Warfarin
Pathway · detail · VKORC1 INR CYP2C9
A coumarin that inhibits VKORC1, depleting the reduced vitamin K needed to carboxylate factors II, VII, IX and X and proteins C and S. It has no effect on factors already carboxylated, so the anticoagulant effect appears over days as those decay — and because protein C and factor VII fall first, the first 48 hours are transiently prothrombotic.
Traced from the start
Detail
- Target
- Vitamin K epoxide reductase complex subunit 1 (VKORC1)
- Monitoring
- INR; full effect takes 3-5 days, set by the 60-72 hour half-life of prothrombin, so heparin cover is needed at initiation
- Metabolism
- CYP2C9 handles the active S-enantiomer; dose requirement varies with CYP2C9 and VKORC1 genotype
- Potentiated by
- Amiodarone, metronidazole, ciprofloxacin, macrolides, fluconazole, SSRIs, binge alcohol and liver disease
- Antagonised by
- Rifampicin, carbamazepine, phenytoin, St John's wort and a high dietary vitamin K intake
When it goes wrong
Warfarin exposure in the first trimester
Warfarin embryopathy — nasal hypoplasia and stippled epiphyses; switch to LMWH, which does not cross the placenta
Loading warfarin without heparin cover in unrecognised protein C deficiency
Warfarin-induced skin necrosis on days 3-5 over fat-rich areas: breast, buttock and thigh
Practise this structure
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