SIM Mechanism of Drug Action

Question 1

Acetylcholine:
Where does it act?
How is it made?

Answer 1

Neuromuscular Junction

Acetyl CoA + Choline + Choline O-acetyletransferase [enzyme]

Question 2

Nicotinic Ach Receptor:
Nature? How many units? What are its subunits?
How many Ach needed for activation?
MOA

Answer 2

Ligand gated ion channel;
5 subunits; 2 alpha, 1 beta, 1 gamma, 1 delta;
Needs two Ach molecules to activate;
Stops influx of Na due to competition with Ach

Question 3

Tubocarine:
MOA, Effect on body
Effect of small dose? of large dose?

Answer 3

Competitive antagonist to Ach hence no AP;
Relaxes muscles;
Competitive inhibitor;
Blockades the receptor;

Question 4

GABA
Where does it act?
How is it made?

Answer 4

In every area of the brain;

Glutamate + glutamic acid decarboxylase [enzyme]

Question 5

GABA Receptor:

Nature? How many units? What are its subunits? MOA? Types?

Answer 5

Ligand Gated ion channel;
5 subunits, 2 alpha, 2 beta, 1 gamma;
Influx of Cl / Efflux of K / No Calcium Entry;

Question 6

GABA-a vs GABA-b:

Nature, MOA, Speed

Answer 6

GABA-a:
ligand-gated ion channel, influx of Cl, fast IPSP

GABA-b:
G-protein coupled, inhibit Ca channels / Efflux of K, slow IPSP

Question 7

Diazepam:

MOA, Effects on Body (5)

Answer 7

Allosteric activator of GABA receptor –> increased Cl influx –> hyperpolarization –> IPSP

SAMAR: Sedation, Anticonvulsant, Muscle Relaxant, Anesthesia, Respiratory depression

Question 8

Two most common enzyme systems of the 7-transmembrane domain

Answer 8

Adenylyl Cyclase and Phospholipase C (PLC)

Question 9

Discuss cAMP Pathway.
What residues does PKA bind to?
How many units does PKA have?
What does CBP do?

Answer 9

Adenylyl Cycles + ATP [substrate] –> cAMP –> activate cAMP dependent PKA –> Phosphorylate cAMP response element binding protein –> recruits CREB binding protein

Serine and Threonine of CREB;
4, 2 catalytic, 2 regulatory (where cAMP binds);
Stimulate gene transcription and protein synthesis;

Question 10

Cholera toxin MOA

Effect on body

Answer 10

Causes ADP ribosylation –> alters alpha subunit –> cannot hydrolyze ATP –> Inc cAMP –> efflux of Cl into gut

Diarrhea

Question 11

Pertussis Toxin MOA

Effect on Body

Answer 11

Causes ADP ribosylation –> alpha subunit alteration –> cannot bind to GTP

Whooping cough

Question 12

Norepinephrine:
Nature? Receptor? cAMP or PLC? MOA
Effect?

Answer 12

Sympathetic;
B2 receptor;
cAMP;
cAMP inactivates Myosine Light Chain Kinase –> unable to phosphorylate myosin –> no contraction

Muscle relaxation, BronchoDILATE

Question 13

Salbutamol:
Nature? MOA? Effect?
What happens if dose is low? if dose is high?

Answer 13

B2 Adrenergic Agonist;
Same ;with Norepinephrine
Low dose: Bronchodilate, B2 specific
High dose: tremors, tachycardia, less B2 specific

Question 14

Cholinergic Transmission:
Ligand? Receptor? Nature of receptor?
cAMP or PLC? MOA? Effect on Body?

Answer 14

Ach; Muscarinic (M2), GPCR, PLC pathway;

PLC hydrolize PIP –> DAG + IP3 –> IP3 inc cytoplasmic Ca / DAG activates PKC;

BronchoCONSTRICT (parasympathetic), reduce contractile forces, slow down HR

Question 15

Atropine:

Components? Nature? Effect

Answer 15

D-hyoscyamine and L-hyoscyamine;
Anticholinergic competitive inhibitor to Ach;
Decrease parasympathetic effect –> BronchoDILATE, for asthma

Question 16

Signal Transduction in Enzyme/Kinase-linked receptors involves ____ and ____.

Answer 16

Dimerization of receptors

Autophosphorylation of Tyrosine residues

Question 17

Tyrosine Kinase Insulin Receptor:
What subunit? How many? How many Insulin Molecules needed?
MOA?

Answer 17

4 subunits, 2 extracellular alpha and 2 transmembrane beta;
2 insulin molecules bind to the alpha sub units –> activate beta –> autophosphorylation of Tyr residues and Insulin Receptor Substrate

Question 18

What is IRS? What is its role/function?

Answer 18

Insulin Receptor Substrate releases PIP and increases GLUT4 transporters

Increased glucose uptake

Question 19

Estrogen:
active forms? secreted by what organ?
2 main targets?
Other targets?

Answer 19

Estrone and estradiol;
ovaries, estrone by adrenal glands;
Breast and Uterus;
Bone, brain, heart, liver

Question 20

Estrogen Receptor:
Stabilizers?
Types?

Answer 20

HSP90 as stabilizers;
ER alpha in andometrium and breast
ER beta in granulose cells and osteoblasts

Question 21

Discuss signal cascade of Estrogen

Answer 21

Estradiol enters cell –> binds to ER at cytoplasm / nucleus –> Release from HSP90 –> binds to Estrogen Response Elements at Nucleus –> gene transcription and protein synthesis

Question 22

TGF alpha vs TGF Beta:

Answer 22

TGF alpha: estrogen stimulated growth, prolif and anchorage

TGF beta: pro-apoptosis, ECM deposition and modeling

Question 23

Tamoxifen:
Nature? Receptor Target? Route?
What happens in liver?
Cytostatic or Cytotoxic? Other effects?

Answer 23

Partial Competitive Agonist inhibitor of estrogen; ER of breast and uterus; Oral route;

Tamoxifen [prodrug] –> Endoxifen [activated]

Cytostatic, suppress IGF1, upregulates TGF-b (pro apoptosis) an inhibit TGF-a

Question 24

2 Limitations of Tamoxifen Therapy

Answer 24

1. Only binds to ER (+) Breast CA

2. Some patients cant metabolize endoxifen due to alteration in CYP2D6

Question 25

2 Mechanisms of Desensitization

Answer 25

Homologous: loss of responsiveness due to continuous stimulation

Heterologous: desensitization of some receptor will desensitize others due to phosphorylation of the receptor by PKA or PKC