Exam 5 - Anti-Platelets

Question 1

What are the purinergic receptors on platelets? What is the mechanism behind their activation and their resulting effects?

Answer 1

Receptors: P2Y1 and P2Y12, both are GPCRs

ADP binds P2Y1 and P2Y12 –> a) activation of platelets, b) inducing aggregation –> a) COX-1 is activated, b) stimulates conformational change in GP IIb/IIIa surface receptors to bind fibrinogen

Question 2

What is the mechanism for Platelet Activation / Aggregation?

Answer 2

Wall defect –> vWF and collagen (C) released –> vWF binds to Gp Ib, C binds to GP Ia on platelet –> platelet releases degranulation (ADP, TXA2, 5-HT) –> all three promote platelet aggregation and activation

Question 3

Aspirin MOA:

Answer 3

non‐selective irreversible inhibitor of cyclooxygenase –> inhibits synthesis of the prostaglandin TXA2

Question 4

Ticlopidine (Ticlid®) MOA:

Answer 4

Permanently inhibits P2Y12

Question 5

Ticlopidine (Ticlid®) t1/2, DOA:

Answer 5

t1/2 = 13 hrs, DOA = long, similar to aspirin

*prodrug metabolized to active thiol metabolite

Question 6

Ticlopidine (Ticlid®) DDIs:

Answer 6

NSAIDs; anti‐coagulants:  increase risk for bleeding

SSRI / SNRI:  increase risk for bleeding via 5‐HT activation

Question 7

Clopidogrel (Plavix®) MOA:

Answer 7

Permanently inhibits P2Y12

Question 8

Clopidogrel (Plavix®) metabolism:

Answer 8

Prodrug; requires activation via CYP 2C19

Question 9

Clopidogrel (Plavix®) DDIs:

Answer 9

NSAIDs; anti‐coagulants: increase risk for bleeding

SSRI or SNRI: increase risk for bleeding via 5‐HT activation

Warfarin: high levels of clopidogrel can inhibit CYP 2C9

Less toxic than ticlopidine

Question 10

Prasugrel (Effient®) MOA:

Answer 10

Irreversible inhibitor of P2Y12

*more potent than clopidogrel

Question 11

Prasugrel (Effient®) metabolism:

Answer 11

Prodrug; metabolism by CYP 2B6 and 3A4 to active metabolite

Question 12

Prasugrel (Effient®) DDIs:

Answer 12

heparin/warfarinrNSAIDs: increased risk for bleeding

impact from CYP 3A4 inhibitors/inducers negligible

Question 13

Ticagrelor (Brilinta®) MOA:

Answer 13

Reversible antagonist at P2Y12

*More potent than clopidogrel

Question 14

Ticagrelor (Brilinta®) metabolism, elimination:

Answer 14

CYP3A4

hepatic elimination

Question 15

Ticagrelor (Brilinta®) t1/2:

Answer 15

t1/2 = 7‐9 hrs

Question 16

Ticagrelor (Brilinta®) DDIs:

Answer 16

strong inhibitors/inducers of CYP 3A4 or Pgp

High dose CYP3A4 substrates (i.e., statins)

Question 17

Cangrelor (Kengreal®) MOA

Answer 17

Reversible antagonist at P2Y12

*I.V. med – transition to clopidogrel/prasugrel post-op

Question 18

Cangrelor (Kengreal®) t1/2:

Answer 18

t1/2 = 3‐6 mins

Question 19

PDE‐I class MOA:

Answer 19

Inhibits phosphodiesterase levels –> increase intracellular cAMP –> decrease in platelet aggregation

Question 20

Dipyridamole (Aggrenox® = DIP + aspirin) MOA:

Answer 20

PDE3‐inhibition –> increase cAMP –> decrease platelet aggregation

Question 21

Dipyridamole (Aggrenox® = DIP + aspirin) t1/2:

Answer 21

t1/2 ~ 45 mins

Question 22

PDE-I function:

Answer 22

Catalyzes conversion of cAMP to adenosine

Question 23

Cilostazol (Pletal®) MOA:

Answer 23

1) PDE3A‐inhibition –> increase cAMP –> decrease platelet aggregation

2) Enhances adenosine uptake via A2‐R
* selectivity for PDE‐3A over dipyridamole