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

3. Drugs Affecting Hemostasis Objectives 1.Describe the different mechanisms by which each class of drug produces its therapeutic action. 2.Know the therapeutic uses for each drug class. 3.Know the drug interactions that seriously affect the use of each drug or the manner in which it is used. 4.List the major adverse actions of these drugs. 5.Describe the important, distinguishing characteristics of these drugs with respect to route of administration and pharmacokinetics.

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

5. Anticoagulants Therapeutic overview Heparin and heparin derivatives Coumarins (warfarin) Directly acting thrombin inhibitors hirudin bivalirudin argatroban arterial thrombosis atrial fibrillation cardiomyopathy cerebral emboli heart valve disease hip surgery vascular prostheses Venous thromboembolism

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

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

8. Drugs Affecting Hemostasis Vitamin K Synthesis of Functional Coagulatio n Factors VII IX X II Mechanism of Action Interferes with liver synthesis C S Z Synthesis of Anti- coagulatio n Proteins

9. Drugs Affecting Hemostasis Vitamin K Action

10. Drugs Affecting Hemostasis Warfarin Mechanism of Action

11. Drugs Affecting Hemostasis Mechanism of Action Warfarin has been called a vitamin K antagonist; however, warfarin is not an antagonist in the sense that it blocks the vitamin K “receptor”. Rather, warfarin prevents the formation of the reduced form of vitamin K which is essential for the synthesis of four clotting factors: II (prothrombin), VII, IX, X, and the anticoagulant proteins S, C and Z. These factors contain about 40 glutamate residues on the amino terminal end of the protein. These glutamate residues are carboxylated post-translationally, and if this fails to occur, these factors have no activity. Reduced vitamin K is an essential cofactor for the carboxylase. Warfarin, therefore, does not interfere with the action of clotting factors already present. When warfarin administration is terminated, its action does not cease until new factors are synthesized.

12. Drugs Affecting Hemostasis Warfarin Pharmacokinetics l ABSORPTION: Rapid, complete. Used orally. l DISTRIBUTION: V d is small; plasma protein binding ≈ 99%. l [Maternal] = [Fetal]. Warfarin is not found in breast milk; other coumadins are! l ELIMINATION: T 1/2 = 40 hr. l ONSET:2-3 days. l DURATION:2-5 days.

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

14. Drugs Affecting Hemostasis 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 1.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. 2.Inhibition of the liver microsomal enzyme system that metabolizes warfarin will increase the availability of warfarin. Example: quinidine. 3.Increasing the warfarin “receptor site” affinity will increase the efficacy of a given plasma level of warfarin. Example: d-thyroxine. 4.Reducing the availability of vitamin K. Example: broad spectrum antibiotics, laxatives. 5.Inhibiting platelet function. Example, aspirin. Drugs depress anticoagulation by 1.Stimulation of the hepatic microsomal enzyme system. This decreases plasma half-life of warfarin. Example: barbiturates. 2.Stimulation of clotting factor synthesis. This antagonizes the effect of warfarin. Example: vitamin K, estrogens. 3.Inhibition of absorption. Example: cholestyramine.

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

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

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

18. Drugs Affecting Hemostasis Mechanism of Action l 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).

19. Drugs Affecting Hemostasis AT III + Heparin Serineprotease Ternary complex Inactive

20. Drugs Affecting Hemostasis LMW Heparin l MW 4,000 - 6,000 l Preferentially binds to factor Xa l T 1/2 2x > standard heparin l Less bleeding l Less effect on platelet activation and factor XIII activation l Clinically effective - e.g., enoxaparin

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

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

23. Drugs Affecting Hemostasis Heparin Adverse Actions * Bleeding is the main concern. l Antidote: protamine sulfate. l Thrombocytopenia (<5%, within a few days). Disappears with cessation of therapy. l 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. l Reversible osteoporosis (6 months). If it occurs, it is usually after 6 months therapy with >15,000 U/day.

24. Drugs Affecting Hemostasis Antiplatelet Drugs

25. Therapeutic overview Platelet aggregation inhibitors AspirinCerebrovascular accident, stroke, coronary bypass surgery, coronary angioplasty/stenting or thrombolysis, myocardial infarction, transient ischemic attack ClopidogrelCoronary artery disease, cerebrovascular accident, stroke, peripheral arterial disease Glycoprotein IIb/IIIa inhibitors Acute coronary syndromes, after coronary artery stenting

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

27. Aspirin inhibits

28. Drugs Affecting Hemostasis Selectivity of aspirin for platelet COX 1. Platelet COX is acetylated in the portal circulation before aspirin is deacylated in the liver. 2. The systemic vasculature is unaffected because platelets are not affected by salicylate.

29. Drugs Affecting Hemostasis Aspirin Pharmacokinetics l ABSORPTION: 70% l DISTRIBUTION: at low doses most is protein bound in plasma; at high doses a smaller percentage is bound and more is available to tissues l 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. l ONSET: 30 min è DURATION: 7-10 days

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

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

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

33. Drugs Affecting Hemostasis Daniel, J. L. et al. J. Biol. Chem. 1998;273:2024-2029 clopidogrel  P2Y1 R P2Y2R ACAC Other Antiplatelet Drugs Ticlopidine and Clopidogrel: P2Y2 purine receptor antagonists

34. Drugs Affecting Hemostasis In platelets Increase cAMP = decreased aggregation Decrease cAMP = increased aggregation

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

36. Drugs Affecting Hemostasis Glycoprotein IIb/IIIa Inhibitors GP IIb/IIIa is a platelet surface integrin ( IIb  3 ) l GP IIb/IIIa is the receptor for fibrinogen and von Willebrand factor. l Thrombin, collagen, TXA 2 activate platelets exposing binding sites for vWf and fibrinogen.

37. Basal platelet with GP IIb/IIIa receptors in inactive state Agonis t Activated platelet with functional GP IIb/IIIa receptors Fibrinog en Fibrinogen mediated platelet aggr egation GP IIb/IIIa antagonis t () Fibrinogen binding to platelets blocked by GP IIb/IIIa receptor antagonist

38. Figure 19-9 Inhibition of platelet aggregation by glycoprotein (GP) IIb/IIIa receptor antagonists. The GP IIb/IIIa receptors on unstimulated platelets exist in an inactive conformation that does not support fibrinogen binding. Activation of platelets by agonists, such as ADP, epinephrine, thrombin, and thromboxane A2, converts the GP IIb/IIIa receptors to an active conformation capable of binding fibrinogen, which leads to the formation of platelet aggregates. Blocking of the GP IIb/IIIa receptors with antagonists, such as abciximab, eptifibatide, and tirofiban, prevents fibrinogen from cross-linking activated platelets, thereby inhibiting thrombus growth.

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

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

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

42. 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

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

44. Drugs Affecting Hemostasis Alteplase (rtPA) l A 65 kDa single-chain enzyme l Half life = 4-5 min. l Administered by continuous intravenous infusion or infused directly into the clogged vessel.

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

46. Drugs Affecting Hemostasis 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

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

48. Drugs Affecting Hemostasis The End