Pharmacology (Basics): Mechanism of drug action

Pharmacology (Basics): Mechanism of drug action

Mechanism of drug action:

Four major bio-molecular targets:

1. Enzymes
2. Ions channels
3. Transporter or carrier molecules
4. Receptors

Enzymes: 

Inhibition of enzymes:

1. Non-specific inhibition: Many Drug è capable of denaturing proteins è Damage to enzyme à alteration in activity.
2. Specific  inhibition :

a.       Competitive equilibrium Type of inhibition: Drug and substrate compete with each other for binding to same catalytic site.

e.g.

                                                       I.            Physostigmine  / Neostigmine  and Ach  à for cholinesterase enzyme

                                                    II.            Sulphonamide and PABA  à for bacterial folate synthatase

                                                 III.            Carbidopa / Methyl dopa  and l-DOPA à for DOPA decarboxylase

b.       Competitive non-equilibrium Type of inhibition: Drug bind to enzyme site with strong covalent bond and high affinity.

e.g. Methotrexate has 50,000 time higher affinity for Dihydrofolate Reductase  (DHFR) than substrate (DHFA – Dihydrofolic acid)

c.       Non-competitive inhibition: Drug and substrate react to differant catalytic site à decreases in catalytic activity.

            e.g.      Aspirin / Indomethacin  -  COX (Cyclooxygenase)

                        Disulfiram  - aldehyde deydrogenase

                        Acetazolamide – Carbonic anhydrase

                        Digoxin – Na⁺-K⁺ ATPase 

Ion Channels:

Types of ion channels:

a.       Voltage gated sodium channels

b.      Voltage gated calcium channels

c.       Renal tubule sodium channels

d.      ATP sensitive potassium channels

e.       GABA gated Chloride channels

e.g.                  Quinidine blocks myocardial Na⁺ channels

                        Nifedipine blocks L-type of voltage gated Ca⁺ channels

Receptors:

Reference: Rang et al, 5th edition, Pharmacology.

Types of receptors:

1. Ligand gated ion channels - Ionotropic receptors
2. G-protein couple receptors – Metabolotropic recetors
3. Kinase linked receptors
4. Nuclear receptors

Ligand gated ion channels - Ionotropic receptors:

ü  Receptors on which fast neurotransmitters act.

ü  e.g.      Nicotinic acetyl choline receptor

            GABA_A receptors

            Glutamate receptors of NMDA

Gating mechanism:

When Ach bound to α-subunit  à Twisting of α-subunit   à Opening of channels  à Increases Na⁺ and K⁺ permeability. à Influx of Na+ ions causes depolarization of cells.

G- Protein Couple receptors:

ü  Receptors of various hormones and slow neurotransmitters

ü  e.g.           Muscarinic acetylcholine receptors

                 Adrenergic receptors

                 Chemokines receptors

α, β, γ Subunits

ü  α Subunit (23 isoforms): contains the GTP/GDP binding site is responsible for identity.

ü  β (5 isoforms) and γ (12 isoforms): are identical or very similar, interchangeable in vitro; most of them are ubiquitously expressed; membrane anchored through prenylation of Gβ.

Subtypes of G-Protein couple receptors:

            Gs = ↑ adenylyl cyclase and ↑ Ca⁺⁺ Channel

            Gi = ↓ adenylyl cyclase and ↑ K⁺ Channel

            G₀ =  ↓ Ca⁺⁺ Channel and ↑ K⁺ Channel

            Gq = ↑ Phospholipase C- β.

Receptors:

It is defined as macromolecule or binding site located on surface or inside the effector cells to recognize the signal molecule (drug) and initiate response to it, but it has no self function.

Agonist: An agent which activates receptors to produce an effect similar to that of physiological signal molecule.

Inverse agonist: An agent which activates receptors to produce an effect in opposite direction to that of agonist.

Partial agonist: An agent which activate receptor produces sub-maximal effect but antagonise the act of full agonist.

Antagonist: An agent which prevents the action of an agonist on receptor, but does not have any effect of its own.

Affinity: Ability of drug to bind to receptor called affinity.

Efficacy or intrinsic activity: Capacity to induce functional changes in receptors called as intrinsic activity.

Agonist : Affinity  and intrinsic activity

Antagonist: Affinity but no intrinsic activity

Partial agonist: Affinity but sub-maximal intrinsic activity

Inverse agonist: Affinity but negative intrinsic activity (0 to -1)