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- 1. Anti-platelet agents Dr. J Pradeep
- 2. Contents • Introduction • Classification • Individual drugs • Newer anti-platelet agents • Summary
- 3. Introduction • Normal hemostasis – Maintenance of blood in a fluid, clot-free state in normal vessels; and – Formation of hemostaticplug at a site of vascular injury. • Opposite : Thrombosis – Thrombi are lysed and blood is made fluid by fibrinolytic system
- 5. • Both hemostasis and thrombosis are regulated by three general components –The vascular wall, –Platelets, and –The coagulation cascade
- 7. • Platelet count:150000 - 400000/mm3 • Lifespan: 7-10 days • No nucleus • Cannot synthesise proteins • Shape: biconcave discs, fully spread cells
- 9. • Receptors on platelets: – GpIa/IIa: receptors for collagen – GpIb: receptor for vWF – GpIIb/IIIa: receptor for fibrinogen – P2Y1/P2Y12: purinergic receptors for ADP – PAR1/PAR4: protease activated receptors for thrombin (IIa)
- 10. • 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
- 11. Platelet adhesion and aggregation
- 12. Classification • TXA2 inhibitors – Aspirin (non selective COX inhibitor) • Phosphodiesterase inhibitors – Dipyridamole • Thienopyridine derivatives – Ticlopidine, Clopidogrel, Prasugrel
- 13. • Glycoprotein (GP) IIb/IIIa inhibitor – Abciximab, Eptifibatide, Tirofiban • Newer anti-platelet agents – Cangrelor, Ticagrelor, SCH530348
- 15. Aspirin • Aspirin blocks production of TxA2by acetylating a serine residue near the active site of platelet cyclooxygenase-1 (COX-1) • The action of aspirin on platelet COX-1 is permanent • Action lasts for the life of the platelet (7-10 days)
- 16. • 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
- 17. TXA2 • 50-320mg/day • Pro - aggregation PGI2 • Higher doses • Anti - aggregation
- 18. • 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
- 19. 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 • cAMPpotentiates PGI2 and interferes with aggregation
- 20. • 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
- 21. Ticlopidine • Ticlopidine is a thienopyridineprodrug that inhibits the P2Y12receptor • Converted to the active thiol metabolite in liver • It is rapidly absorbed and highly bioavailable • It permanently inhibits the P2Y12receptor and has prolonged action
- 23. • 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
- 24. Side effects • Common: nausea, vomiting, diarrhoea • Serious adverse effect: severe neutropenia • Fatal agranulocytosis with thrombocytopenia has occurred within the first 3 months of therapy
- 25. • 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
- 26. Therapeutic uses • Prevention of stroke and TIAs • Intermittent claudication • Unstable angina • Prevention of MI • Preventing restenosis and stent thrombosis after PCI
- 27. Clopidogrel • Similar to ticlopidine • Theinopyridine pro drug with slow onset of action (only 15% is activated by CYP3A4) • Irreversible inhibitor of platelet P2Y12 • More potent and lesser side effects • Usual dose is 75 mg/day with or without an initial loading dose of 300 or 600 mg
- 28. • 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
- 29. • 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
- 30. Uses • To reduce the rate of stroke, myocardial infarction, and death in – Patients with recent myocardial infarction or stroke – Established peripheral arterial disease – Acute coronary syndrome
- 31. 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
- 32. Prasugrel • Thienopyridineprodrug • Rapid onset of action • Greater inhibition of ADP induced platelet aggregation • Almost completely absorbed from the gut • Almost all of the drug is activated
- 34. • Irrversible inhibitor of P2Y12 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
- 35. • However, it has higher rates of fatal and life- threatening bleeding • Contraindicated in those with a history of cerebrovasculardisease - high risk of bleeding • Caution is required if prasugrel is used in patients weighing <60 kg or in those with renal impairment
- 36. • 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
- 37. Glycoprotein IIb/IIIa inhibitors • Block final step in platelet aggregation induced by any agonist • Abciximab • Eptifibatide • Tirofiban
- 38. 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
- 39. • 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 • Expensive
- 40. 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
- 41. • Use: – Acute coronary syndrome – Angioplastic coronary interventions • Adverse effects: – Bleeding (10%) – Thrombocytopenia (0.5-1%)
- 42. Tirofiban • Similar to eptifibatide • Value in antiplatelet therapy after acute myocardial infarction is limited • Used in conjunction with heparin
- 43. 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 t1/2 Short Long (2.5h) Long (2.0h) Platelet-bound t1/2 Long (days) Short (sec) Short (sec) Renal clearance No Yes Yes
- 44. Newer anti-platelet agents • Cangrelor • Ticagrelor • SCH530348 • E5555
- 45. Cangrelor • Adenosine analogue • Reversible inhibitor of P2Y12 receptor • T1/2: 3-6 min • Duration of action: 60 min • Administration: IV bolus followed by infusion • Little or no advantage over other drugs
- 46. Ticagrelor • Orally active reversible inhibitor of P2Y12 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
- 47. 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
- 48. 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 cornerst one of antiplatelet therapy owing to its prove n clinical benefit and very good cost– effectiveness profile.
- 49. • 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
- 50. THANK YOU.
- 51. References • Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12th 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, 8th edition, Section IV, Hemodynamic disorders, Thromboembolic disease and shock. Hemostasis and thrombosis. • Tripathi K D, essentials of medical pharmacology, 6th 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 Ph armacol. 2012;;5(3):319--336
- 52. Dazoxiben • It inhibits the enzyme thromboxane synthetase so reduces the concentration of thromboxane A2 • Its antiplatelet action is not satisfactory, when used alone. • However may be useful when used with aspirin.
- 53. PROSTACYCLINE ANALOGUES • Ex are epoprostenol, iloprost • These group of drugs block all pathway for platelet activation. • They also inhibits the expression of GPIIb/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. • iloprost is similar to epoprostenol but iloprost is longer acting.