Mechanism of Drug Action

Dr.Sudha JProff. & HODDept. of Pharmacology

Drug Targets Sites

Drugs can interact with the following target sites in a cell1. Receptors2. Ion channels which incorporate a receptor and act as

target sites3. Enzymes4. 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 forces2. Hydrogen bonding3. Ionic interaction4. Covalent bonding

Types of Receptors andSignal transduction mechanisms

Type I: Ionotropic receptors (Ligand gated ion channels)

Type II: Metabotropic receptors (G proteins coupled receptors(GPCR))1. Adenyl cyclase: cAMP system2. Phospholipase-C: Inositol Phosphate system3. Ion channel regulation

Type III: Enzyme linked receptors a. Intrinsic enzyme receptorsb. 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 Ca2+

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