Basics in Pharmacology - 3

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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

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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
GABA
A
receptors
Glutamate receptors of NMDA

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Gating mechanism:
When Ach bound to -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

, , Subunits
Subunit (23 isoforms): contains the GTP/GDP binding site is responsible for
identity.
(5 isoforms) and (12 isoforms): are identical or very similar, interchangeable
vitro; most of them are ubiquitously expressed; membrane anchored through
prenylation of G.
Subtypes of G-Protein couple receptors:
Gs = adenylyl cyclase and Ca
Gi = adenylyl cyclase and K
G
0
= Ca
++
Channel and
Gq = Phospholipase C
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subunit Twisting of -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
(5 isoforms) and (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- .
Basics in Pharmacology
Page 5 of 9
Opening of channels
Influx of Na+ ions causes depolarization of cells.

(5 isoforms) and (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 IP
3
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 -
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 IP
3
pathway is linked to activation of
1
-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 (IP
3
) from
phosphatidylinositol biphosphate (PIP
2
). Increased IP
3
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 IP
3
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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