Pharmacodynamics

PHARMACODYNAMIC CONCEPTS
Receptors:
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 ligandbinding characteristics.
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:
Effectors are molecules that translate the drugreceptor interaction into a change in cellular activity.
The best examples of effectors are enzymes such as
adenylyl cyclase.
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 sodiumpotassium channel of the nicotinic acetylcholine
receptor.

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:
Efficacy, often called maximal efficacy, is the
maximal effect (Emax) an agonist can produce if
the dose is taken to very high levels.
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.

:Potency
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 drug.
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
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 exist.

 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 drug's effects.
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 diffusion.
The two most important plasma proteins with
significant binding capacity are albumin and
orosomucoid (1-acid glycoprotein).

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 inhibitor.

Competitive and Irreversible

Pharmacologic Antagonists:
Competitive antagonists are drugs that bind to
the receptor in a reversible way without
activating the effector system for that receptor.
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 reached.

 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 agonist.
Competitive antagonists increase the ED50; irreversible
antagonists do not (unless spare receptors are present).

ED50

:Physiologic Antagonists
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 inhibiting.
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).

Chemical Antagonists:
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 chemical antagonist.

Pralidoxime
Cholinesterase generator
Chemical antagonist

Nerve Agents
Organophosphate insecticides
Cholinesterase inhibitors
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 doseresponse 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

= 150/3
= 50

Signaling Mechanisms:
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 membrane.
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 dimers.
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 transcription.

Tyrosinekinasereceptors
Structure:
Receptorsexistasindividualpolypeptides
Eachhasanextracellularsignalbindingsite
Anintracellulartailwithanumberoftyrosines
andasinglehelixspanningthemembrane

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.

Ionchannelreceptors
Structure:
Proteinporesinthe
plasmamembrane

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 membrane effectors.
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.

Gproteinlinkedreceptors
Structure:
Singlepolypeptidechain
threadedbackandforth
resultingin7transmembrane
helices
TheresaGproteinattachedto
thecytoplasmicsideofthe
membrane(functionsasa
switch).

More than 20 types of G proteins have been identified;

three of the most important are listed in this table.

Signal transduction
1.

enzyme linked
(multiple actions)

2.

ion channel linked

(speedy)

3. G protein linked
(amplifier)

4. nuclear (gene) linked

(long lasting)