Outline the pharmacology of warfarin.
The “traditional” pharmacology answer structure was useful to avoid omitting key details. Warfarin is a synthetic coumarin derivative presented in tablet form for oral use . It is a racemic mixture. S-enantiomer is 2-5 times more potent than the R-enantiomer. It is used for anticoagulation and the usual dosing involves a loading dose ( 3 to 5 mg for 1 to 3 days) then maintenance dose titrated to INR. It was expected answers would then detail mechanism of action, absorption (commenting on bioavailability), distribution, elimination, excretion and adverse effects. Warfarin has contraindications in pregnancy being teratogenic in first trimester and increasing the risk of fetal haemorrhage in third trimester. Better answers provided increased detail on mechanism of action including the initial procoagulant effect due to protein C and S inhibition and some details about monitoring effect with INR / PT. Warfarin has several important drug interactions and detailing these gained additional marks. Additional credit was given for discussion of reversal options, which includes 1) Stop administration - days 2) Prothrombinex - hours 3) FFP - hours 4) Vitamin K depends on dose given.
|Class||Vitamin K antagonist|
|Routes of administration||Oral only|
High oral bioavailablility (~ 100%)
Maximum blood concentration about 90 minutes after administration
|Solubility||pKa 5.87; practically insoluble in water|
|Distribution||VOD=0.08-0.12, 99% protein-bound|
|Target receptor||vitamin K epoxide reductase complex 1|
|Metabolism||The more potent S-isomer is metabolised by hepatic CYP2C9 to 7-hydroxywarfarin, an inactive hydroxylated metabolite.
Another route is through reductases, into reduced metabolites (warfarin alcohols) with minimal anticoagulant activity.
|Elimination||All of the metabolites ultimately make their way out in the urine. 92% of the radiolabelled dose is recovered in urine after 1 week.
Minimal free warfarin is renally excreted
|Time course of action||Terminal half-life of warfarin after a single dose is approximately 1 week;
Effective half-life ranges from 20 to 60 hours
Mean half-life is about 36-42 hours.
|Mechanism of action||Warfarin interferes with the cyclic interconversion of vitamin K and its 2,3 epoxide (vitamin K epoxide), thereby modulating the γ-carboxylation of glutamate residues (Gla) on the N-terminal regions of vitamin K-dependent proteins.Vitamin K-dependent coagulation factors II, VII, IX, and X require γ-carboxylation for their procoagulant activity; thus warfarin therapy results in the hepatic synthesis of ineffective factors.
Initial stages of therapy are usually characterised by a procoagulant state, where protein C and S are depleted before other factors.
|Clinical effects||Bleeding, skin necrosis, systemic microemboli, calciphylaxis|
|Specific reversal strategies||
Tran, Huyen, et al. "New oral anticoagulants: a practical guide on prescription, laboratory testing and peri‐procedural/bleeding management." Internal medicine journal 44.6 (2014): 525-536.
Ansell, Jack, et al. "The pharmacology and management of the vitamin K antagonists." Chest 126.suppl 3 (2004): 204S-233S.