Anti platelet agents

1. Anti-platelet agents Dr. J Pradeep

2. Contents Introduction Classification Individual drugs Newer anti-platelet agents Summary

3. Introduction Normal hemostasis M aintenance of blood in a fluid, clot-free state in normal vessels; and Formation of hemostatic plug at a site of vascular injury . Opposite : Thrombosis Thrombi are lysed and blood is made fluid by fibrinolytic system

4. Both hemostasis and thrombosis are regulated by three general components The vascular wall, Platelets, and The coagulation cascade

5. Platelet count:150000 - 400000/mm3 Lifespan: 7-10 days No nucleus Cannot synthesise proteins Shape: biconcave discs, fully spread cells

6. Receptors on platelets: GpIa/IIa : receptors for collagen GpIb : receptor for vWF GpIIb/IIIa : receptor for fibrinogen P2Y 1 /P2Y 12 : purinergic receptors for ADP PAR1/PAR4: protease activated receptors for thrombin ( IIa )

7. Platelets provide the initial hemostatic plug at sites of vascular injury They also participate in pathological thromboses that lead to myocardial infarction, stroke, and peripheral vascular thromboses

8. Platelet adhesion and aggregation

9. Classification TXA 2 inhibitors – Aspirin (non selective COX inhibitor) Phosphodiesterase inhibitors – Dipyridamole Thienopyridine derivatives – Ticlopidine , Clopidogrel , Prasugrel

10. Glycoprotein (GP) IIb/IIIa inhibitor – Abciximab , Eptifibatide , Tirofiban Newer anti-platelet agents – Cangrelor , Ticagrelor , SCH530348

11. Aspirin Aspirin blocks production of TxA 2 by acetylating a serine residue near the active site of platelet cyclooxygenase-1 (COX-1 ) T he action of aspirin on platelet COX-1 is permanent Action lasts for the life of the platelet (7-10 days )

12. Cumulative effect on repeated doses Should be stopped atleast one week prior to any surgical procedure Complete inactivation of platelet COX-1 is achieved with a daily aspirin dose of 75 mg Maximal effective doses is 50-320 mg/day

13. Anti-thrombotic dose is much lower than doses required for other actions Higher doses do not improve efficacy Potentially less efficacious because of inhibition of prostacyclin production Higher doses also increase toxicity, especially bleeding

14. Dipyridamole Interferes with platelet function by increasing the cellular concentration of cyclic AMP This effect is mediated by inhibition of cyclic nucleotide phosphodiesterases and Blockade of uptake of adenosine cAMP potentiates PGI 2 and interferes with aggregation

15. Dipyridamole alone has little clinically significant effect Inhibits embolization from prosthetic heart valves when used in combination with warfarin May potentiate the action of aspirin in preventing strokes in patients with TIA, No additional benefit as combination with aspirin in preventing MI

16. Ticlopidine Ticlopidine is a thienopyridine prodrug that inhibits the P2Y 12 receptor Converted to the active thiol metabolite in liver It is rapidly absorbed and highly bioavailable It permanently inhibits the P2Y 12 receptor and has prolonged action

17. Cumulative effect is seen Maximal inhibition of platelet aggregation is not seen until 8-11 days after starting therapy The usual dose is 250 mg twice daily Like aspirin it has short half life and inhibition of platelet aggregation lasts for few days after stopping drug

18. Side effects Common: nausea, vomiting, diarrhoea Serious adverse effect: severe neutropenia Fatal agranulocytosis with thrombocytopenia has occurred within the first 3 months of therapy

19. Frequent blood counts and platelet counts are advised in first few months of therapy Discontinue therapy if counts fall Thrombotic thrombocytopenic purpura -hemolytic uremic syndrome (TTP-HUS ) – rare adverse effect

20. Therapeutic uses Prevention of stroke and TIAs Intermittent claudication Unstable angina Prevention of MI Preventing restenosis and stent thrombosis after PCI

21. Clopidogrel Similar to ticlopidine Theinopyridine pro drug with slow onset of action (only 15% is activated by CYP3A4) Irreversible inhibitor of platelet P2Y 12 M ore potent and lesser side effects Usual dose is 75 mg/day with or without an initial loading dose of 300 or 600 mg

22. Secondary prevention of stroke : somewhat better than aspirin Prevention of recurrent ischemia in patients with unstable angina: better as combination with aspirin Synergistic with aspirin since mechanism of action is different

23. Wide inter-individual variability in efficacy of clopidogrel is seen Genetic polymorphism in CYP2C19 Patients with reduced function of CYP219*2 allele show less inhibition of platelets by clopidogrel and have higher rate of cardiovascular events

24. Uses To reduce the rate of stroke, myocardial infarction, and death in P atients with recent myocardial infarction or stroke E stablished peripheral arterial disease A cute coronary syndrome

25. Interactions Proton pump inhibitors , inhibitors of CYP2C19 , produce a small reduction in the inhibitory effects of clopidogrel on ADP-induced platelet aggregation Atorvastatin , a competitive inhibitor of CYP3A4, reduced the inhibitory effect of clopidogrel on ADP-induced platelet aggregation

26. Prasugrel Thienopyridine prodrug Rapid onset of action Greater inhibition of ADP induced platelet aggregation Almost completely absorbed from the gut Almost all of the drug is activated

27. Irrversible inhibitor of P2Y 12 receptor Has prolonged effect after discontinuation Better than clopidogrel in reducing incidence of non fatal MI The incidence of stent thrombosis also was lower with prasugrel than with clopidogrel

28. However, it has higher rates of fatal and life-threatening bleeding Contraindicated in those with a history of cerebrovascular disease - high risk of bleeding Caution is required if prasugrel is used in patients weighing <60 kg or in those with renal impairment

29. After a loading dose of 60 mg, prasugrel is given once daily at a dose of 10 mg Patients >75 years of age or weighing <60 kg may do better with a daily prasugrel dose of 5 mg It is reasonable alternative to clopidogrel in patients with the loss-of-function CYP2C19 allele because there is no association with decreased anti platelet action in prasugrel

30. Glycoprotein IIb /IIIa inhibitors Block final step in platelet aggregation induced by any agonist Abciximab Eptifibatide Tirofiban

31. Abciximab Abciximab is the Fab fragment of a humanized monoclonal antibody directed against the GpIIb/IIIa receptor Uses: percutaneous angioplasty for coronary thromboses prevent restenosis , recurrent myocardial infarction, and death: used in combination with aspirin and heparin

32. T1/2: 30 min Duration of action: 18 – 24 hrs Dose: 0.25-mg/kg bolus followed by 0.125 g /kg/min for 12 hours or longer, IV Adverse effects: Hemorrhage (1-10%) Thrombocytopenia (2%) Platelet transfusions can reverse the aggregation defect E xpensive

33. Eptifibatide Cyclic peptide inhibitor of the fibrinogen binding site on GpIIb/IIIa receptor Dose: 180 g /kg IV bolus followed by 2 g /kg/min for up to 96 hours Short duration of action: 6-12 hrs Given with aspirin and heparin

34. Use: Acute coronary syndrome Angioplastic coronary interventions Adverse effects: Bleeding (10%) Thrombocytopenia (0.5-1%)

35. Tirofiban Similar to eptifibatide Value in antiplatelet therapy after acute myocardial infarction is limited Used in conjunction with heparin

36. GpIIb/IIIa inhibitors Features Abciximab Eptifibatide Tirofiban Description Fab fragment of humanized mouse monoclonal antibody Cyclical heptapeptide Nonpeptide Specific for GPIIb/IIIa No Yes Yes Plasma t 1/2   Short Long (2.5h) Long (2.0h) Platelet-bound t 1/2   Long (days) Short (sec) Short (sec) Renal clearance  No Yes Yes

37. Newer anti-platelet agents Cangrelor Ticagrelor SCH530348 E5555

38. Cangrelor Adenosine analogue Reversible inhibitor of P2Y 12 receptor T1/2: 3-6 min Duration of action: 60 min Administration: IV bolus followed by infusion Little or no advantage over other drugs

39. Ticagrelor Orally active reversible inhibitor of P2Y 12 receptor Rapid onset and offset of action Twice daily dosage First new antiplatelet drug to demonstrate a reduction in cardiovascular death compared with clopidogrel in patients with acute coronary syndromes

40. SCH530348, E5555 SCH530348 an orally active inhibitor of PAR-1, is under investigation as an adjunct to aspirin or aspirin plus clopidogrel . Two large phase III trials are under way. E5555 is an oral PAR-1 antagonist in early developement

41. Summary Potent inhibitors of platelet function have been developed in recent years These drugs act by discrete mechanisms; thus, in combination, their effects are additive or even synergistic Aspirin has  remained,  for  over  50  years,  the  cornerstone  of  antiplatelet  therapy  owing  to  its  proven  clinical  benefit and  very  good  cost–effectiveness  profile.

42. Their availability has led to a revolution in cardiovascular medicine, whereby angioplasty and vascular stenting of lesions now are feasible with low rates of restenosis and thrombosis when effective platelet inhibition is employed

43. Thank you.

44. References Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12 th edition,  Section III. Modulation of Cardiovascular Function, Chapter 30. Blood Coagulation and Anticoagulant, Fibrinolytic , and Antiplatelet Drugs   Robbins and Cotran’s Pathologic basis of disease, 8 th edition, Section IV, Hemodynamic disorders, Thromboembolic disease and shock. Hemostasis and thrombosis. Tripathi K D, essentials of medical pharmacology, 6 th edition, Section ten, Drugs affecting blood and blood formation. Drugs affecting coagulation, bleeding and thrombosis. Kallirroi  I  Kalantzi,  Maria  E  Tsoumani,   ET. AL. Pharmacodynamic  Properties  of  Antiplatelet  Agents - Current  Knowledge  and  Future  Perspectives , Expert  Rev  Clin  Pharmacol.  2012;;5(3):319-­336

45. Dazoxiben It inhibits the enzyme thromboxane synthetase so reduces the concentration of thromboxane A 2 Its antiplatelet action is not satisfactory, when used alone. However may be useful when used with aspirin.

46. PROSTACYCLINE ANALOGUES Ex are epoprostenol , iloprost These group of drugs block all pathway for platelet activation. They also inhibits the expression of GP IIb / IIIa receptor. Epoprostenol has a very short half life of 3 mins so it has to be used by iv infusion. It causes headache and flushing due to vasodilation. i loprost is similar to epoprostenol but iloprost is longer acting.