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Anticoagulant Drugs: Mechanism, Uses, and Toxicity | Presented by Dr. Sasan Zaeri PharmD, PhD

Learn about the mechanism, clinical uses, and toxicity of anticoagulant drugs such as Heparin, LMW Heparin, Fondaparinux, Direct Thrombin Inhibitors, and Warfarin. Understand how these drugs affect blood coagulation, when they are used, and their potential side effects.

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Anticoagulant Drugs: Mechanism, Uses, and Toxicity | Presented by Dr. Sasan Zaeri PharmD, PhD

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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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