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Drugs Used in Coagulation Disorders

Drugs Used in Coagulation Disorders. Presented by Dr. Sasan Zaeri PharmD , PhD. Mechanism of blood coagulation. Mechanism of blood coagulation. Fibrinolysis. ANTICOAGULANTS Classification. Three major types of anticoagulants: Heparin and related products

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Drugs Used in Coagulation Disorders

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  1. Drugs Used in Coagulation Disorders Presented by Dr. SasanZaeri PharmD, PhD

  2. Mechanism of blood coagulation

  3. Mechanism of blood coagulation

  4. Fibrinolysis

  5. ANTICOAGULANTSClassification • Three major types of anticoagulants: • Heparin and related products • must be used parenterally • Direct thrombin inhibitors • used parenterally • Orally active coumarin derivatives (e.g. warfarin)

  6. ANTICOAGULANTSHeparin • A large sulfated polysaccharide polymer obtained from animal sources • Highly acidic and can be neutralized by basic molecules • Protamine sulfate (heparin antidote) • Given IV or SC to avoid the risk of hematoma associated with IM injection

  7. ANTICOAGULANTSHeparin • Low-molecular-weight (LMW) heparin • Enoxaparin, Dalteparin, Tinzaparin • Greater bioavailability (SC) • Longer durations of action • Administered once or twice a day • Fondaparinux • A small synthetic drug that contains the biologically active pentasaccharide • Administered SC once daily

  8. HeparinMechanism and effects • Heparin binds to antithrombinIII (ATIII): • irreversible inactivation of thrombin and factor Xa • 1000-fold faster than ATIII alone • Heparin provides anticoagulation immediately after administration • Heparin monitoring • Activated partial thromboplastin time (aPTT)

  9. Mechanism of blood coagulation

  10. Mechanism and effects • LMW heparins and fondaparinux • bind ATIII • same inhibitory effect on factor Xa as heparin–ATIII • they fail to affect thrombin • a more selective action • aPTT not required • potential problem in renal failure due to decreased clearance

  11. Clinical uses • When anticoagulation is needed immediately e.g. when starting therapy • Common uses: • DVT • Pulmonary embolism • acute myocardial infarction • in combination with thrombolytics for revascularization • in combination with glycoprotein IIb/IIIa inhibitors during angioplasty and placement of coronary stents • The drug of choice in pregnancy

  12. Toxicity • Increased bleeding (most common) • may result in hemorrhagic stroke • Protamine as antidote • Not effective for LMW heparins and fondaparinux • Heparin-induced thrombocytopenia (HIT) • Due to antibody against complex of heparin and platelet factor 4 • May yield venous thrombosis • less likely with LMW heparins and fondaparinux • Osteoporosis • Due to prolonged use of unfractionated heparin

  13. Direct Thrombin Inhibitors • Lepirudin • Recombinant form hirudin (Hirudomedicinalis) • Desirudin and Bivalirudin • Modified forms of hirudin • Argatroban • A small molecule with a short half-life • Dabigatran • Orally active

  14. Mechanism and effects • These drugs inhibit both soluble thrombin and the thrombin enmeshed within developing clots • Bivalirudin • also inhibits platelet activation

  15. Clinical uses • Alternatives to heparin • primarily in patients with HIT • Coronary angioplasty • Bivalirudin in combination with aspirin • Monitoring using aPTTrequiured

  16. Toxicity • Bleeding • No reversal agents exist • Anaphylactic reactions • Prolonged infusion of lepirudin induces antibodies that form a complex with lepirudinand prolong its action

  17. Warfarin • Small lipid-soluble molecule • readily absorbed after oral administration • Highly bound to plasma proteins (>99%) • Its elimination depends on metabolism by cytochrome P450 enzymes

  18. Mechanism of action • Warfarin inhibits vitamin K epoxide reductase(VKOR) in liver • ↓ reduced form of vitamin K → ↓ factors II, VII, IX, X, protein C and S

  19. Anticoagulant effect is observed within 8-12 h • The action of warfarin can be reversed by: • Vitamin K1 (slowly within 6-24 h) • Transfusion with fresh or frozen plasma (more rapid reversal) • Warfarin monitoring: • Prothrombintime (PT) expressed by INR • INR: 2-3

  20. Clinical uses • Chronicanticoagulation in all of the clinical situations described for heparin • Exception: anticoagulation in pregnant women • In DVT • Heparin + warfarin (5-7 days) • Warfarin (3-6 months)

  21. Warfarin toxicity • Bleeding (most common) • Hypercoagulability early in therapy → dermal vascular necrosis • due to deficiency of protein C • Bone defects and hemorrhage in fetus • Contraindicated in pregnancy

  22. Warfarin toxicity • Drug interactions • Cytochrome P450 inducers • carbamazepine, phenytoin, rifampin, barbiturates • Cytochrome P450 inhibitors • amiodarone, selective serotonin reuptake inhibitors, cimetidine

  23. THROMBOLYTIC AGENTS • Streptokinase • synthesized by streptococci • Alteplase, Tenecteplaseand Reteplase • Recombinant forms of t-PA

  24. Mechanism of Action • Conversion of plasminogen to plasmin

  25. Clinical Uses • Alternative to coronary angioplasty • Best result in ST-elevated MI and bundle branch block • Prompt recanalization if used within 6 h • Ischemic stroke • Better clinical outcome if used within 3 h • Cerebral hemorrhage must be ruled out before such use • Severe pulmonary embolism

  26. Toxicity • Bleeding • Same frequency with all thrombolytics • Cerebral hemorrhage (most serious manifestation) • Allergic reactions (streptokinase) • Even at first dose (streptococcal infection history) • Loss of drug efficacy • Not observed with recombinant forms of t-PA • BUT, t-PAis more expensive and not much more effective

  27. ANTIPLATELET DRUGS

  28. ANTIPLATELET DRUGS • Aspirin acts on COX irreversibly • several-day effect • Other NSAIDs not used as antiplatelet drug • May interfere with aspirin antiplatelet effect • Abciximab(monoclonal antibody), eptifibatide and tirofiban • reversibly inhibit glycoprotein IIb/IIIa • Clopidogrel, ticlopidine • irreversibly inhibit the platelet ADP receptor

  29. ANTIPLATELET DRUGS • Dipyridamoleand cilostazol • Inhibit phosphodiesteraseenzymes → ↑ cAMP • Inhibit uptake of adenosine by endothelial cells and RBCs • Adenosine acts through platelet adenosine A2 receptors to increase platelet cAMP

  30. Clinical Uses • Aspirin • To prevent first or further MI • To prevent transient ischemic attacks, ischemic stroke, and other thrombotic events

  31. Clinical Uses • Glycoprotein IIb/IIIainhibitors • To prevent restenosis after coronary angioplasty • In acute coronary syndromes (unstable angina and non-Q-wave acute MI) • Clopidogreland ticlopidine • To prevent transient ischemic attacks and ischemic strokes • especially in patients who cannot tolerate aspirin • To prevent thrombosis in patients with coronary artery stent (clopidogrel)

  32. Clinical Use • Dipyridamole • To prevent thrombosis in those with cardiac valve replacement (adjunct to warfarin) • To treat intermittent claudication (a manifestation of peripheral arterial disease)

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