Overview Anticoagulants decrease the formation of fibrin clots heparin warfarin (coumadin) bivalirudin Heparin Mechanism catalyzes the binding of antithrombin III to multiple clotting factors inactivates several factor IIa (thrombin) Xa IXa XIa XIIa Clinical use immediate anticoagulation pulmonary embolism acute coronary syndrome stroke MI DVT DIC during pregnancy does not cross placenta Toxicity bleeding osteoporosis heparin-induced thrombocytopenia (HIT) heparin binds to platelet factor IV antibodies bind to and activate platelets leads to hypercoagulable state and thrombocytopenia hypersensitivity Pharmacology IV delivery only for theurapeutic anticoagulation short half-life (2h) large, water-soluble polysaccharide low-molecular-weight heparins (e.g. enoxaparin) have advantages of longer half-lives (2-4x) less thrombocytopenia enhanced activity against factor Xa administered subcutaneously without laboratory (PTT) monitoring not easily reversible Monitoring partial thromboplastin time (PTT) Antagonist protamine sulfate positively charged to bind negatively charged heparin Warfarin (coumadin) Mechanism ↓ hepatic synthesis of vitamin K-dependent clotting factors prevents the reduction of vitamin K, a necessary step in the synthesis of clotting factors vitamin K epoxide reductase is inhibited γ-carboxylation of clotting factors cannot occur affected clotting factors include II VII IX X protein C protein S no effect on clotting factors already present affects the extrinsic pathway Clinical use chronic anticoagulation DVT prophylaxis post-STEMI heart valve damage atrial arrhythmias Toxicity transient hypercoagulability transient protein C deficiency when beginning warfarin treatment due to short half life of protein C can lead to skin necrosis and dermal vascular thrombosis pain, bullae formation, and skin necrosis following initiation of warfarin likely has warfarin-induced skin necrosis often occurs in women who have protein C deficiency treatment includes administration of vitamin K and discontinuation of warfarin give heparin as you begin warfarin treatment bleeding retroperitoneal hematoma - back/abdominal pain and hemodynamic compromise CT scan to identify and guide treatment teratogenic bone dysmorphogenesis not used in pregnancy drug interactions P450 metabolism inducers → ↓ PT increase in P450 degrades more warfarin and levels fall carbamazepine, barbiturates, rifampin inhibitors → ↑ PT decrease in P450 degrades less warfarin and levels rise macrolides, cimetidine, imidazoles ASA, sulfonamides, phenytoin displace warfarin from plasma proteins, leading to increased free fraction → ↑ PT cholestyramine ↓ oral absorption due to low pKa Pharmacology oral long half life (>30 hr) small, lipid-soluble Monitoring prothrombin time (PT) INR (tested PT / reference PT)^(calibration value) Antagonist vitamin K (slow onset) fresh frozen plasma (fast onset) Lepirudin, bivalirudin Mechanism direct inihibtors of thrombin (IIa) Clinical use alternative to heparin e.g. during HIT unstable angina during percutaneous transluminal coronary angioplasty