DRUGS_AFFECTING_HAEMOSTASIS_AND_THROMBOSIS.pptx

Pharmacology

1. DRUGS THAT AFFECT HAEMOSTASIS AND THROMBOSIS Dr Sindwa Kanyimba Lecturer, Pharmacology 1

2. The term ' haemostasis ' refers to the normal response of the vessel to injury by forming a clot that serves to limit haemorrhage Thrombosis is pathological clot formation that results when haemostasis is excessively activated in the absence of bleeding Drugs can be used to modify haemostasis and thrombosis in three ways: (1) By modifying coagulation (2) By modifying platelet aggregation (3) By modifying fibrinolysis INTRODUCTION 2

3. Anticoagulants prevent thrombus formation or extension of an existing thrombus in the slower moving venous side of the circulation Anti-platelet agents inhibit adhesion, activation and aggregation of platelets and therefore prevent thrombosis. They are mostly used for prevention of arterial thrombosis. Thrombolytic drugs are used to lyse thrombi in blood vessels in arterial and venous thrombosis, and are useful in conditions such as acute myocardial infarction occurring due to coronary thrombosis INTRODUCTION …. CONT’D 3

4. Anti-thrombolytic drugs inhibit thrombolysis and are used in conditions where there is need to inhibit excessive thrombolysis e.g. treatment of excessive effect of thrombolytic drugs INTRODUCTION …. CONT’D 4

5. ANTI-COAGULANT DRUGS 5

6. LEARNING OBJECTIVES Describe the role of vitamin K in coagulation and l ist the clinical uses of vitamin K Classify anticoagulant drugs based on route of administration and mechanism of action Describe the mechanisms of action, clinical uses and adverse effects of the various categories of anticoagulant drugs Explain the pharmacotherapeutic implications of the pharmacokinetics and time course of action of warfarin and heparin 6

7. VITAMIN K Forms of vitamin K K1 ( Phytomenadione ) – found in plants K2 ( Menaquinone ) – synthesized by bacteria e.g. E.coli in the mammalian gut K3 ( Menadiol ) – synthetic and water soluble Vitamin K1 and K2 are fat soluble and require bile for absorption while vitamin K3 does not require bile for absorption 7

8. Role of vitamin K in coagulation Vitamin K in the reduced form is required as a co-factor for the final stages of the synthesis of clotting factors II, VII, IX and X (gamma carboxylation of the glutamate residues on these proteins) When vitamin K is deficient or inhibited, the clotting factors formed are not functional 8

9. Clinical uses of vitamin K Bleeding resulting from vitamin K antagonists such as warfarin ( phytomenadione is preferred as it has a rapid action) Haemorrhagic disease of the newborn Vitamin K deficiency: e.g. caused by obstructive jaundice, mal-absorption syndromes and reduced gut flora (as in neonates and use of broad spectrum antibiotics) Use the water soluble vitamin K3 for deficiency arising from biliary obstruction and mal-absorption syndromes 9

10. ANTI-COAGULANTS There are four categories of anti-coagulants : Oral: Vitamin K antagonists e.g. warfarin Oral: Direct thrombin inhibitors and direct Xa inhibitors Parenteral: Heparin and low molecular weight heparins Parenteral: H irudin and its analogues 10

11. Uses of anti-coagulants Anticoagulants are used in the prevention and treatment of deep vein thrombosis in the legs and pulmonary embolism They are of less use in preventing thrombus formation in arteries 11

12. Goals of anti-coagulant therapy To stop expansion of established clots To prevent thromboembolism complications To prevent formation of new thrombi NB: Anticoagulants do not lyse established thrombi 12

13. ORAL ANTICOAGULANTS: WARFARIN The first oral anticoagulant to be used clinically and is the most widely used Mechanism of action Warfarin is an antagonist of vitamin K (structurally similar) It inhibits vitamin K reductase, the enzyme that reduces vitamin K. This impairs the gamma carboxylation of clotting clotting factors II, VII, IX and X and thus the clotting factors formed are not functional 13

14. WARFARIN: PHARMACOKINETICS Well absorbed from the GIT 99% protein bound to albumin Unbound warfarin readily crosses membranes including the placenta Metabolised in the liver Half-life is 2 days 14

15. WARFARIN: Time course of effects Initial response starts at 8-12 hours It takes about 72 hours for the full anticoagulant effect to be seen (warfarin has no effect on clotting factors already present prior to the time of drug administration) On discontinuation of treatment, coagulation remains inhibited for 2-5 days due to the long half-life 15

16. WARFARIN: CLINICAL USES Prophylaxis against venous thrombosis Prevention of thromboembolism in patients with prosthetic valves Prophylaxis against thrombosis in the atria in atrial fibrillation Due to slow onset of action, warfarin is not used in emergency situations (heparin is used instead) Warfarin is the drug of choice for long-term anticoagulation for all patients except pregnant women who should be treated with heparin 16

17. WARFARIN: MONITORING THERAPY Monitored by measuring prothrombin time (expressed as INR). The t herapeutic target is INR 2-3. Warfarin has a narrow therapeutic index thus close monitoring is required 17

18. WARFARIN …. CONT’D Adverse effects: (1) Haemorrhage (2) Cutaneous reactions: purpura , dermatitis, alopecia, pruritic lesions (3) F etotoxic and teratogenic Treatment of warfarin overdose: V itamin K Contra-indications : (1) Vitamin K deficiency (2) Liver disease (3) Alcoholism (4) Pregnancy (5) Lactation 18

19. WARFARIN: DRUG INTERACTIONS Drugs that increase anticoagulant effect of warfarin Drugs that displace warfarin from albumin: aspirin, salicylates , phenylbutazone , sulfonamides Drugs that inhibit metabolism of warfarin : cimetidine , disulfiram , phenylbutazone , metronidazole , imipramine , ciprofloxacin Drugs that reduce synthesis of clotting factors: broad spectrum antibiotics e.g. ampicillin (inhibit bacterial synthesis of vitamin K) 19

20. WARFARIN: DRUG INTERACTIONS …. CONT’D Drugs whose effects on bleeding are enhanced by warfarin Other anti-thrombotic drugs Drugs that reduce the effects of warfarin Inducers of drug metabolizing enzymes e.g. barbiturates, carbamazepine, phenytoin, rifampicin, griseofulvin Drugs that promote synthesis of clotting factors: vitamin K, hormonal contraceptives Drugs that decrease absorption of warfarin: cholestyramine , colestipol 20

21. ORAL DIRECT THROMBIN INHBITORS & ORAL DIRECT Xa INHIBITORS In comparison with warfarin, these drugs: Have equivalent anticoagulant efficacy Have lower bleeding rates Have a rapid onset of action Have a wider therapeutic window Do not require monitoring for dosage optimization Have fewer drug interactions 21

22. ORAL DIRECT Xa INHIBITORS Include rivaroxaban and apixaban I nhibit factor Xa , in the final common pathway of clotting They are given as fixed doses and do not require monitoring for dosage optimization They have a rapid onset of action and shorter half-lives than warfarin The main toxicity is bleeding 22

23. ORAL DIRECT Xa INHIBITORS …. CONT’D Clinical uses P revention of embolic stroke in patients with atrial fibrillation without valvular heart disease P revention of venous thromboembolism following hip or knee surgery T reatment of venous thromboembolic disease 23

24. ORAL DIRECT THROMBIN INHBITORS Include dabigatran Dabigatran is a direct thrombin inhibitor Advantages of oral direct thrombin inhibitors include Predictable pharmacokinetics and bioavailability, which allow for fixed dosing and predictable anticoagulant response, thus routine coagulation monitoring not necessary Rapid onset and offset of action allowing for immediate anticoagulation 24

25. DABIGATRAN …. CONT’D Clinical uses Prevention of embolic stroke and systemic embolism with non- valvular atrial fibrillation Treatment of venous thromboembolism following 5–7 days of initial heparin or LMWH therapy Venous thromboembolism prophylaxis following hip or knee replacement surgery Adverse effects The primary toxicity of dabigatran is bleeding 25

26. HEPARIN Standard heparin ( unfractionated heparin) A large polymer composed of repeating units of two disaccharides with a molecular weight of 3000-40,000 daltons An acidic molecule Has many negatively charged groups and is therefore highly polar In the body, heparin is found in mast cells, plasma and endothelial cells 26

27. STANDARD HEPARIN …. CONT’D Mechanism of action and time course of action Heparin augments the effects of anti-thrombin III Anti-thrombin III is a naturally occurring inhibitor of clotting factors IIa , IXa , Xa and XIIa and thereby suppresses fibrin formation Heparin binds to anti-thrombin III and accelerates its rate of activity making it instantaneous Effects occur quickly (within minutes) because it acts directly to inhibit clotting factor activity 27

28. STANDARD HEPARIN …. CONT’D Pharmacokinetics Heparin is not absorbed from the GIT due to its large size and polarity Administered IV or SC (not given IM because of the potential for haematoma formation) Metabolized in the liver and the metabolites are excreted in urine Half-life is 40-90 minutes, and is dose dependent Duration of activity S everal hours (varies with dosage, and is prolonged in hepatic and renal disease ) 28

29. STANDARD HEPARIN: CLINICAL USES Anticoagulant of choice in pregnancy and in situations that require rapid onset of anticoagulant effects Used in the management of pulmonary embolism, massive deep vein thrombosis, evolving stroke Used in open heart surgery and renal dialysis to prevent coagulation in the extracorporeal circulation device Used for prevention of post-operative veno -thrombosis Used in the management of disseminated intravascular coagulation 29

30. STANDARD HEPARIN …. CONT’D Adverse effects: (1) H aemorrhage (2) T hrombocytopaenia (3) Hypersensitivity reactions: chills, fever, urticaria (4) Osteoporosis (with long term therapy) Treatment of heparin overdose: Treated with protamine sulphate a strong basic protein that forms an inactive complex with heparin Contra-indications : (1 ) Thrombocytopaenia (2) Surgery of the eye, brain and spinal cord (3) Lumbar puncture 30

31. STANDARD HEPARIN: MONITORING THERAPY Heparin therapy is monitored by measuring activated partial thromboplastin time (APTT ) [target: 1.5x the normal APTT] Monitoring is required because of the unpredictable pharmacokinetics of standard heparin 31

32. LOW MOLECULAR WEIGHT HEPARINS (LMWHs) Include enoxaparin and dalteparin LMW heparins act on anti-thrombin III to inhibit factors X and XI, and they have little effect on thrombin (factor II) As effective as standard heparin Associated with lower risk of haemorrhage Less likely to produce hypersensitivity reactions, thrombocytopaenia and osteoporosis 32

33. LMWHs …. CONT’D Have longer half-lives compared to standard heparin and have more predictable pharmacokinetics Do not require APTT monitoring Can be used on an outpatient basis Given subcutaneously 33

34. HIRUDIN AND ITS ANALOGUES Hirudin and its analogues ( bivalirudin , desirudin and lepirudin ) directly bind to and inhibit thrombin (they do not require anti-thrombin III) All are administered parenterally (IV or SC, and not IM) They are used in patients with unstable angina undergoing angioplasty and percutaneous coronary interventions Lepirudin is used as an alternative to heparin in patients who develop heparin induced thrombocytopaenia 34

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36. ANTI-PLATELET AGENTS THROMBOLYTIC AGENTS ANTI-THROMBOLYTIC AGENTS HAEMOSTATIC AGENTS 36

37. LEARNING OBJECTIVES Describe the mechanisms of actions, clinical uses and adverse effects of the drugs that affect haemostasis and thrombosis: Platelet aggregation inhibitors Thrombolytic drugs A nti - thrombolytic and haemostatic drugs 37

38. PLATELET AGGREGATION INHIBITORS These drugs decrease the formation or the action of chemical signals that promote platelet aggregation They inhibit thrombus formation in arteries Include: Aspirin: inhibits the rate limiting step (inhibits the enzyme cyclo-oxygenase ) in the synthetic pathway for thromboxane A 2 Adenosine diphosphate (ADP) receptor inhibitors: clopidogrel , ticlopidine , p rasugrel and ticagrelor Glycoprotein IIb / IIIa receptor inhibitors: abciximab , eptifibatide and tirofiban 38

39. ASPIRIN MOA: Inhibits the synthesis of thromboxane A 2 (TXA 2 ) in platelets by irreversible inhibition of cyclo-oxygenase , a key enzyme in TXA 2 synthesis pathway. TXA 2 is one of the factors required in platelet aggregation. Because platelets lack nuclei, they cannot synthesize new enzyme. Thus the lack of TXA 2 persists for the lifetime of the platelet (7-10 days). Given orally 39

40. ASPIRIN …. CONT’D When used to inhibit platelet aggregation, aspirin is used at much lower doses than those required for anti-inflammatory action At higher doses (> 325mg/day), aspirin will have reduced anti-thrombotic action by decreasing endothelial synthesis of prostacyclin Low doses impair prostaglandin synthesis in platelets more than in endothelial cells and thus the anti-thrombotic effect is preserved 40

41. ASPIRIN …. CONT’D Uses of aspirin as a platelet aggregation inhibitor Prophylactic treatment of transient cerebral ischaemia Primary and secondary prophylaxis of myocardial infarction In the management of acute myocardial infarction In the management of unstable angina Adverse effects Increased incidence of haemorrhagic stroke Gastro-intestinal bleeding (hence contraindicated in peptic ulcer disease) 41

42. ADP RECEPTOR INHIBITORS Include ticlopidine , clopidogrel , prasugrel and ticagrelor MOA : These drugs reduce platelet aggregation by irreversibly inhibiting the platelet ADP receptor (P2Y 12 receptor) (except ticagrelor is a reversible inhibitor) thus blocking ADP binding to platelets ADP is one of the main platelet-activating factors and is required for binding of platelets to fibrinogen and to each other Adverse effects : H aemorrhage , dyspepsia, nausea 42

43. ADP RECEPTOR INHIBITORS …. CONT’D Clinical uses M anagement of unstable angina P rimary and secondary prophylaxis of myocardial infarction P rophylaxis of transient cerebral ischaemia and ischaemic stroke P revention of atherosclerotic events in peripheral arterial disease 43

44. ADP RECEPTOR INHIBITORS …. CONT’D ADP receptor inhibitors can be used as alternatives to aspirin or in combination with aspirin Clopidogrel is the most widely used ADP receptor inhibitor Ticlopidine causes leukopenia and thrombocytopaenia ; it is therefore no longer used Prasugrel and ticagrelor are approved for patients with acute coronary syndromes (in combination with aspirin) Prasugrel is contraindicated in patients with history of cerebrovascular accident because of increased bleeding risk 44

45. PLATELET GLYCOPROTEIN IIb / IIIa RECEPTOR INHIBITORS I nclude abciximab (monoclonal antibody), eptifibatide (peptide) and tirofiban (non-peptide). They are all given intravenously . MOA : The glycoprotein IIb / IIIa receptor complex on platelets acts as a receptor for fibrinogen. Activation of the glycoprotein IIb / IIIa receptor complex is the final common pathway for platelet aggregation. Inhibition of the receptor prevents platelet aggregation by blocking the binding of fibrinogen to platelets. 45

46. PLATELET GLYCOPROTEIN IIb / IIIa RECEPTOR INHIBITORS …. CONT’D Clinical uses M anagement of acute coronary syndromes (unstable angina and myocardial infarction) To prevent thrombosis in patients undergoing percutaneous coronary intervention Adverse effects Bleeding Abciximab also causes hypersensitivity reactions 46

47. THROMBOLYTIC (FIBRINOLYTIC) DRUGS Include streptokinase, alteplase , reteplase , tenecteplase and urokinase Promote lysis of thrombi (clots) All are given intravenously MOA : Convert plasminogen to plasmin. Plasmin digests the fibrin meshwork of clots Major adverse effect of thrombolytic drugs is haemorrhage 47

48. STREPTOKINASE A protein derived from beta- haemolytic streptococci Acts on both circulating plasminogen and fibrin-bound plasminogen Causes allergic reactions (anaphylaxis, urticaria , fever, bronchospasm). Thus avoid re-use between 5 days and 12 months. 48

49. ALTEPLASE, RETEPLASE & TENECTEPLASE Alteplase is recombinant tissue type plasminogen activator ( tPA ), which is selective for plasminogen bound to fibrin in thrombi. H ence the incidence of bleeding is less than with streptokinase. Alteplase is not antigenic and therefore can be re-used within 1 year. Reteplase and tenecteplase are genetically engineered forms of human tPA and have a longer half-life, higher specificity for fibrin and greater resistance to plasminogen activator inhibitor than naturally occurring tPA . They are not antigenic. 49

50. UROKINASE Prepared from cultured kidney cells using recombinant technology Activates both circulating and fibrin-bound plasminogen Used in the treatment of pulmonary embolism Less antigenic than streptokinase and so it is indicated in patients sensitive to streptokinase 50

51. THROMBOLYTIC DRUGS: CLINICAL USES Lysis of coronary artery thrombi associated with acute myocardial infarction Deep vein thrombosis Pulmonary embolism Acute ischaemic stroke (thrombotic stroke) 51

52. THROMBOLYTIC DRUGS: CONTRAINDICATIONS Recent haemorrhage , trauma or surgery, coagulation defects, bleeding diathesis, severe uncontrolled hypertension, recent stroke, recent symptoms of peptic ulcer disease, severe liver disease, oesophageal varices, acute pancreatitis, heavy vaginal bleeding and coma 52

53. ANTI-FIBRINOLYTIC AGENTS AMINOCAPROIC ACID Aminocaproic acid, which is chemically similar to the amino acid lysine, is a synthetic inhibitor of fibrinolysis It competitively inhibits plasminogen activator Given orally or IV Adverse effects: Intravascular thrombosis, hypotension, myopathy, abdominal discomfort, diarrhea, and nasal stuffiness Contraindications: Disseminated intravascular coagulation 53

54. AMINOCAPROIC ACID …. CONT’D Clinical indications Haemophilia Bleeding from fibrinolytic therapy Prophylaxis for re-bleeding from intracranial aneurysms Post-surgical gastrointestinal bleeding Post-prostatectomy bleeding Bladder hemorrhage secondary to radiation- and drug-induced cystitis 54

55. ANTI-FIBRINOLYTIC AGENTS: TRANEXAMIC ACID Tranexamic acid is an analog of aminocaproic acid and also acts by inhibiting plasminogen activator Given intravenously Adverse effects: Nausea, diarrhoea , orthostatic hypotension and intravascular thrombosis Indications: (1) To prevent hyper- plasminaemic bleeding states that result from damage to tissues rich in plasminogen activator e.g. after prostatic surgery, tonsillectomy (2) In haemophiliacs after dental extraction (3) To reduce bleeding after ocular trauma (4) Overdosage with thrombolytic agents (5) Thrombocytopaenia (6) Upper GIT haemorrhage 55

56. HAEMOSTATIC AGENT: DESMOPRESSIN Desmopressin is a longer acting analogue of vasopressin Stimulates the release of factor VIII and von Willebrand factor Indications: (1) Haemophilia A (2) von W illebrand’s disease (mild disease) Routes of administration: Intranasal, oral, sublingual and IV 56

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