Pharmacodynamics is the study of physiological and biochemical effects of
drugs and how these effects relate to a drug’s mechanism of action. It focuses on the
action and the effects of drugs within the body. In general, pharmacodynamics
characterizes what a drug does to a patient. In contrast, the study of
pharmacokinetics addresses what the patients body does to a drug. Effective use of
a drug requires knowledge of the drug’s pharmacokinetic and pharmacodynamic
PRINCIPLES OF DRUG ACTION:
Drugs (except those gene based) do not impart new functions to any system,
organ or cell. They only alter the pace of ongoing activity. The basic types of drug
action can be broadly classed as follows:
1. Stimulation: It is a selective enhancement of the level of activity of specialized
cells. Example – adrenaline stimulates heart, pilocarpine stimulates salivary
glands. However, excessive stimulation is often followed by depression of that
function. Example – High dose of picrotoxin, a CNS stimulant produces
convulsions followed by coma and respiratory depression.
2. Depression: It is a selective diminution of activity of specialized cells. Example –
Barbiturates depress CNS, quinidine depresses heart. Certain drugs stimulate
one type of cells but depress the other. Example – acetylcholine stimulates
intestinal smooth muscles but depress the SA node in the heart. Most drugs can
not be just classed as stimulants or depressants.
3. Irritation: This connotes a non-selective, often noxious effect and is particularly
applied to specialized cells like epithelium, connective tissue etc. Mild irritation
may stimulate associated function like bitters increase salivary and gastric
secretions and counterirritants increase blood flow to the site. But strong irritation
results in inflammation, corrosion, necrosis and morphological damage. This may
result in diminution or loss of function.
4. Replacement: This refers to the use of natural metabolites, hormones or their
congeners in deficiency states like insulin in diabetes and fluids in dehydration.
5. Cytotoxic effect: Selective cytotoxic action for invading parasites or cancer cells,
attenuating them without significantly affecting the host cells is utilized for cure or
palliation of infections and neoplasms.
BASIC MECHANISMS OF DRUG ACTION:
Mechanisms of drug action can be grouped as non-cellular mechanisms of
drug action and cellular mechanisms of drug action.
Non-cellular mechanisms of drug action: Drug reactions that occur extracellularly
and that involve non-cellular constituents include the following:-
1. Physical effects: Examples include protective, adsorbent and lubricant properties
of locally active agents that are applied to cutaneous and membrane surfaces.
2. Chemical reactions: A number of drugs produce their effects through a chemical
union with an endogenous or foreign substance. Examples include the
inactivation of heparin (an organic acid) by protamine (an organic base), the
chelation of lead by calcium disodium edentate, neutralization of hydrochloric
acid in the stomach by antacids such as aluminum hydroxide or sodium
bicarbonate, treatment of alkali poisoning with weak acids, conversion of
haemoglobin to methaemoglobin by nitrites, precipitation of proteins by
astringents and oxidation reactions initiated by certain antiseptics and
3. Physicochemical mechanisms: Certain drugs act by altering the physicochemical
or biophysical properties of specific fluids or even components of cells. Examples
of the former include the surface-active agents or surfactants. Surfactants reduce
the surface tension of the interface between two immiscible phases because their
molecules contain two localized regions, one being hydrophilic in nature and the
other hydrophobic. Detergents, emulsifiers, antifoaming agents and several
antiseptics and disinfectants possess surfactant properties.
4. Modifications of the composition of body fluids: Several therapeutic manipulations
involve the administration of substances that exert osmotic effects across
particular cell membranes. Examples of osmotically active agents include
magnesium sulphate as a purgative, mannitol as a diuretic, hypertonic poultices
applied to the skin and use of dextran as plasma volume expander. In addition,
acid-base electrolyte derangements which occur in the extracellular fluid in many
diseases can be corrected by the appropriate and judicious use of various
electrolyte solutions. Also acidifying and alkalinizing salts may be administered to
alter the pH of the urine for specific therapeutic purposes.
Cellular mechanisms of drug action: Most of the responses elicited by drugs
occur at cellular level and involve either functional constituents or more commonly,
specific biochemical reactions.
1. Physicochemical and biophysical mechanisms: Certain drugs appear to act by
altering the physicochemical or biophysical characteristics of specific components
of cells. Examples include the effect of general inhalant anaesthetics on the lipid
matrix and perhaps the hydrophobic proteins in neuronal membranes within the
2. Modification of cell membrane structure and function: Various drugs may
influence either the structure or specific functional components of cell
membranes and thereby initiate their characteristic effects. These mechanisms of
action may also involve enzyme stsyems or receptor mediated reactions. A few
examples include, local anaesthetics that bind to components of the sodium
channels in excitable membranes and prevent depolarization, calcium channel
blockers that inhibit the entry of calcium into cells, insulin that facilitates the
transport of glucose, neurotransmitters that increase or decrease sodium ion
permeability and antifungal antibiotics that disrupt the sterol component of fungal
3. Mechanisms associated with neurohumoural transmission: A number of drugs
interfere with the synthesis, release, effects or re-uptake of neurotransmitters.
Once again enzyme and/or receptor mediated effects may be responsible. For
example, reserpine blocks the transport system of adrenergic storage granules,
while amphetamine displaces norepinephrine from axonal terminals. Botulinum
toxin prevents the release of acetylcholine from cholinergic terminals and
bretylium inhibits the release of norepinephrine from adrenergic terminals.
4. Enzyme inhibition: Certain enzymes exert their effects by inhibiting the activity of
specific enzyme systems either in the host animal or the invading pathogens.
This inhibition may be competitive or non-competitive. Non-competitive inhibition
may be reversible or irreversible.
PROTEIN TARGETS FOR DRUG BINDING:
Four main kinds of regulatory proteins are commonly involved as primary drug
Carrier molecules (transporters)
J.N. Langley (1878) introduced the concept of receptor while he was studying
about the actions of atropine and pilocarpine on salivary flow. He used the term
receptive substance. The term receptor was first used by Paul Ehrlich (1913) to
describe the hypothetical specific chemical groupings of “side chains” on cells upon
which the chemotherapeutic agents were postulated to act.
Receptors are sensing elements in the system of chemical communications
that coordinates the function of different cells in the body, the chemical messengers
being hormones, transmitter substances or other mediators. Many therapeutically
useful synthetic drugs act as agonists or antagonists on receptors for known
endogenous mediators. Receptors are macromolecular structures with which a drug
interacts to initiate its pharmacologic effects. Receptors elicit many different types of cellular effect, some of which may be rapid, such as those involved in synaptic transmission. A receptor is often defined in terms of the endogenous substance or ligand that produces a given effect upon interaction with a given biological substrate.
A number of binding sites exist in biological tissues for drugs and toxins for which
there is no known endogenous ligand.
Binding of drugs to receptors necessarily obeys the Laws of Mass Action. At
equilibrium, receptor occupancy is related to drug concentration. The higher the
affinity of the drug for the receptor, the lower is the concentration at which it
produces a given level of occupancy. The same principles apply when two or more
drugs compete for the same receptors; each of which has the effect of reducing the
apparent affinity for the other.
Properties of receptors: To define a receptor, three criteria should be satisfied
namely saturability, specificity and reversibility.
Saturability: A finite number of receptors per cell should be present as
revealed by a saturable binding curve. By adding increasing amounts of the
drug, the number of drug molecules bound should form a plateau at the
number of binding sites present.
Specificity: The drug should be structurally complementary to the receptor.
This can be demonstrated by a series of drugs that vary slightly in chemical
structure and showing that affinity is affected by chemical structure. Also, if
the drug is optically active, then the two isomers should have markedly
Reversibility: The drug should bind to the receptor and then dissociate in its
non-metabolized form. This property distinguishes receptor-drug interactions
from enzyme-substrate interactions.
Types of receptors:
1. Type 1: Ligand-gated ion channels (also known as ionotropic receptors):
These are membrane receptors that are coupled directly to ion channels and are
the receptors on which fast neurotransmitters act. Examples include the nicotinic
acetylcholine receptor; GABAA receptor; and glutamate receptors.
2. Type 2: G-protein-coupled receptors (GPCRs): These are also known as
metabotropic receptors or 7-transmembrane-spanning (heptahelical)
receptors. They are membrane receptors that are coupled to intracellular
effector systems via a G-protein. This class includes receptors for many
hormones and slow transmitters, for example the muscarinic acetylcholine
receptor and adrenergic receptors.
3. Type 3: Kinase-linked and related receptors: These are membrane receptors
that incorporate an intracellular protein kinase domain within their structure. They
include receptors for insulin, various cytokines and growth factors.
4. Type 4: Nuclear receptors: These are receptors that regulate gene transcription.
The term nuclear receptor is something of a misnomer, because some are
actually located in the cytosol and migrate to the nuclear compartment when a
ligand is present. They include receptors for steroid hormones, thyroid hormone,
and other agents such as retinoic acid and vitamin D.
Function of receptors:
To propagate regulatory signals from outside to within the effector cell when the
molecular species carrying the signal can not itself penetrate the cell membrane.
To amplify the signal.
To integrate various extra cellular and intracellular regulatory signals.
To adopt short term and long term changes in the regulatory milieu and maintain
Structure activity relationships (SAR): The ability of a drug to combine with a
receptor to produce an effect is dependent on the three dimensional chemical
structure of the drug. Relatively minor modifications in the drug molecule may result
in major changes in pharmacological properties. Changes in structure can change
the activity of the drug, some actions may be affected while others are not, drug may
have lesser toxic side effects with better pharmacokinetic characteristics.
Non-receptor mediated reactions: Some drugs produce an effect without
combining with receptors. Some important examples are given below:-
Mannitol is used as a diuretic. Mannitol molecules circulate in the blood and are
excreted in the urine. These molecules drag water from the body into the urine by
osmosis. Mannitol does not bring about this effect by combining with any
Chelators are also examples of non-receptor mediated actions. They physically
combine with ions or other selected compounds in the environment to produce
their effects. For example, chelators like BAL are used to facilitate removal of
lead from the body by chelation. EDTA, an anticoagulant also acts by chelation.
Antacids also form another group of drugs whose action is not mediated through
receptors. Calcium, magnesium or aluminium in the antacid drug combines with
the strong hydrochloric acid in the stomach thereby reducing stomach irritation.
1. Affinity and Efficacy: Affinity describes the tendency of a drug to combine with a
particular kind of a receptor whereas efficacy (or intrinsic activity) of a drug
refers to the maximal effect the drug can produce. That is why; a partial agonist
has less intrinsic activity/ efficacy than a full agonist.
2. Potency: It refers to the dose of a drug that must be administered to produce a
particular effect of given intensity. It is influenced by the affinity of a drug. It varies
inversely with dose. It is a relative rather than an absolute expression of drug
activity. Potency of a drug is not necessarily correlated with its efficacy or safety
and the most potent drug within a series is not necessarily clinically superior. Low
potency is a disadvantage only if the effective dose is so large that it is too costly
to produce or too cumbersome to administer.
3. Selectivity: It depends on the capacity of a drug to preferentially produce a
particular effect. The characteristic effect of the drug is produced at lower doses
than those required to elicit other responses. For instance, clenbuterol has a high
degree of selectivity for 2 receptors (in lungs). At higher doses, 1 receptors (in
heart) are also activated.
4. Specificity: When all the effects produced by a drug are due to a single
mechanism of action, the drug is said to be specific. A specific drug acts at only
one type of receptor, but may produce multiple pharmacological effects because
of location of receptors in various organs. For instance, atropine is a specific drug
in that its varied effects can be attributed to its antimuscarinic action.
Effects of a non-specific drug results from several mechanisms of
action. For instance, the potential effects of phenothiazine tranquilizers (e.g.
acepromazine) include sedation (due to increased rate of dopamine turnover in
brain), an antiemetic action (due to depressed activity of CTZ), hypotension
(due to -adrenergic receptor blockade), an antispasmodic effect on GI smooth
muscles (due to anticholinergic action) and hypothermia (due to interference
with hypothalamic control of temperature regulation).
5. Agonist: An agonist is a drug that possesses affinity for a particular receptor and
causes a change in the receptor that result in an observable effect. Agonists are
further categorized as:
Full agonist: Produces a maximal response by occupying all or a fraction of
receptors. (Affinity=1, Efficacy=1)
Partial agonist: Produces less than a maximal response even when the drug
occupies all of the receptors. A partial agonist has less intrinsic activity than a full
agonist. (Affinity=1, Efficacy= 0 to 1)
Inverse agonist: Activates a receptor to produce an effect in the opposite
direction to that of the well recognized agonist. (Affinity=1, Efficacy= –1 to 0)
6. Antagonist: An antagonist is a drug that blocks the response produced by an
agonist. Antagonists interact with the receptor or other components of the effector
mechanism, but antagonists are devoid of intrinsic activity (Affinity=1,
Efficacy=0). Antagonism can be classified as:-
(i) Competitive Antagonism: It is completely reversible; an increase in the
concentration of the agonist in the immediate vicinity of its site of action or biophase will overcome the effect of the antagonist.
Example: Atropine (Antimuscarinic agent)
Diphenhydramine (H1 receptor blocker)
Propranolol (-adrenergic blocker)
Spironolactone (Aldosterone antagonist)
(ii) Non-competitive antagonism: A non-competitive antagonist conceptually
removes the receptor or response potential from the system. Addition of more
agonist to the bio-phase of inhibited receptor will not overcome the
antagonism achieved by a non-competitive antagonist. Thus, the agonist has
no influence upon the degree of antagonism or its reversibility.
Example: Platelet inhibiting action of aspirin (The thromboxane synthase
enzyme of platelets is irreversibly inhibited by aspirin, a process that is
reversed only by production of new platelets).
7. Drug action: It is the initial combination of the drug with its receptor resulting in
conformational change in the latter (in case of agonist), or prevention of
conformational change through exclusion of the agonist (in case of antagonists).
8. Drug effect: It is the ultimate change in biological function brought about as a
consequence of drug action, through a series of intermediate steps.