Exam 5 - Anti-Platelets Flashcards
What are the purinergic receptors on platelets? What is the mechanism behind their activation and their resulting effects?
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
What is the mechanism for Platelet Activation / Aggregation?
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
Aspirin MOA:
non‐selective irreversible inhibitor of cyclooxygenase –> inhibits synthesis of the prostaglandin TXA2
Ticlopidine (Ticlid®) MOA:
Permanently inhibits P2Y12
Ticlopidine (Ticlid®) t1/2, DOA:
t1/2 = 13 hrs, DOA = long, similar to aspirin
*prodrug metabolized to active thiol metabolite
Ticlopidine (Ticlid®) DDIs:
NSAIDs; anti‐coagulants: increase risk for bleeding
SSRI / SNRI: increase risk for bleeding via 5‐HT activation
Clopidogrel (Plavix®) MOA:
Permanently inhibits P2Y12
Clopidogrel (Plavix®) metabolism:
Prodrug; requires activation via CYP 2C19
Clopidogrel (Plavix®) DDIs:
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
Prasugrel (Effient®) MOA:
Irreversible inhibitor of P2Y12
*more potent than clopidogrel
Prasugrel (Effient®) metabolism:
Prodrug; metabolism by CYP 2B6 and 3A4 to active metabolite
Prasugrel (Effient®) DDIs:
heparin/warfarinrNSAIDs: increased risk for bleeding
impact from CYP 3A4 inhibitors/inducers negligible
Ticagrelor (Brilinta®) MOA:
Reversible antagonist at P2Y12
*More potent than clopidogrel
Ticagrelor (Brilinta®) metabolism, elimination:
CYP3A4
hepatic elimination
Ticagrelor (Brilinta®) t1/2:
t1/2 = 7‐9 hrs
Ticagrelor (Brilinta®) DDIs:
strong inhibitors/inducers of CYP 3A4 or Pgp
High dose CYP3A4 substrates (i.e., statins)
Cangrelor (Kengreal®) MOA
Reversible antagonist at P2Y12
*I.V. med – transition to clopidogrel/prasugrel post-op
Cangrelor (Kengreal®) t1/2:
t1/2 = 3‐6 mins
PDE‐I class MOA:
Inhibits phosphodiesterase levels –> increase intracellular cAMP –> decrease in platelet aggregation
Dipyridamole (Aggrenox® = DIP + aspirin) MOA:
PDE3‐inhibition –> increase cAMP –> decrease platelet aggregation
Dipyridamole (Aggrenox® = DIP + aspirin) t1/2:
t1/2 ~ 45 mins
PDE-I function:
Catalyzes conversion of cAMP to adenosine
Cilostazol (Pletal®) MOA:
1) PDE3A‐inhibition –> increase cAMP –> decrease platelet aggregation
2) Enhances adenosine uptake via A2‐R
* selectivity for PDE‐3A over dipyridamole