The VKAs produce their anticoagulant effect by interfering with the cyclic interconversion of vitamin K and its 2,3 epoxide (vitamin K epoxide), thereby modulating the y-carboxylation of glutamate residues (Gla) on the N-terminal regions of vitamin K-dependent proteins (Fig 1).
The vitamin K coagulation factors II, VII, IX, and X require y-carboxylation for their procoagulant activity, and treatment with coumarins results in the hepatic production of partially carboxylated and decarboxylated proteins with reduced coagulant activity. Carboxylation is required for a calcium-dependent conformational change in coagulation proteins that promotes binding to cofactors on phospholipid surfaces. In addition, the VKAs inhibit carboxylation of the regulatory anticoagulant proteins C and S, and thereby have the potential to be procoagulant. However, under most circumstances the anticoagulant effect of the coumarins is dominant. Car-boxylation requires the reduced form of vitamin K (vitamin KH2), molecular oxygen, and carbon dioxide. The oxidation-reduction reaction between vitamin KH2 and vitamin K epoxide involves a reductase pair. The first, vitamin K epoxide reductase, is sensitive to coumarins, whereas vitamin K reductase is less sensitive. Therefore, the anticoagulant effect of the coumarins can be overcome by low doses of vitamin K1 (phytonadione) [Fig 1]. Patients treated with large doses of vitamin K1 can become resistant to warfarin for up to 1 week or more because the vitamin K1 accumulating in the liver is available to the coumarin-insensitive reductase.
The coumarins also interfere with the carboxylation of Gla proteins that are synthesized in bone. Although these effects contribute to fetal bone abnormalities when mothers are treated with a coumarin during pregnan-cy, there is no evidence that coumarins directly affect bone metabolism when administered to children or adults.
Pharmacokinetics and pharmacodynamics of warfarin
Warfarin is the most common coumarin that is in clinical use. It is a racemic mixture of two optically active isomers, the R and S forms. Warfarin is rapidly absorbed from the GI tract, has high bioavailability, and reaches maximal blood concentrations about 90 min after oral administration. Warfarin has a half-life of 36 to 42 h, circulates bound to plasma proteins (mainly albumin), and accumulates in the liver, where the two isomers are metabolically transformed by different pathways. The relationship between the dose of warfarin and the response is modified by genetic and environmental factors that can influence the absorption of warfarin, its pharmacokinetics, and its pharmacodynamics.