Overview Anticoagulantsdecrease the formation of fibrin clots heparin warfarin (coumadin) bivalirudin Heparin Mechanism catalyzes the binding of antithrombin III to multiple clotting factors inactivates several factors IIa (thrombin) Xa IXa XIa XIIa Clinical use immediate anticoagulation pulmonary embolism acute coronary syndrome stroke MI DVT DIC cardiovascular surgery pulmonary embolism acute coronary syndrome stroke MI DVT DIC cardiovascular surgery pulmonary embolism acute coronary syndrome stroke MI DVT DIC cardiovascular surgery during pregnancy does not cross placenta pulmonary embolism acute coronary syndrome stroke MI DVT DIC cardiovascular surgery 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 therapeutic 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 coagulation factors have relatively long half lives can lead to skin necrosis and dermal vascular thrombosis give heparin as you begin warfarin treatment bleeding teratogenic bone dysmorphogenesis not used in pregnancy drug interactions P450 metabolism inhibitors → ↑ PT decrease in P450 degrades less warfarin and levels rise mnemonics SICKFACES.COM Sodium valproate Isoniazid Cimetidine Ketoconazole Fluconazole Alcohol (binge drinking) Chloramphenicol Erythromycin Sulfonamides Ciprofloxacin Omeprazole Metronidazole inducers → ↓ PT increase in P450 degrades more warfarin and levels fall mnemonics BS CRAP GPS "induces" rage Barbiturates St John's Wort Carbamazepine Rifampin Alcohol (chronic) Phenytoin Griseofulvin Phenobarbital Sulfonylureas ASA, sulfonamides, and 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) prothrombin complex concentrates (fast onset, low volume) Lepirudin and Bivalirudin Mechanism direct inhibtors of thrombin (IIa) Clinical use alternative to heparin during heparin-induced thrombocytopenia unstable angina during percutaneous transluminal coronary angioplasty Direct Factor Xa Inhibitors (Apixaban, Rivaroxaban, Edoxaban, and Betrixaban) Mechanism noncompetitive inhibitors of factor Xa Clinical use treatment and prophylaxis for deep venous thrombosis and pulmonary embolism stroke prophylaxis for patients with atrial fibrillation Monitoring PT and PTT are not reliable Chromogenic anti-Xa assay Antagonist andexanet alfa