Question 10

Outline the pharmacology of warfarin. 

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College Answer

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.

Discussion

  Warfarin
Class Vitamin K antagonist
Chemistry Coumarin derivative
Routes of administration Oral only
Absorption Rapidly absorbed
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
  • INR 4.5 – 10.0 and no bleeding: stop warfarin
  • INR 4.5 – 10.0 and high risk of bleeding: Vitamin K 0.5 – 1.0 mg iv
  • Immediate reversal: Prothrombinex  25 – 50 IU/kg + Vitamin K - 5-10mg IV
  • Haemorrhage is into a critical organ (eg. brain):  5-10mg of Vit K, and prothrombinex 50.0 units/kg, and FFP 150–300mL.
  • FFP is generally reserved for situations when the prothrominex is not readily available. The maximum dose is 15ml/kg.

References

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.