Mechanism of

Drug Action

Dr.Sudha J
Proff. & HOD
Dept. of Pharmacology
Drug Targets Sites
Drugs can interact with the following target sites in a cell
1. Receptors
2. Ion channels which incorporate a receptor and act as
target sites
3. Enzymes
4. Carrier molecules
• Based on the drug target sites, the
mechanisms of drug action can be classified
broadly as,

– Receptor mediated mechanisms

– Non-receptor mediated mechanisms

 RECEPTOR MEDIATED
MECHANISM
• Receptor: It is a membrane bound or
intracellular macromolecular protein which is
capable of binding the specific functional
groups of the drug or endogenous substance.

• Binding of a drug with its receptor results in the

formation of drug receptor complex (DR) which
is responsible for triggering the biological
response.

D+R= (DR) → Response

“LOCK & KEY” model of RECEPTORS
• Affinity: The capacity of a drug to form the complex
with its receptor (DR complex) e.g., the key entering
the hole of the lock has got an affinity to its levers.

• Intrinsic activity (or) Efficacy: The ability of a drug

to trigger the pharmacological response after making
the drug-receptor complex .

• Ligand: Any molecule which attaches selectively to

particular receptors or sites
• Agonists: Agent which activates a receptor to produce an effect similar to
that of the physiologic signal molecule
Have both high affinity as well as high intrinsic activity, therefore
can trigger the maximal biological response

• Antagonists: Agent which prevents the action of an agonist on a receptor

but doesn’t have any effect of its own.
Have only affinity but no intrinsic activity. These drugs bind to
the receptor and block the binding of an endogenous agonist.

• Partial agonists: Agent which activates a receptor to produce a sub

maximal effect but antagonizes the actions of full agonist.
Have full affinity but with low intrinsic activity and hence are only
partly as effective as agonists.

• Inverse (Negative) agonists: Agent which activates a receptor to produce

an effect in the opposite direction to that of the agonist
Have full affinity but intrinsic activity ranges between 0 to -1
• Four types of binding takes place between
the receptor and the drug molecule
1. Van der Waals forces
2. Hydrogen bonding
3. Ionic interaction
4. Covalent bonding
Types of Receptors and
Signal transduction mechanisms

Type I: Ionotropic receptors (Ligand gated ion channels)

Type II: Metabotropic receptors (G proteins coupled receptors(GPCR))

1. Adenyl cyclase: cAMP system
2. Phospholipase-C: Inositol Phosphate system
3. Ion channel regulation

Type III: Enzyme linked receptors

a. Intrinsic enzyme receptors
b. JAK-STAT-kinase binding receptors

Type IV: Receptors regulating gene expression

Ionotropic receptors
• Also called as “Ligand gated ion channels”
• These are cell surface receptors
• Enclose ion selective channels (for Na+,K+,Ca2+ or Cl-)
within their molecules.
• Agonist binding opens the channel, and causes
depolarization/hyperpolarization/changes in the ionic
composition

• Examples: nicotinic cholinergic, GABA-A, glycine

(inhibitory), excitatory AA(kainate, NMDA or N-methyl
D-aspartate, quisqualate) and 5HT3 receptors
• Nicotinic cholinergic receptor
G-Protein coupled receptors

• These are a large family of cell membrane receptors linked to

the effector through GTP activated proteins (G-Proteins).

• G-Proteins: 7 helical membrane spanning hydrophobic amino

acid (AA) segments which run into 3 extracellular and 3
intracellular loops.

• Agonist binding site is located on extracellular face, while

another recognition site formed by cytosolic segments binds
the coupling G-protein.

• Examples: Muscarinic, Dopamine D2, β-adrenergic, α1-

adrenergic, α2-adrenergic, GABAB , 5-HT
G-Protein coupled receptors
G-Protein coupled receptors
• There are three major effector pathways through which GPCRs function
1. Adenyl cyclase: cAMP system: Activation of AC results in
intracellular accumulation of second messenger cAMP which functions
through cAMP dependant protein kinase (PKA). The PKA phosphorylates
and alters the functions of many enzymes, ion channels, transporters
and structural proteins.

2. Phospholipase-C: IP3-DAG pathway: Activation of Phospholipase-

C(PLc) hydrolises the membrane PIP2 to generate IP3 and DAG. IP3
mobilizes Ca2+ and DAG enhances protein kinase C (PKc) activation by
Ca2+

3. Ion channel regulation: The activated G-proteins can also open or

close ionic channels specific for Ca2+ ,K+ or Na+, without the intervention
of any second messenger like cAMP or IP3 and bring about
depolarization/hyperpolarization/changes in intracellular Ca 2+
Enzyme linked receptors

• This class of receptors have a subunit with enzymatic property

(intrinsic) or bind a JAK (Janus-Kinase) enzyme on activation.
The agonist binding site and the catalytic site lie respectively on
the outer and inner face of the plasma membrane.

• Intrinsic enzyme receptors: The intracellular domain is either

a protein kinase or guanyl cyclase
Examples: Insulin, Epidermal growth factor (EGF), Nerve
growth factor (NGF) receptors

• JAK-STAT-kinase binding receptors: These do not have

intrinsic activity, but agonist induced dimerization increases
affinity for a cytoplasmic tyrosine protein kinase JAK.
Examples: Growth hormone, many cytokines, interferons
Enzyme linked receptor
Eg: Insulin receptor
Receptors regulating gene
expression
• These are intracellular (cytoplasmic or nuclear)
soluble proteins which respond to lipid soluble
chemical messengers that penetrate the cell
• Kept inhibited till the hormone binds
• Capable of binding to specific genes and facilitates
their expression so that specific mRNA is
synthesized.

• Examples: All steroid hormones, thyroxin, vit. D and

vit. A
• Protein synthesis regulating receptor
Non-receptor mediated mechanisms
Non-receptor mediated
mechanisms
• By counterfeit or False incorporation
mechanisms
Eg: Sulfa drugs and anti-neoplastic drugs
• By virtue of being Protoplasmic poisons
Eg: Germicides and antiseptics
• Through formation of antibodies
Eg: Vaccines, Antisera
• Through placebo action
• Targeting specific genetic changes