortunately, factors such as the varying slopes of dose-response
curves make this estimate a poor safety index.
• The therapeutic window, a more clinically relevant index of safety,
describes the dosage range between the minimum effective
therapeutic concentration or dose, and the minimum toxic
concentration or dose.
• For example, if the average minimum therapeutic plasma
concentration of theophylline is 8 mg/L and toxic effects are
observed at 18 mg/L, the therapeutic window is 8-18 mg/L.
The therapeutic index = TD50 (or LD50) / ED50
• Once an agonist drug has bound to its receptor, some effector
mechanism is activated.
• For most drug-receptor interactions, the drug is present in the
extracellular space while the effector mechanism resides
inside the cell and modifies some intracellular process.
• Thus, signaling across the membrane must occur.
• Five major types of transmembrane signaling mechanisms for
receptor-effector systems have been defined:
1. Receptors that are intracellular:
• 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.
• No specialized transmembrane signaling device is required.
2. Receptors located on membrane-spanning enzymes:
• Drugs that affect membrane-spanning enzymes combine with
a receptor on the extracellular portion of enzymes and modify
their intracellular activity.
• For example, insulin acts on a tyrosine kinase that is located in
• The insulin receptor site faces the extracellular environment
and the enzyme catalytic site is on the cytoplasmic side.
• When activated, the receptors dimerize and phosphorylate
specific protein substrates.
3. Receptors located on membrane-spanning molecules that bind
separate intracellular tyrosine kinase molecules:
A. Receptors have extracellular and intracellular domains and form
B. After receptor activation by an appropriate drug, the tyrosine
kinase molecules (,Janus kinases; JAKs) are activated, resulting in
phosphorylation of "STAT" molecules (signal transducers and
activators of transcription).
C. STAT dimers then travel to the nucleus, where they regulate
•Receptors exist as individual polypeptides
•Each has an extracellular signal-binding site
•An intracellular tail with a number of tyrosines
and a single a helix spanning the membrane
4. Receptors located on membrane ion channels:
• Receptors that regulate membrane ion channels may directly
cause the opening of an ion channel (eg, acetylcholine at the
nicotinic receptor) or modify the ion channel's response to
other agents (eg, benzodiazepines at the GABA channel).
• The result is a change in transmembrane electrical potential.
Ion channel receptors
•Protein pores in the
5. Receptors linked to effectors via G proteins:
• A very large number of drugs bind to receptors that
are linked by coupling proteins to intracellular or
• The best defined examples of this group are the
sympathomimetic drugs, which activate or inhibit
adenylyl cyclase by a multistep process:
– activation of the receptor by the drug results in
activation of G proteins that either stimulate or
inhibit the cyclase.
G protein-linked receptors
•Single polypeptide chain
threaded back and forth
resulting in 7 transmembrane a
•There’s a G protein attached to
the cytoplasmic side of the
membrane (functions as a
More than 20 types of G proteins have been identified;
three of the most important are listed in this table.
1. enzyme linked
2. ion channel linked
3. G protein linked
4. nuclear (gene) linked