Clinical Pharmacokinetic Considerations in the Control of Oral Anticoagulant Therapy

Abstract

Aspects of the pharmacokinetics of warfarin that are clinically relevant are reviewed here. Since warfarin is normally completely absorbed, resistance to treatment due to impaired absorption is unusual, even in severe short bowel syndrome. Warfarin is highly albumin-bound; thus, hypoalbuminaemic states result in an increased free fraction of the drug and a decreased half-life but, as might be expected, there is no evidence of altered response at steady-state. Warfarin is completely metabolised by the liver to hydroxy-warfarins and warfarin alcohols, and although the latter have some biological activity they do not contribute significantly to the drug effect. No information is available concerning the metabolism of warfarin in chronic liver disease, but there is evidence of increased sensitivity due to impaired vitamin K-dependent clotting factor synthesis. Impaired renal function does not appear to alter the effect of warfarin. Lowered response to the drug may be secondary to poor compliance, kinetic resistance or pharmacodynamic resistance. These factors can be identified using algorithms based on population values for plasma warfarin concentrations and clearances at steady-state. The pharmacokinetics and pharmacodynamics of warfarin indicate that several days' overlap with heparin on initiation of warfarin, and gradual (rather than sudden) discontinuation of warfarin, might theoretically be necessary. However, those studies which have been performed have indicated that a long overlap and gradual discontinuation are not associated with greater safety or efficacy of the drug. Because of the long elimination half-life of warfarin and the short elimination half-life of vitamin K, many days' treatment with phytomenadione may be required after warfarin overdose. The elimination half-life and therefore the duration of therapy may be reduced by regular oral cholestyramine, although the means by which the latter enhances warfarin elimination is still unknown.

Simultaneous pharmacokinetics assessment of caffeine, warfarin, omeprazole, metoprolol, and midazolam intravenously or orally administered to Microminipigs

“…The bioavailability of caffeine in male and female Microminipigs, 79% and 71%, respectively, was similar to the P450 1A-mediated metabolism of caffeine reported in humans (Turpault et al, 2009). Involvement of human P450 2C9 in warfarin metabolism with high affinity, but low V max has been reported (He et al, 1999), resulting in approximately 100% bioavailability (Shetty et al, 1989). The bioavailability of warfarin in Microminipigs was approximately 80% suggesting similarly slow first-pass metabo- (Andersson et al, 1993), as well as, 54% bioavailability of omeprazole in humans (Regårdh et al, 1986).…”

International Normalized Ratio Decreases After Hemodialysis Treatment in Patients Treated With Warfarin

“…15 The Vd of the R and S forms are similar. 9 Although patients with nephrotic syndrome and hypoalbuminemia show a 2-fold increase in the free fraction and a 3-fold increase in warfarin clearance compared with controls, there are no reported major changes in Vd or anticoagulant response. 16 In the present study, patients were administered warfarin for more than 3 months in a steady state, so it was considered that the total amounts of warfarin in the body were not altered during the 4-hour HD session.…”

“…In addition, impaired renal function is unlikely to greatly affect its pharmacokinetics or physiological effect because it is almost entirely metabolized in the liver, is almost totally cleared by the hepatic metabolism, and because renally excreted metabolites have only a very low anticoagulant effect. 9 However, to our knowledge, no reports have examined the pharmacokinetics and anticoagulant effects of warfarin before and after 4-hour sessions of HD treatment, which might affect the volume of distribution (Vd) and protein-binding rate over a short duration. The purpose of this investigation was therefore to determine alterations in INR during HD treatment in patients receiving warfarin.…”

Evaluation of Excessive Anticoagulation in a Group Model Health Maintenance Organization

“…9 Doses of phytonadione greater than 10 mg have been associated with difficulty in reestablishing therapeutic oral anticoagulation. 10 An examination of the pharmacodynamic response to the administration of 10 mg of phytonadione revealed that the effects of warfarin on clotting factor synthesis were antagonized at 168 hours.…”