Drugs that affect hemostasis

1. Drugs that affect hemostasis Ahmad Shihada Silmi Msc, FIBMS IUG Faculty of Sciences Medical Technology Dep.

2. Drugs that affect hemostasis Drugs are categorized according to the process they target. An injured blood vessel • Contracts • Forms a platelet plug (1º hemostasis) • Forms a protein clot (2º hemostasis) • Once healed, solubilizes the clot (fibrinolysis) Drugs Affecting Hemostasis

3. Anticoagulants

4. Oral anticoagulants 4-Hydrdroxycoumarin and indan-1,3-dione are the parent molecules.

5. Warfarin Interferes with the synthesis of the vitamin K-dependent clotting factors MechanismDrugs Affecting Hemostasis

6. Mechanism of ActionInterferes with liver synthesis Vitamin K VII Synthesis of Functional Coagulation Factors IX X II C Synthesis of Anti- coagulation Proteins S Z Drugs Affecting Hemostasis

7. Vitamin K Action Drugs Affecting Hemostasis

8. Warfarin Mechanism of Action Drugs Affecting Hemostasis

9. Warfarin Pharmacokinetics • ABSORPTION: Rapid, complete. Used orally. • DISTRIBUTION: Vd is small; plasma protein binding ≈ 99%. • [Maternal] = [Fetal]. Warfarin is not found in breast milk; other coumadins are! • ELIMINATION: T1/2 = 40 hr. • ONSET: 2-3 days. • DURATION: 2-5 days. Drugs Affecting Hemostasis

10. Warfarin: Adverse Actions • Bleeding is the main concern • vitamin K, clotting factors, fresh frozen plasma • Crosses the placenta and is teratogenic during weeks 6-12 • Alopecia, urticaria, dermatitis, fever, nausea, diarrhea, abdominal cramps, anorexia, skin necrosis Drugs Affecting Hemostasis

11. Drug Interactions Drug interactions are particularly important with oral anticoagulants, and the result may be either an increase or a decrease in the effect of the anticoagulant. Frequent monitoring of the prothrombin time is essential when administering another drug with warfarin, and changing the dose of warfarin may be necessary. Drugs increase anticoagulation by Displacement of protein bound warfarin. Because of the high degree of warfarin bound to plasma proteins, even a small decrease in the amount bound can lead to significant increases in free drug levels. Examples: salicylates such as aspirin. Inhibition of the liver microsomal enzyme system that metabolizes warfarin will increase the availability of warfarin. Example: quinidine. Increasing the warfarin “receptor site” affinity will increase the efficacy of a given plasma level of warfarin. Example: d-thyroxine. Reducing the availability of vitamin K. Example: broad spectrum antibiotics, laxatives. Inhibiting platelet function. Example, aspirin. Drugs depress anticoagulation by Stimulation of the hepatic microsomal enzyme system. This decreases plasma half-life of warfarin. Example: barbiturates. Stimulation of clotting factor synthesis. This antagonizes the effect of warfarin. Example: vitamin K, estrogens. Inhibition of absorption. Example: cholestyramine. Drugs Affecting Hemostasis

12. Heparin • 2-40 kDa MW, naturally occurring N- & O-sulfated sugars polymerized by glycoside bonds found in the secretory granules of mast cells. Drugs Affecting Hemostasis

13. Heparin • 2-40 kDa MW, naturally occurring N- & O-sulfated sugars polymerized by glycoside bonds found in the secretory granules of mast cells. • Lower MW polymers possess most of the biological activity. • Active in vitro as well as in vivo. • The most acidic organic acid in the body. • Is not absorbed following oral administration. Drugs Affecting Hemostasis

14. Mechanism of Action • Accelerates the inactivation of factors IIa, Xa, IXa, XIa and XIIa by the serine protease inhibitor, antithrombin III (AT III). Drugs Affecting Hemostasis

15. Mechanism of Action • Unique pentasaccharide sequence binds to antithrombin III (AT III) with high affinity but a polysaccharide of at least 18 units is required (5 for LMWH). Drugs Affecting Hemostasis

16. AT III + Heparin Serine protease Inactive Ternary complex Drugs Affecting Hemostasis

17. LMW Heparin • MW 4,000 - 6,000 • Preferentially binds to factor Xa • T1/2 2x > standard heparin • Less bleeding • Less effect on platelet activation and factor XIII activation • Clinically effective - e.g., enoxaparin Drugs Affecting Hemostasis

18. AT III IIa Heparin > 18 monosaccharide units Heparin ATIII < 18 monosaccharide units Heparin AT III Xa LMWH Drugs Affecting Hemostasis

19. Heparin Pharmacokinetics • No oral absorption; IV or subQ. • Vd is small due to extensive binding. Binding can influence the effect of heparin. • Onset: IV, immediate; subQ, 20-60 min Drugs Affecting Hemostasis

20. Heparin Adverse Actions • Bleeding is the main concern. • Antidote: protamine sulfate. • Thrombocytopenia (<5%, within a few days). Disappears with cessation of therapy. • Rapid and profound thrombocytopenia (<5%, 8-10 days) with paradoxical arterial or venous thrombosis. Results from the formation of anti-heparin antibodies. Heparin-Ab bind to platelets causing inappropriate aggregation and thrombus formation. May be life-threatening. • Reversible osteoporosis (6 months). If it occurs, it is usually after 6 months therapy with >15,000 U/day. Drugs Affecting Hemostasis

21. Antiplatelet Drugs Drugs Affecting Hemostasis

22. Therapeutic overview

23. Aspirin Mechanism of Action Aspirin irreversibly inactivates cyclooxygenase by covalent acetylation. Drugs Affecting Hemostasis

24. Aspirin inhibits Aspirin inhibits

25. Selectivity of aspirin for platelet COX • Platelet COX is acetylated in the portal circulation before aspirin is deacylated in the liver. • The systemic vasculature is unaffected because platelets are not affected by salicylate. Drugs Affecting Hemostasis

26. Aspirin Pharmacokinetics • ABSORPTION: 70% • DISTRIBUTION: at low doses most is protein bound in plasma; at high doses a smaller percentage is bound and more is available to tissues • ELIMINATION: hepatic metabolites (75%) and parent compound excreted in urine. At low doses half-life is 4 hr and is 1st order. High doses show saturation kinetics and half-life is 15 hr. Faster in alkaline urine. • ONSET: 30 min • DURATION: 7-10 days Drugs Affecting Hemostasis

27. Aspirin Adverse Actions Primarily gastrointestinal • Epigastric pain, heartburn, nausea • GI blood loss • Gastric ulcer • Others: rash, tinnitus, nasal polyps, gout, acid-base disturbances Drugs Affecting Hemostasis

28. Aspirin Drug Interactions • Decreases the effectiveness of antihypertensives: usually not a problem with low doses. • Increases the effect of warfarin. • Attenuates the actions of uricosuric agents, e.g. probenecid. Drugs Affecting Hemostasis

29. Ticlopidine and Clopidogrel P2Y2 purine receptor antagonists. Drugs Affecting Hemostasis

30. Other Antiplatelet Drugs Ticlopidine and Clopidogrel: P2Y2 purine receptor antagonists clopidogrel  P2Y1R P2Y2R AC Drugs Affecting Hemostasis Daniel, J. L. et al. J. Biol. Chem. 1998;273:2024-2029

31. Clopidogrel • Reduces the incidence of stroke and myocardial ischemia. • Particularly effective combined with aspirin. • Currently the drug of choice in the prophylaxis of subacute stent thrombosis and post ischemic stroke treatment. Drugs Affecting Hemostasis

32. Glycoprotein IIb/IIIa Inhibitors GP IIb/IIIa is a platelet surface integrin (aIIb3) • GP IIb/IIIa is the receptor for fibrinogen and von Willebrand factor. • Thrombin, collagen, TXA2 activate platelets exposing binding sites for vWf and fibrinogen. Drugs Affecting Hemostasis

33. Basal platelet with GP IIb/IIIa receptors in inactive state Activated platelet with functional GP IIb/IIIa receptors Fibrinogen Agonist GP IIb/IIIa antagonist () Fibrinogen mediated platelet aggregation Fibrinogen binding to platelets blocked by GP IIb/IIIa receptor antagonist

34. Glycoprotein IIb/IIIa Inhibitors • Abciximab--Fab fragment directed to the GPIIb/IIIareceptor. Can be used only once. • Eptifibatide--a cyclic peptide • Tirofiban--a nonpeptide inhibitor Drugs Affecting Hemostasis

35. Fibrinolytics Restore blood flow to an injured area by lysing the thrombus into soluble fibrin degradation products. Drugs Affecting Hemostasis

36. Alteplase (rtPA) Urokinase Streptokinase Anistreplase Drugs Affecting Hemostasis

37. Site of action of drugs acting on the fibrinolytic system. Fibrinolytic drugs accelerate the conversion of plasminogen to plasmin, which is a protease that breaks down fibrinogen and fibrin to degradation products. © 2005 Elsevier

38. tPA, tissue plasminogen activator L, lysine binding sites PI, plasmin inactivator Drugs Affecting Hemostasis

39. Treatment Goals Rapid reperfusion of the infarcted area to preserve more tissue. Drugs Affecting Hemostasis

40. Fibrinolytic success is dependent upon the time lapse between the onset of symptoms and administration of the fibrinolytic. • DVT: < 7 days • Pulmonary embolism: < 2 days • Myocardial infarction: 2 - 4 hr • Stroke: < 3 hr Drugs Affecting Hemostasis

41. Fibrinolytics: Adverse Actions Unwanted BLEEDING is the MAJOR side effect. Drugs Affecting Hemostasis

42. The End Drugs Affecting Hemostasis