PHARMACODYNAMICS

Pharmacodynamics denotes the action of a drug on biologic

systems, including receptor interactions, dose-response
phenomena, and mechanisms of therapeutic and toxic actions;

whereas pharmacokinetics describes the actions of the

biologic system on the drug, including absorption, distribution,
metabolism and elimination.

Biodisposition is a term sometimes used to describe

the processes of metabolism and excretion.

So, drugs are substances that act on

biologic systems at the chemical
(molecular) level and alter their
functions. Drugs actions are mediated
through the effects of drug molecules
on drug-receptors in the body.

Drug
receptors

the
molecular
components of the body with which drugs
interact to bring about their effects.

Most receptors are proteins, that are

responsible for transducing extracellular
signals into intracellular responses.

Receptor site (recognition site) specific region of the

receptor macromolecule to which the drug binds and has a
relatively high and selective affinity for the drug molecule.

Inert binding molecule or site a molecule to which a

drug may bind without changing any function.

Effectors (second messenger) are molecules that

translate the drug-receptor interaction into a change in
cellular activity (or cellular response); often a channel or
enzyme molecule. The best examples of effectors are
enzymes such as adenylyl cyclase; a tyrosine kinase effector
is part of the receptor molecule.

SIGNALING MECHANISMS
Once an agonist drug has bound to its receptor, some effector
mechanism is activated. For the largest group of drugreceptor interactions, the drug is present in the
extracellular space while the effector mechanism resides
inside the cell and modifies some intracellular process by
transmembrane signaling.

Five major signaling mechanisms are recognized:

1.receptors that are intracellular (example, steroid receptors);
2.receptors
located on membrane spanning enzymes
transmembrane enzyme-linked receptors);

(or

Known transmembrane signaling mechanisms: 1: A lipid-soluble chemical signal crosses the plasma
membrane and acts on an intracellular receptor (which may be an enzyme or a regulator of gene
transcription); 2: the signal binds to the extracellular domain of a transmembrane protein, thereby
activating an enzymatic activity of its cytoplasmic domain; 3: the signal binds to the extracellular
domain of a transmembrane receptor bound to a separate protein tyrosine kinase, which it activates; 4:
the signal binds to and directly regulates the opening of an ion channel; 5: the signal binds to a cellsurface receptor linked to an effector enzyme by a G protein.

3. receptors located on membrane spanning molecules that

bind separate intracellular tyrosine kinase molecules
(insulin receptors);
4. receptors located on membrane ion channels (example,
GABA-receptor for benzodiazepines, nicotinic receptors for
acetylcholine, sodium-channels for local anesthetics);
5. receptors linked to effectors via G proteins
(or Gprotein-coupled
receptors)

example
and
adrenoceptors. G proteincoupled receptors are the most
abundant type of receptors, and their activation accounts for
the actions of most therapeutic agents. Important processes
mediated by G-proteincoupled receptors include neurotransmission, olfaction, and vision.

Agonist a drug that

activates its receptor upon
binding.

A full agonist - is a drug

capable of fully activating
the effector system (or
drug produces a maximal
biologic response) when it
binds to the receptor.
In general, a full agonist has
a strong affinity for its
receptor and good efficacy.

 Antagonist

- if drug-receptor binding
results in inhibition of the receptor,
the drug is termed an antagonist, that
is antagonists are drugs that decrease
or oppose the actions of another drug
or endogenous ligand. An antagonist
has no effect if an agonist is not
present. Many antagonists act on the
identical receptor macromolecule as
the agonist.

Partial

agonist - A drug that binds to

its receptor but produces a smaller
effect at full dosage than the full
agonist. That is, partial agonists have
efficacies greater than zero but less
than that of a full agonists. A unique
feature of these drugs is that, in the
presence of a full agonist, a partial
agonist
acts
as
an
inhibitor

(nalorphine in the presence of

morphine).

Pharmacologic
antagonist - a drug that
binds without activating
its receptor and thereby
prevents activation by an
agonist.
Competitive antagonist
- If both the antagonist and the
agonist bind to the same site on
the receptor, they are said to be
competitive. The competitive
antagonist will prevent an agonist
from binding to its receptor and
maintain the receptor in its
inactive conformational state. For
example,
the
antihypertensive
drug terazosin competes with the
endogenous
ligand,
norepinephrine,
at
1adrenoceptors, thus decreasing
vascular smooth muscle tone and

Thus, they are drugs (competitive antagonists) that bind 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 maximal
response of the agonist can be obtained by increasing the
amount of agonist administered. So, a pharmacologic
antagonist can be overcome by increasing the
concentration of agonist.

Irreversible
(noncompetetive)
antagonist
A
pharmacologic antagonist that cannot be overcome by
increasing agonist concentration. In the presence of the
noncompetitive antagonist, a maximal response is not
observed even with increasing dose of the agonist.
Physiologic (functional) antagonist - A drug that
counters the effects of another by binding to a different
receptor and causing opposing effects. A familiar example
of physiologic antagonist is the antagonism of the
bronchoconstrictor action of histamine (histamine receptor)
by epinephrines bronchodilator action (mediated at adrenoceptors).
Chemical antagonist - A drug that counters the effects of
another by binding the agonist drug (not the receptor). A
chemical antagonist interacts directly with the drug. For
instance, pralidoxime combines with the phosphorus in
organophosphate cholinesterase inhibitors, and protamine
sulfate is a chemical antagonist for heparin.

Allosteric agonist, antagonist - A drug that binds to

a receptor molecule without interfering with normal
agonist binding but alters the response to the normal
agonist. Thus, if the antagonist binds to a site other
than where the agonist binds, the interaction is
allosteric (or physiologic).
So, an agonist is defined as an agent that can bind to a
receptor and elicit a biologic response. An agonist
usually mimics the action of the original endogenous
ligand on the receptor such as norepinephrine on
1-receptors of the heart.
The magnitude of the drug effect depends on the drug
concentration at the receptor site, which, in turn, is
determined by both the dose of drug administered and
by the drugs pharmacokinetic profile, such as rate of
absorption, distribution, metabolism, and elimination.

RECEPTOR REGULATION

Receptors are dynamically regulated in number, location, and

sensitivity. Changes can occur over short times (minutes) and
longer periods (days).

Repeated or continuous administration of an agonist (or an

antagonist) may lead to changes in the responsiveness of the
receptor. Frequent or continuous exposure to agonists often
result in short-term diminution of the receptor response,
sometimes called TACHYPHYLAXIS. The receptor becomes
desensitized to the action of the drug.

Long-term

reductions
in
receptor
number
(downregulation) may also occur in response to continuous
exposure to agonists. The opposite change upregulation
inductions in receptor number, occurs when receptor
activation is blocked for prolonged periods (usually several
days) by pharmacologic antagonists or by denervation.

GRADED DOSERESPONSE RELATIONS

As the concentration of a drug increases, the magnitude of its
pharmacologic effect also increases. Plotting the magnitude of
the response against increasing doses of a drug produces a
graph, the graded doseresponse curve, that provides
information about the nature of the drug-receptor
interaction.

Graded doseresponse curve A graph of

increasing response to increasing drug
concentration or dose .
The effect of dose on the magnitude of pharmacologic
response.
EC50 = drug dose that shows 50 percent of maximal
response

TWO IMPORTANT PROPERTIES OF DRUGS, POTENCY AND EFFICACY, CAN BE

DETERMINED BY GRADED DOSERESPONSE CURVES.
THE FIRST PROPERTY IS POTENCY, A MEASURE OF THE AMOUNT OF DRUG
NECESSARY TO PRODUCE AN EFFECT OF A GIVEN MAGNITUDE. THAT IS, THE
CONCENTRATION OF DRUG PRODUCING AN EFFECT THAT IS 50 PERCENT OF THE
MAXIMUM IS USED TO DETERMINE POTENCY AND IS COMMONLY DESIGNATED AS THE
EC50.

IN

FIGURE, THE EC50 FOR DRUGS A AND B ARE INDICATED. DRUG A IS MORE POTENT
THAN DRUG B, BECAUSE A LESSER AMOUNT OF DRUG A IS NEEDED WHEN COMPARED
TO DRUG B TO OBTAIN 50-PERCENT EFFECT.

The second drug property that can be determined from graded

doseresponse plots is the efficacy of the drug. This is the
ability of a drug to elicit a response when it interacts with a
receptor. The maximal response (E max), or efficacy, is more
important than drug potency. A drug with greater efficacy is
more therapeutically beneficial than one that is more potent.
Maximal efficacy of a drug assumes that all receptors are
occupied by the drug, and no increase in response will be
observed if more drugs are added.
Thus, efficacy, maximal efficacy (Emax) - The maximum
effect that can be achieved with a particular drug,
regardless of dose. So, efficacy represents the ability of a
drug to accomplish a specified effect, whereas potency
reflects the amount of drug (the dose) required to cause
an effect.

A drug may have high efficacy but

low potency or vice versa.
Efficacy is determined mainly by the:
nature of the drug;
nature of the receptor and its associated
effector system.
Potency is determined mainly by the:
affinity of the receptor for the drug;
the number of receptors available.

We should also know the following terms with

abovementhioned:
EC50 (or ED50) median effective dose
TD50 - median toxic dose
LD50 median lethal dose
EC50, ED50, TD50, etc - In graded dose-response curves, the
concentration or dose that causes 50% of the maximum
effect or toxicity (or shows half-maximal effect or toxicity).

In quantal dose-response curves,

the concentration or dose of
drug
causes
a
specified
response in 50% of the
population under study.

Kd - The concentration of drug

that binds 50% of the receptors
in the system and is useful
measure of the affinity of a drug
molecule for its binding site on
the receptor molecule.

Bmax the concentration of drug

that binds maximal number of
receptors.

Thus, quantal dose - response curve

A graph of
the fraction of a population that shows a specified response
at progressively increasing doses.
Quantal doseresponse curves are useful for determining
doses to which most of the population responds.

THERAPEUTIC INDEX AND THERAPEUTIC

WINDOW
THERAPEUTIC INDEX

The therapeutic index (TI) of a drug

is the ratio of the dose that
produces toxicity to the dose that
produces a clinically desired or
effective response in a population
of individuals :
Therapeutic index = TD50/ED50
where TD50 = the drug dose that produces a
toxic effect in half the population, and ED50
= the drug dose that produces a
therapeutic or desired response in half the
population.

The therapeutic window, a more clinically useful index of the safety

of a drug, 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.
When the therapeutic index is low, it is possible to have a range of
concentrations in which the effective and toxic responses overlap.
That is, some patients hemorrhage, whereas others achieve the
desired two- to threefold prolongation of INR in the treatment
with warfarin (a drug with a small therapeutic index).
Agents with a low therapeutic index (that is, drugs for which dose
is critically important) are those drugs for which bioavailability
critically alters the therapeutic effects. In case of penicillin with a
large therapeutic index, bioavailability does not critically alter the
therapeutic or clinic effects.

DRUG INTERACTIONS
Drug interactions occur when one drug modifies the actions of
another drug in the body. Drug interactions can result from
pharmacokinetic alterations, pharmacodynamic changes, or a
combination of both. Elderly patients have a high incidence of
drug interactions because they often have age-related changes
in drug clearance and commonly take multiple medications.
Additive effects - the effect of 2 drugs given together is equal
to the sum of the responses to the same doses given
separately (that is, additive interaction describes the algebraic
summing of the effects of 2 drugs). For example, additive
depression of CNS function is caused by concomitant
administration of sedatives, hypnotics, and opioids with each
other or with the consumption of ethanol.

Synergism (supra - additive) - The effect of 2 drugs given

together is greater than the sum of the 2 (drugs used alone)
responses when they are given separately. Warfarin and aspirin,
NSAIDs increase anticoagulant effects via pharmacodynamic
mechanisms. The best example is the therapeutic synergism of
certain antibiotic combinations sulfonamides and trimethoprim,
another example of this type of interaction is the therapeutic
interaction of -lactamase inhibitors such as clavulonic acid with
-lactamase-susceptible penicillins.
Antagonism - The effect of 2 drugs given together is less than
the sum of the responses to the same doses given separately.
Some drug antagonisms appear to be based on receptor
interactions. For example, antagonism of the bronchodilating
effects of 2 - adrenoceptor activators used in asthma is to be
anticipated if a -blocker is given for another condition.

The older term "Physical (physiologic) dependence" is now

generally denotes as dependence, whereas psychological
dependence - is more simply called addiction. Addiction
compulsive drug-using behavior in which the person uses the
drug for personal satisfaction, often in the face of known risks
to health, formerly termed psychological dependence.
Dependence - A state characterized by signs and symptoms,
frequently the opposite of those caused by a drug, when it is
withdrawn from chronic use or when the dose is abruptly
lowered; formerly termed physical or physiologic dependence.
Tolerance - Reduction in drug effect requiring an increase in
dosage to maintain the same response. This can result from
increased disposition of the drug (metabolic tolerance);
an ability to compensate for the effects of a drug (behavioral
tolerance) or;
changes in receptor or effector systems involved in drug
actions (functional tolerance).