Antiplatelet and thrombolytic drugs

1. Antiplatelet and thrombolytic drugs

2. Vascular Injury Tissue factor exposure Exposure of collagen and vWF Platelet adhesion and release Activation of coagulation Thrombin generation Platelet recruitment and activation Fibrin formation Platelet aggregation Platelet – fibrin thrombus

3. Plaque Disruption Collagen vWF Platelet adhesion and secretion X COX-1 Aspirin ADP Thrombin generation TXA2 X Platelet recruitment and activation GPllb / llla activation AbciximabEptifibatide Tirofiban X Platelet aggregation

4. Components of hemostatic System:- • Platelets • Plasma proteins – Coagulation & Fibrinolytic factors & inhibitors • Vessel wall itself • Steps of normal homeostasis :- • Platelet plug formation:- • Adhesion, activation, aggregation • Fibrin clot formation:- • Coagulation - intrinsic • - extrinsic • Trigger for coagulation – Tissue factor

5. ANTI – THROMBOLYTIC Mechanisms • Endothelial cells • prostacyclin, NO & ectoADPase / CD 39 • Anticoagulant factors – heparanproteoglycans, antithrombin, TF pathway inhibitors & thrombomodulin • Fibrinolytic mechanisms – tPA1, urokinase, PA inhibitor, Annexin-2 • Antithrombin III – major inhibitor of thrombin. Protein C - > activated by thrombin -> anticoagulant cofactor -> Protein S -> vit K dependent post translational modification • Tissue factor pathway inhibitor

6. FIBRINOLYSIS - REGULATION • Plasminogen activator inhibitors PAIs, 1&2 • 2 anti plasmin

7. ANTI COAGULANTS

8. INDIRECT THROMBIN INHIBITORS • Heparin • LMWH – Enoxaparin, dalteparin • Fondaparinaux • Rivaroxiban (1st oral factor Xa inhibitor)

9. DIRECT THROMBIN INHIBITORS • Hirudin – Lepirudin • Bivalirudin • Argatroban • Melagatran • Ximelagatran (oral) • Dabigatran (oral)

10. FIBRINOLYTICS • Streptokinase • Urokinase • Anistreplase • t-PA • Reteplase • tenecteplase

11. ANTIPLATELETS • Aspirin • ADP receptor antagonists – clopidogrel, ticlopidine • GP IIB/IIIA inhibitors – Abciximab, Eptifibatide, Tirofiban • Dipyridamole • Cilostazol

19. Antithrombotic drugs Fibrinolytics

20. Antithrombotic drugs Fibrinolytics

21. Antithrombotic drugs Fibrinolytics

22. Antithrombotic drugs Fibrinolytics

23. The role of platelets

24. The role of platelets

25. The role of platelets

26. The role of platelets

28. Antiplatelet drugs Antiplatelet drugs Acetylsalicylicacid (aspirin) GPIIb/IIIaantagonists P2Y12 antagonists Dipyridamole Used widely in patients at risk of thromboembolic disease Beneficial in the treatment and prevention of ACS and the prevention of thromboembolic events Secondary prevention in patients following stroke, often in combination with aspirin Administered intravenously, are effective during percutaneous coronary intervention (PCI)

29. Acetylsalicylic acid – mechanism of action

30. Acetylsalicylic acid – mechanism of action

31. Acetylsalicylic acid – mechanism of action

32. Acetylsalicylic acid – mechanism of action

33. Acetylsalicylic acid – mechanism of action

34. Acetylsalicylic acid – pharmacokinetics • Rapid absorption of aspirin occurs in the stomach and upper intestine, with the peak plasma concentration being achieved 15-20 minutes after administration • The peak inhibitory effect on platelet aggregation is apparent approximately one hour post-administration • Aspirin produces the irreversible inhibition of the enzyme cyclo-oxygenase and therefore causes irreversible inhibition of platelets for the rest of their lifespan (7 days)

35. Acetylsalicylic acid – major use • Secondary prevention of transient ischaemic attack (TIA), ischaemic stroke and myocardial infarction • Prevention of ischaemic events in patients with angina pectoris • Prevention of coronary artery bypass graft (CABG) occlusion

36. Acetylsalicylic acid – major drawbacks • Risk of gastrointestinal adverse events (ulceration and bleeding) • Allergic reactions • Is not a very effective antithrombotic drug but is widely used because of its ease of use • Lack of response in some patients (aspirin resistance) • The irreversible platelet inhibition

37. ADP-receptor antagonists – mechanism of action

38. ADP-receptor antagonists – mechanism of action

39. ADP-receptor antagonists – mechanism of action

40. ADP-receptor antagonists – mechanism of action

41. ADP-receptor antagonists – pharmacokinetics • Both currently available ADP-receptor antagonists are thienopyridines that can be administered orally, and absorption is approximately 80-90% • Thienopyridines are prodrugs that must be activated in the liver

42. ADP-receptor antagonists– major use • Secondary prevention of ischaemic complications after myocardial infarction, ischaemic stroke and established peripheral arterial disease • Secondary prevention of ischaemic complications in patients with acute coronary syndrome (ACS) without ST-segment elevation

43. ADP-receptor antagonists – major drawbacks • Clopidogrel is only slightly more effective than aspirin • As with aspirin, clopidogrel binds irreversibly to platelets • In some patients there is resistance to clopidogrel treatment

44. Dipyridamole – mechanism of action

45. Dipyridamole – mechanism of action

46. Dipyridamole – mechanism of action

47. Dipyridamole – pharmacokinetics • Incompletely absorbed from the gastrointestinal tract with peak plasma concentration occuring about 75 minutes after oral administration • More than 90% bound to plasma proteins • A terminal half-life of 10 to 12 hours • Metabolised in the liver • Mainly excreted as glucuronides in the bile; a small amount is excreted in the urine

48. Dipyridamole– major use • Secondary prevention of ischaemic complications after transient ischaemic attack (TIA) or ischaemic stroke (in combination with aspirin)

49. Dipyridamole – major drawbacks • Is not a very effective antithrombotic drug • Dipyridamole also has a vasodilatory effect and should be used with caution in patients with severe coronary artery disease; chest pain may be aggravated in patients with underlying coronary artery disease who are receiving dipyridamole

50. GPIIb/IIIa-receptor antagonists – mechanism of action