Skip to Main Content

++

OVERVIEW

++

Following the isolation of hemorrhagic agents from spoiled sweet clover hay in the 1930s and development of 3-phenyacetyl ethyl, 4-hydroxycoumarin as a rat poison in 1948, warfarin has been the primary oral anticoagulant used in North America since its approval for medical use in 1954.1 Even following the availability of new oral anticoagulant classes, it is widely used for its various indications including prophylaxis and treatment of venous thrombosis and pulmonary embolism, prophylaxis and treatment of thromboembolic complications of atrial fibrillation and heart valve replacement, and postmyocardial infarction (MI) reduction in the risk of death, recurrent MI, and thromboembolic events such as stroke or systemic embolization.2

++

Warfarin, a vitamin K antagonist (VKA), inhibits the C1 subunit of vitamin K epoxide reductase (VKORC1) complex, preventing the regeneration of vitamin K1 epoxide. This interferes with the carboxylation and activation of vitamin K-dependent clotting factors, factors II, IV, IX, and X (Figure 21-1).2, 3, and 4 At the same time, carboxylation of the natural anticoagulants proteins C and S is inhibited as well.4 This effect can be reversed with the administration (pharmacologically or nutritionally) of vitamin K1, which is also called phytonadione.4 Prolongation of the prothrombin time (PT) is seen with warfarin therapy, and a standardized measurement of this effect, the international normalized ratio (INR), is utilized for warfarin monitoring because it has been shown to correlate with efficacy.2,5,6

++
FIGURE 21-1.

Mechanism of action of warfarin.

Graphic Jump Location
++

PHARMACOKINETICS

++

Warfarin has nearly 100 percent oral bioavailability, achieving peak concentrations within 4 hours of administration.2 Its volume of distribution is small, 0.14 L/kg, and is limited by 99 percent protein binding, primarily to albumin.2,4 Commercially available warfarin products are equal, racemic mixtures of the R and S enantiomers.4 The S-warfarin enantiomer is five times more potent. It is primarily metabolized by cytochrome P-450 (CYP) 2C9, and in part by CYP 2C19. The less potent R-warfarin enantiomer is metabolized by CYP 1A2 and CYP 3A4.7 The products of metabolism are inactive and 92 percent excreted in the urine.2 The pharmacokinetic half-life of warfarin is 36–42 hours2,4; therefore, ≥4 days is required to achieve steady-state concentrations of any given warfarin dose. However, the chief pharmacodynamic effect of warfarin is caused by its inhibition of factor II (thrombin). The full effect of warfarin is therefore determined by the half-life of factor II (60–72 hours), so complete factor II inhibition can take 10 days or more to achieve.4 It is for the same reason that when warfarin is initiated, its antithrombotic effect is not realized until at least 5 days of treatment has elapsed. Therefore, overlap with another form of anticoagulation with a faster onset, historically unfractionated or ...

Pop-up div Successfully Displayed

This div only appears when the trigger link is hovered over. Otherwise it is hidden from view.