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Basics in Pharmacology:

Mechanism of drug action:

Four major bio-molecular targets:

I. Enzymes

II. Ions channels

III. Transporter or carrier molecules

IV. Receptors



Enzymes:

Inhibition of enzymes:

1. Non-specific inhibition: Many Drug � capable of denaturing proteins � Damage to

enzyme � 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 � for cholinesterase enzyme

II. Sulphonamide and PABA � for bacterial folate synthatase

III. Carbidopa / Methyl dopa and l-DOPA � 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

� 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

Transporters or carrier molecule

e.g.

Desipramine blocks reuptake of nor-adrenaline

Fluoxetine blocks reuptake of serotonin (5HT)



Receptors:

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:

� Receptors on which fast neurotransmitters act.

� e.g. Nicotinic acetyl choline receptor

GABAA receptors

Glutamate receptors of NMDA

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Gating mechanism:

When Ach bound to α-subunit

Increases Na+ and K

+ permeability.

G- Protein Couple receptors:

� Receptors of various hormones and slow neurotransmitters

� e.g. Muscarinic acetylcholine receptors

Adrenergic receptors

Chemokines rec

α, β, γ Subunits

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

identity.

� β (5 isoforms) and γ (12 isoforms): are identical or very similar, interchangeable

vitro; most of them are ubiquitously expressed; membrane anchored through

prenylation of Gβ.

Subtypes of G-Protein couple receptors:

Gs = ↑ adenylyl cyclase and ↑ Ca

Gi = ↓ adenylyl cyclase and ↑ K

G0 = ↓ Ca++ Channel and

Gq = ↑ Phospholipase C

Pharmacology Basics in Pharmacology

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subunit � Twisting of α-subunit � Opening of channels

permeability. � Influx of Na+ ions causes depolarization of cells.

Protein Couple receptors:

hormones and slow neurotransmitters

Muscarinic acetylcholine receptors

Adrenergic receptors

Chemokines receptors

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

β (5 isoforms) and γ (12 isoforms): are identical or very similar, interchangeable

; most of them are ubiquitously expressed; membrane anchored through

Protein couple receptors:

↑ adenylyl cyclase and ↑ Ca++ Channel

↓ adenylyl cyclase and ↑ K+ Channel

Channel and ↑ K+ Channel

↑ Phospholipase C- β.

Basics in Pharmacology

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Opening of channels �

Influx of Na+ ions causes depolarization of cells.

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

β (5 isoforms) and γ (12 isoforms): are identical or very similar, interchangeable in

; most of them are ubiquitously expressed; membrane anchored through



Three major effector pathways :

1. Adenyl cyclase / C-AMP pathway.

2. Phospholipase C / Inositol phosphate pathway Or IP3 – DAG pathway

3. Channel regulation

Adenyl cyclase / C-AMP pathway:

G-proteins are linked to an enzyme, adenylyl cyclase, that dephosphorylates ATP to form

cyclic AMP (cAMP). Gs-protein (stimulatory G-protein) activation (e.g., via β-

adrenoceptors) increases cAMP by activating adenylyl cyclase. cAMP then activates PK-A

(cAMP stimulated protein kinase) and causes increased cellular influx of Ca++ by

phosphorylation and activation of L-type calcium channels, and enhanced release of Ca++ by

the sarcoplasmic reticulum in the heart. These and other intracellular events increase inotropy



(muscle contractility), chronotropy (heart rate), dromotropy (velocity of electrical

conduction) and lusitropy (relaxation rate).

Activation of Gi-proteins (inhibitory G-protein), for example by adenosine and muscarinic

agonists binding to their receptors, decreases cAMP (through adenylyl cyclase inactivation),

inactivates PK-A, decreases Ca++ entry into the cell and release by the sacroplasmic

reticulum, and increases outward, hyperpolarizing K+ currents. Activation of the Gi-protein

pathway therefore enhances repolarization.

Phospholipase C : IP3 –DAG pathway

The IP3 pathway is linked to activation of α1-adrenoceptors, angiotensin II (AII) receptors,

and endothelin-1 (ET-1) receptors and therefore is stimulated by alpha-agonists, angiotensin

II and endothelin-1. These receptors are coupled to a phospholipase C (PL-C)-coupled Gq-

protein, which when activated, stimulates the formation of inositol triphosphate (IP3) from

phosphatidylinositol biphosphate (PIP2). Increased IP3 stimulates Ca++ release by the

sarcoplasmic reticulum in the heart, thereby increasing inotropy as one of its actions.

Channel regulation :

Activation of G – protein couple receptors � open and close ionic channel (Ca+2, K

+ or Na

+)

� Activation of second massanger C-AMP or IP3 � Hyperpolarzation or depolarization

(depends on ionic flow)

Gs = Myocardium –Ca+2 , Go and Gi = Opens K

+ channel (Heart and smooth muscle)



Kinase Linked and related receptors:

Enzymatic in nature � protein kinase or Guanylyl cyclise

Drug-receptor complex � Protein phosphorylation � Gene transcription � Protein

synthesis

e.g. Insulin receptors and various cytokines

Nuclear Receptors:

Receptors which regulates the gene transcription. Receptors located in cytosol and migrates

towards the nucleus along with the ligand.

e.g. Thyroid hormones, Estrogens and various steroid receptors



Receptors:

It is defined as macromolecule or binding site located on surface or inside the effector

cells to recognise 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 : Afinity 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)

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