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Drugs influencing coagulation

Drugs influencing coagulation. Dr Sanjeewani Fonseka Department of Pharmacology. Classes of Drugs. Prevent coagulation Dissolve clots Prevent bleeding and hemorrhage - Hemostatic Overcome clotting deficiencies (replacement therapies). Classes of Drugs. Prevent coagulation

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Drugs influencing coagulation

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  1. Drugs influencing coagulation Dr Sanjeewani Fonseka Department of Pharmacology

  2. Classes of Drugs • Prevent coagulation • Dissolve clots • Prevent bleeding and hemorrhage - Hemostatic • Overcome clotting deficiencies (replacement therapies)

  3. Classes of Drugs • Prevent coagulation • Dissolve clots • Prevent bleeding and hemorrhage - Hemostatic • Overcome clotting deficiencies (replacement therapies)

  4. Haemostasis Arrest of blood loss from damaged blood vessels

  5. Blood Clotting • Vascular Phase • Platelet Phase • Coagulation Phase • Fibrinolytic Phase

  6. Vascular Phase • Vasoconstriction • Exposure to tissues activateTissue factor and initiate coagulation Tissue Factor

  7. Coagulation Phase • Two major pathways • Intrinsic pathway • Extrinsic pathway • Both converge at a common point • 13 soluble factors are involved in clotting • Normally inactive and sequentially activated

  8. Intrinsic Pathway Extrinsic Pathway Tissue Injury Blood Vessel Injury XIIa Tissue Factor XII XIa XI IXa IX VIIa VII Xa X X Prothrombin Thrombin Fribrin monomer Fibrinogen

  9. Intrinsic Pathway • Activated partial thromboplastin test (aPTT) Extrinsic Pathway • Prothrombintest (PT/INR)

  10. Vitamin K-Dependent Clotting Factors Vitamin K VII Synthesis of Functional Coagulation Factors IX X II

  11. Natural anti- coagulant

  12. Thrombosis Pathological formation of haemostatic plug within the vasculature in the absence of bleeding

  13. Arterial Venous Red White head and red tail Embolus • White • Platelet and WBC • With atheroscerosis • Causes ischemia

  14. Drugs effect ; Drugs influencing coagulation Anticoagulants Antiplatelet drugs Thrombolytic drugs • fibrin formation • Platelet function • Fibrinolysis

  15. Drugs influencing coagulation • Anticoagulants • Antiplatelet drugs • Thrombolytic drugs

  16. Anticoagulants • Antithrombin activators • Direct thrombin inhibitors • Direct Factor Xa inhibitors • Drugs that oppose action of Vitamin K

  17. Anticoagulants • Antithrombin activators • Heparin / LMWH • Synthetic pentasaccharide analogues • Direct thrombin inhibitors • Direct Factor Xa inhibitors • Drugs that oppose action of Vitamin K

  18. Heparin • Heterogeneous mixture of branched glycosaminoglycans • Potentiates the inhibition of IIa, IXa, Xa, XIa, XIIa by AT • Binds to AT through a unique pentasaccharide sequence leading to a conformational change

  19. Intrinsic Pathway Extrinsic Pathway Tissue Injury Blood Vessel Injury Tissue Factor XIIa XII Thromboplastin XIa XI IXa IX VIIa VII Xa X X Prothrombin Thrombin Factors affected By Heparin Fribrin monomer Fibrinogen

  20. Heparin mechanism of action Heparin Antithrombin III Thrombin

  21. Heparin • Given s.c. or i.v. • Binds to plasma proteins, endothelial cells & macrophages • Elimination • Depolymerisation in endothelial cells & macrophages (rapid, saturable) • Renal (slow, non-saturable) and RES

  22. Heparin: variable anticoagulant effect • Variable protein binding • Clearance varies with chain length • Therefore, anticoagulant response monitored by activated partial thromboplastin time (APTT) • Target 1.5 – 2.5 times control

  23. Heparin: clinical uses • Venous thrombosis ± embolism • Acute coronary syndromes • Arterial thrombosis • Extracorporeal devices (e.g. haemodialysis)

  24. Heparin: adverse effects • Bleeding • Heparin-induced thrombocytopenia (HIT) • Immune-mediated • Osteoporosis

  25. Low-molecular-weight heparins (LMWHs) • Derived from UFH by chemical or enzymatic depolymerization • Molecular weight 2000 – 9000 • About 15 monosaccharide units per molecule

  26. Molecular weight distributions of LMWHs and heparin

  27. Differences in Mechanism of Action • Any size of heparin chain can inhibit the action of factor Xa by binding to antithrombin (AT) • In contrast, in order to inactivate thrombin (IIa), the heparin molecule must be long enough to bind both antithrombin and thrombin • Less than half of the chains of LMWH are long enough

  28. LMWHs • Dalteparin • Enoxaparin • Tinzaparin

  29. Synthetic pentasaccharide analogues • Bioavailability(s.c.)eliminationhalf life (h) • LMWH 80-90% renal 4 • Fondaparinux 100% renal 17 • Idraparinux 100% renal 80

  30. Anticoagulants • Antithrombin activators • Direct thrombin inhibitors • Direct Factor Xa inhibitors • Drugs that oppose action of Vitamin K

  31. Direct thrombin inhibitors • Recombinant hirudins • Bivalirudin • Ximelagatran / Melagatran • Dabigatran

  32. Recombinant hirudins

  33. Recombinant hirudins • Given i.v. , s.c. • Elimination renal • Half life 1-2 h

  34. Bivalirudin • Given i.v. • Elimination renal & hepatic • Half life 25 min

  35. Ximelagatran • Promising oral direct thrombin inhibitor • Converted to the active form melagatran in vivo • No dosing problems • No monitoring needed. • Recent atrial fibrillation study showed it to possibly be superior to warfarin.

  36. Dabigatran • Given orally • Elimination renal • Half life 12 h • Substrate for P-glycoprotein in kidney, GIT

  37. Anticoagulants • Antithrombin activators • Direct thrombin inhibitors • Direct Factor Xa inhibitors • Drugs that oppose action of Vitamin K

  38. Apixaban • Direct Factor Xa inhibitor • Oral bioavailability 60% • Half life 12 h • Elimination hepatic > renal

  39. Rivaroxaban • Direct Factor Xa inhibitor • Oral bioavailability 80% • Half life 7-11 h • Elimination renal > hepatic

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