Pharmacodynamics

Pharmacodynamics describes the actions of a

drug on the body and includes-

 The principles of receptor interactions

 Mechanisms of the therapeutic & toxic
actions
 Dose-response relationships
Relationship between pharmacokinetics
and Pharmacodynamics

The pharmacokinetic processes of absorption,

distribution, metabolism and excretion
determine how quickly and to what extent a
drug will appear at a target site.

Pharmacodynamics concepts explain the

pharmacological effects of drugs and their
mechanism of action.
Figure: The relationship between pharmacokinetic and
pharmacodynamic components.
Receptor interactions
Recepto
rs
Are protein macromolecules on the surface or
within the cell that combine chemically with
either an endogenous ligand or a drug to
mediate a physiologic or pharmacologic effect.

Must be selective in their ligand-binding

characteristics.

Drug + Receptor  Drug-receptor complex

Biologic effect
There are mainly two functions of receptors:
- Ligand or drug binding (receptor: things
that receive)
Ligands are molecules which attach selectively
to a particular receptor. It may be (drug,
hormone, neurotransmitter) by different
chemical interactions (covalent, ionic,
hydrogen, Van der Waals)
Ligand is any chemical substance that
combines with the receptors and produce an
effect.
 - Activation of an effector system
(message propagation)
The signal from the ligand to several subcellular
elements e.g. enzymes, second messenger, or
ion channels
► intra-cellular biochemical response
Effector
sAre molecules that translate the drug-receptor
interaction into a cellular activity.
Commonly there are four types of effector
mechanisms:
Figure: Known effector mechanisms.
1. Intracellular
Lipid soluble drugs or diffusible agents can
cross cell membrane. For example thyroid and
steroid hormones, nitric oxide, vitamin D.

These drugs can binds to cytosolic or nuclear

receptors to form complexes (effectors) and
interact with DNA to changes in protein
synthesis in target tissues.
2, 3.
Transmembrane
Some ligands such as insulin bind to receptors
that have both an extracellular and intracellular
component. Binding of the extracellular
component stimulates the intracellular
component, which is coupled to an enzyme for
example tyrosine kinase.

Binding of the ligand (for example insulin) ►

activation of cytoplasmic tyrosine kinase
enzyme ► phosphoryation of target proteins.
i.e. Some receptors can also act as an effectors
e.g. tyrosine kinase effector is part of the
insulin receptor.
4. Ligand-gated ion
channels
Drugs binds to these receptors, which then
alter the conductance of ions through the cell
membrane channels.

Ach + Nicotinic receptors ► Open Na+ channels

GABA + GABAA receptors ► Open Cl- channels

Simultaneous binding of two acetylcholine

(ACh) molecules to the two α-subunits results in
opening of the ion channel, with entry of Na+
(and exit of some K+), membrane
depolarization, and triggering of an action
5. Second messenger
system
Drugs binds to receptors, that activate second
messenger systems involving G proteins.

The receptor facilitates activation of G-protein

(Guanine nucleotide binding protein) ► regulate
activity of adenylyl cyclase enzyme (effector) ►
change in the synthesis of cAMP from ATP.

e.g. Dopamine receptors, α & β adrenergic

receptors, muscarinic receptors, opiate
receptors.

Best known second messengers are: cAMP,

++
Mechanisms of the therapeutic & toxic
actions
Agonist
- An agonist is a drug capable of fully activating
the effector system when it binds to the
receptors.
- Drugs mimic the endogenous regulatory
substances such as neurotransmitter or
hormone.
- Drugs which stimulate the receptors.
- Has affinity and efficacy.
Affinity:
The chemical forces that cause the drug to
associate with the receptor.

Efficacy:
The extent of functional change imparted to a
receptor upon binding of a drug.

Dissociation constant (Kd):

Measure of a drug’s affinity for a given
receptor.
Defined as the concentration of drug required
in solution to achieve 50% occupancy of its
The smaller the Kd the greater the affinity of the
drug for its receptor.

Spare receptors:
If the maximal drug response is obtained at
less than maximal occupation of the receptors.
If the EC50 is less than Kd, spare receptors are
said to exist. i.e. to achieve 50% of maximum
effect, fewer than 50% of the receptors must
be activated.
Spare receptors
Full agonist
Strong affinity
Strong intrinsic activity

Partial agonist
Strong affinity
Weak intrinsic activity
 100 …………………………………………… Full
agonist
% of maximum

……………………………………………
Partial
effect

agonist

Log concentration
[A]
Antagonist
- Drugs bind to receptors without directly
altering the receptor function, but it prevents
the binding and blocks the biologic actions of
agonist molecules.
- Drugs which block the receptors.
- They have affinity but no efficacy.
- They prevent the action of agonist.
Full antagonist
Strong affinity
No intrinsic activity

Partial antagonist
Strong affinity
Weak intrisic activity
Pharmacologic
1. Reversible competitive antagonists:
antagonists
- Antagonist compete with ligand or agonist for
the same receptor.
- Reversibly bind to receptors.
- Can be displaced by excess agonist (conc.
dependent).
- Cause parallel shift of the log dose response
curve to the right (decrease potency same
efficacy of agonist).
- Slope and maximal effect (Emax) are not
changed.
2. Irreversible non-competitive
antagonists:
- Antagonist binds to the same receptor as
agonist irreversibly.
- The antagonist cannot overcome by excess
agonist or increase ED50.
- Decreases efficacy of the agonist but does not
alter EC50.
- Causes non-parallel (downward) shift of dose-
response curve to the right (until spare
receptors are present).
- Slope and maximal
Phenoxybenzamine, effect
an irreversible are decreased.
α–adrenoreceptor antagonist.
 Agonist

Agonist + Antagonist

EC50
3. Allosteric antagonists:
- Non-competitive mechanism, conc.
independent.
- Antagonist and agonist bind to different site
on same receptor.
- Binding of antagonist to receptor alter the
shape of binding site for agonist.
- The bound antagonist may prevent
conformational changes in the receptor
required for receptor activation after the
agonist binds.
Physiologic
antagonists
Two drugs have opposite effects through
differing mechanisms
A drug that binds to a different receptor,
producing an effect opposite to that produced
by the drug it is antagonizing.
e.g. Antagonism of a bronchoconstrictor effect
of histamine by epinephrine bronchodilator
action.
Chemical antagonists
A drug that interacts directly with the drug
being antagonized to remove it or to prevent it
from reaching its target.
e.g. Dimercaprol, a chelator of lead and some
other toxic metals.
e.g. Pralidoxime which combines with the
phosphorous in organophosphate
cholinesterase inhibitors.
Dose-response relationships
1. Graded dose-response relations
The effect of a drug is most easily analyzed by
plotting the magnitude of the response versus
the drug dose, this is, a graded dose-response
curve, which is reflected by a rectangular
hyperbolic curve (A), but it is frequently
convenient to plot the magnitude of effect
versus log dose, because a wide range of drug
concentrations is easily displayed. In this case,
the result is the symmetric sigmoidal log dose-
effect curve (B). This curve is steep in the
middle and even in both extremities.
Dose-response curve
After this point,
increasing dose
do not produce
a stronger
effect
100

80
Respons

60

40
e

20

0
0 200 400 600 800 1000

Dose
Dose-response curve

100 Ceiling
80
Respons

60
EC
ED50
40

Threshold
e

20

0
0.1 1 10 100 1000 10000

Dose
Rectangular hyperbolic curve Sigmoidal curve
Aim of plotting the dose-response curve is to
compare the relative potencies and efficacies of
different drugs:

Efficacy: Efficacy is the maximal response

(Emax) produced by a drug. It depends on the
number of drug-receptor complexes formed
and the efficiency with which the activated
receptor produces a cellular action.
It can be measured with a graded dose-
response curve only.
For example, if two drugs, Drug A and Drug B,
are both claimed to reduce a patient’s heart
rate by 25%, then both drug have the same
Potency: Absolute amount of drug required to
produce an effect.
Potency of a drug termed effective dose or
concentration, is a measure of how much drug
is required to elicit a given response. The lower
the dose required for a given response, the
more potent the drug.
The smaller the EC50, the greater the potency of
the drug.
For example, only 1 mg of drug A needs to be
given to achieve a reduction in heart rate,
where as 10 mg of drug B are needed.
Therefore, drug A is considered as more potent
EC50
Potency is most often expressed EC50.
The EC50 is the concentration of the drug that
produces a response equal to the 50% of the
maximal response.

The smaller
the EC50,
the greater
the
potency of
the drug.
2. Quantal dose-response relations
Quantal dose-response is the relationship
between no. of patients response and dose.
It describes the relationship that how many
patients have exhibited the predefined
response (say like 20% decrease in blood
pressure) at the specified dose (how much
minimum amount of drug is required to reach
at 20% decrease in blood flow.)
In quantal dose response curve ED50, TD50 and
LD50 are potency variables.
Normal distribution Cumulative frequency
Therapeutic index
The therapeutic index 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 or
LD50/ED50
TD50(Median toxic dose): The drug dose that
produces a toxic effect in half of the population.
ED50(Median effective dose): The drug dose that
produces the desired therapeutic effect in half
of the population.
LD50(Median lethal dose): The dose of a drug
that produces death in 50% of the animal
population tested.
Drug’s safety margin
Must be >1 for drug to be
usable
Digitalis has a TI of 2
Penicillin has TI of >100
 ……………………………….
…………..…..

…………..…..
?? mg ?? mg
ED50 TD50
………………………………….…………….
…………..…..

…………..…..
?? mg ?? mg
ED50 TD50
Regulation of
receptors
Continued stimulation of cells with agonists
generally results in a state of desensitization
such that the effect that follows continued or
subsequent exposure to the same
concentration of drug is diminished.

An example is attenuated response to the

repeated use of β receptor agonists as
bronchodilators for the treatment of asthma
Desensitization can be the result of temporary
inaccessibility of the receptor to agonist or the
result of fewer receptors synthesized and
available at the cell surface (down regulation).
Hyperractivity (up-regulation of the
receptors):
Antagonists may raise the number of receptors
in a cell by preventing down regulation caused
by endogenous agonists.

When the antagonist is withdrawn, the elevated

receptor number allows an exaggerated
response to physiological concentration of
agonists.

For example, severe tachycardia or

arrhythmias which could occur after sudden
withdrawal of propranolol. So the dose must