# Warfarin > Warfarin — vitamin K antagonist, INR targets, interactions, skin necrosis, pregnancy contraindication — MBBS Pharmacology notes for exams. - Canonical URL: https://prepelephant.com/topics/mbbs/pharmacology/warfarin - Exam / course: MBBS · Subject: Pharmacology - Publisher: PrepElephant (https://prepelephant.com) — Prepared and reviewed by the PrepElephant Academic Review Team - First published: 2026-10-02 - Last updated: 2026-10-02 - How to cite: "Warfarin", PrepElephant, https://prepelephant.com/topics/mbbs/pharmacology/warfarin ## Direct answer Warfarin inhibits vitamin K epoxide reductase, depleting the reduced vitamin K needed to gamma-carboxylate clotting factors II, VII, IX and X and the natural anticoagulants protein C and S; its effect is monitored as the international normalised ratio (INR), with 2.0–3.0 the standard target. Because functional anticoagulation lags several days behind the first dose and protein C depletion initially favours thrombosis, warfarin must overlap with heparin for at least 4–5 days; its enormous interaction profile, teratogenicity and need for monitoring explain the shift to direct oral anticoagulants, but mechanical heart valves and severe renal failure still belong to warfarin. ## What you must remember - Target INR 2.0–3.0 for atrial fibrillation, venous thromboembolism and most indications; 2.5–3.5 for mechanical mitral valves and recurrent thrombosis on treatment. - Half-life 36–42 hours; the full anticoagulant effect takes 4–5 days because existing factors must decay — factor VII falls first (6 hours half-life), factor II lasts longest (60 hours). - Heparin overlap until INR is therapeutic for 24–48 hours prevents warfarin-induced skin necrosis from early protein C depletion. - Skin necrosis presents on days 3–8 as painful breast, buttock or thigh erythema progressing to necrosis, classically in protein C deficiency; stop warfarin, restart heparin. - Teratogenic between weeks 6 and 12 (nasal hypoplasia, stippled epiphyses) plus fetal bleeding risk — use LMWH in pregnancy, warfarin only in specific mechanical-valve cases after counselling. - Interactions: amiodarone, metronidazole, co-trimoxazole and fluconazole potentiate; rifampicin, carbamazepine and phenytoin reduce effect; broad-spectrum antibiotics deplete gut vitamin K. - Reversal: vitamin K (oral for INR 4.5–10 without bleeding, slow intravenous 5–10 mg with bleeding) plus 4-factor prothrombin complex concentrate or fresh frozen plasma for major haemorrhage. - Dietary consistency matters — green leafy vegetables supply vitamin K; the advice is consistency, not avoidance. - S-warfarin, the more potent enantiomer, is metabolised by CYP2C9 — the pharmacogenetic basis of variable dose requirement. ## Worked example — bridging and bleeding A 45-year-old with a mechanical mitral valve on warfarin (INR 2.8) needs an elective cholecystectomy. The perioperative reasoning is standard. Stop warfarin three to five days before surgery, tracking the INR daily; because a mechanical valve mandates continued anticoagulation, bridge with therapeutic LMWH as the INR falls below 2.0, stopping the last dose 24 hours before surgery. After surgery, restart warfarin at the usual dose the evening of the procedure if haemostasis is secure, and continue LMWH bridging until the INR is above 2.0 for two consecutive days — the same overlap logic as initiation, because a rising INR does not mean immediate safe anticoagulation. Contrast the opposite scenario: the same patient arrives with gum bleeding and an INR of 8. Withhold warfarin, give vitamin K 2.5–5 mg orally; the INR falls over 24–48 hours and the valve risk does not justify aggressive reversal. With intracranial haemorrhage, give 10 mg vitamin K intravenously over 30 minutes plus prothrombin complex concentrate immediately. Both ends of the INR spectrum are exam questions, and both answers begin with "stop warfarin and assess bleeding". ## Where students slip Three slips cost marks. First, quoting the "INR 3 or bridging" thresholds without the protein C story — the exam wants the mechanism of skin necrosis (early depletion of the short half-life natural anticoagulant before factors II and X fall), not just its description. Second, the antibiotic question: candidates write "all antibiotics potentiate warfarin" instead of naming the culprits (metronidazole, co-trimoxazole, erythromycin inhibit metabolism; broad-spectrum agents deplete vitamin K-producing gut flora). Third, forgetting that warfarin remains the drug of choice for mechanical valves — the RE-ALIGN trial showed dabigatran to be harmful in this setting, so writing a DOAC for a mechanical valve is a remembered wrong answer. Purple toe syndrome from cholesterol microembolisation is a final favourite one-liner. ## Frequently asked questions ### Why must heparin overlap warfarin at initiation? Warfarin first depletes protein C, transiently tipping the balance toward thrombosis; heparin covers the 4–5 days until factors II and X have decayed, preventing skin necrosis and venous gangrene. ### What is the INR target for a mechanical mitral valve? 2.5–3.5, higher than the standard 2.0–3.0, because mitral mechanical valves carry the greatest thrombogenicity; DOACs are contraindicated in all mechanical valves. ### How is an INR of 8 without bleeding managed? Withhold warfarin and give vitamin K 2.5–5 mg orally, rechecking INR in 24–48 hours; routine aggressive reversal with plasma is reserved for bleeding, and subcutaneous vitamin K is unpredictable and avoided. ### Which drugs most strongly potentiate warfarin? Amiodarone, metronidazole, co-trimoxazole, fluconazole and azoles — through CYP2C9 and CYP3A4 inhibition; the warfarin dose is usually reduced by a third to a half when they start. ### Why is warfarin contraindicated in pregnancy? It crosses the placenta, causing warfarin embryopathy (nasal hypoplasia, stippled epiphyses) between weeks 6 and 12, fetal bleeding and miscarriage; LMWH throughout pregnancy is the standard alternative.