Warfarin Flashcards
What is the mechanism of action of warfarin?
Warfarin inhibits vitamin K epoxide reductase (which is required for converting vitamin K into its active state), preventing gamma carboxylation of vitamin K, reducing synthesis of vitamin K dependent clotting factors, II, VII, IX, and X, and the natural anticoagulation proteins C & S.
What are the main indications for warfarin therapy?
Atrial fibrillation, venous thromboembolism (VTE), DVT prophylaxis, mechanical heart valves, hypercoagulable disorders.
How is warfarin administered?
orally
What is Warfarin’s onset of action?
8-12 hours
Which clotting factors are inhibited by warfarin?
Factors II, VII, IX, X, and anticoagulants protein C and protein S.
Which coagulation pathway does warfarin impact most significantly?
Due to factor VII, the extrinsic pathway is most affected.
Why does warfarin initially increase thrombosis risk?
Protein C and S have shorter half-lives than clotting factors, leading to a temporary hypercoagulable state.
What test is used to monitor warfarin therapy?
Prothrombin Time (PT)/International Normalized Ratio (INR).
What is the therapeutic INR range for most indications?
INR 2.0–3.0 for most indications; 2.5–3.5 for mechanical heart valves.
What drugs increase warfarin effect (↑ INR)?
CYP2C9 inhibitors (azoles, amiodarone), metronidazole, quinolones, acetaminophen (reduces vitamin K recycling).
What drugs decrease warfarin effect (↓ INR)?
CYP2C9 inducers (rifampin, phenytoin, St. John’s Wort), oral contraceptives, green leafy vegetables (↑ vitamin K intake).
How does amiodarone affect warfarin metabolism?
Amiodarone inhibits CYP2C9, reducing warfarin metabolism and increasing INR. Warfarin dose should be reduced by 25-50%.
What dietary factors can reduce warfarin efficacy?
Increased vitamin K intake (e.g., green leafy vegetables) can decrease INR by increasing clotting factor synthesis.
How do NSAIDs interact with warfarin?
NSAIDs increase bleeding risk by inhibiting platelet function but do not affect INR.
What herbal supplements increase warfarin bleeding risk?
Ginkgo biloba (unknown mechanism), garlic, and ginger.
How does warfarin compare to heparin in onset of action?
Warfarin has a delayed onset (3-5 days) due to the need to deplete existing clotting factors, while heparin acts immediately.
What is the antidote for warfarin overdose?
Vitamin K (for mild elevations) and fresh frozen plasma or prothrombin complex concentrate (for life-threatening bleeding).
Why must warfarin be bridged with heparin in acute thromboembolism?
Due to initial warfarin-induced hypercoagulability from protein C depletion, heparin prevents early thrombosis. Warfarin induced skin necrosis (WISN), which is also prevented using a heparin bridge.
What genetic polymorphisms affect warfarin metabolism?
Polymorphisms in CYP2C9 (slower metabolism) and VKORC1 (altered warfarin sensitivity).
What conditions increase warfarin sensitivity?
Liver disease (reduced clotting factor synthesis), congestive heart failure (reduced metabolism), advanced age.
What is warfarin’s effect on pregnancy?
Warfarin is teratogenic (contraindicated in pregnancy) and can cause fetal warfarin syndrome (nasal hypoplasia, stippled epiphyses).
What is a major complication of warfarin therapy?
Warfarin-induced skin necrosis due to rapid depletion of protein C in patients with predisposing conditions (e.g., protein C deficiency).
How does alcohol affect warfarin metabolism?
Chronic alcohol use induces CYP2C9 (↓ warfarin effect), while acute alcohol use inhibits CYP2C9 (↑ warfarin effect).
What is the preferred anticoagulant in pregnancy?
Low molecular weight heparin (e.g., enoxaparin) is preferred over warfarin due to its safety profile.
How does liver disease affect warfarin metabolism?
Liver disease decreases clotting factor synthesis, increasing INR and enhancing warfarin’s anticoagulant effect.
How should warfarin dosing be adjusted when starting amiodarone?
Warfarin dose should be reduced by 25-50% due to CYP2C9 inhibition by amiodarone.
