In warfarin

Tab. 4.1 Known causes of individual variability in warfarin therapy in thromboembolism...

Obayashi, K., Nakamura, K., Kawana, J., et at. (2006) VKORCl gene variations are the major contributors of variation in warfarin dose in Japanese patients. Clin. Pharmacol. Then 80,169-178. 

No need to adjust INR in warfarin anticoagulated patients with topical hemostatic mouthwash use... 

In 12 patients chronically maintained on warfarin, atorvastatin 80 mg/day for 2 weeks reduced mean prothrombin times slightly, but only for the first few days of the 2-week treatment period (35). Thus, atorvastatin had no consistent effect on the anticoagulant activity of warfarin and adjustments in warfarin doses should not be necessary. 

Vitamin K quinone is reduced to the active hydroquinone substrate for the epoxidase reaction by either a dithiol-linked reductase that is almost certainly the same enzyme as the epoxide reductase or NADPH-dependent quinone reductase, like the epoxide reductase, the dithiol-linked reductase is inhibited by warfarin. In warfarin-resistant rats, there is a warfarin-insensitive epoxide reductase, which also has quinone reductase activity (Hildebrandt et al., 1984 Gardill and Suttie, 1990). 

The NADPH-dependent reduction of vitamin K quinone to the hydroquinone is not inhibited by warfarin. In the presence of adequate amounts of vitamin K, the carboxylation of glutamate residues can proceed normally, despite the presence of warfarin, with the stoichiometric formation of vitamin K epoxide that cannot be reutilized. Small amounts of vitamin K epoxide, and hydroxides formed by its reduction by other enzymes, are normally found in plasma. In warfarin-treated animals and patients, there is a significant increase in the plasma concentration of both. There is also an increase in the urinary excretion of the products of side-chain oxidation of the epoxide and hydroxides. 

Leek, J.B., Park, B.K. (1981). A comparative study of the effects of warfarin and brodifacoum on the relationship between vitamin K1 metabolism and clotting factor activity in warfarin-susceptible and warfarin-resistant rats. Biochem. Pharmacol. 30 123-8. 

U.S.Army cadet unsuccessfully attempted to commit suicide by taking massive doses of the compound. The incident prompted further clinical trials that resulted in warfarin being used as the anticoagulant of choice for prevention of thromboembolic disease (177). 

The maternal rate of bleeding comphcations during heparin treatment is about 2%. This is consistent with the reported rates of bleeding associated with heparin therapy in non-pregnant women, and in warfarin therapy when used for the treatment of venous thrombosis (95). Subcutaneous heparin given just before labor can also cause a persistent anticoagulant effect at the time of delivery the mechanism of this prolonged effect is unclear (96). 

Boulis NM, Bobek MP, Schmaier A, Hoff JT. Use of factor IX complex in warfarin-related intracranial hemorrhage. Neurosurgery 1999 45(5) 1113-19. 

The mechanism of this interaction has not been elucidated. Ropinirole is metabolized by CYP1A2, but that is not the major isoform involved in warfarin metabolism. 

Monterrey-Rodrigues et al., 2002). Because bromelian in papaya and pineapple modulates the arachidonate cascade, INR rates are also increased with concomitant use of warfarin (Shaw et al., 1997). In contrast, the vitamin K in a variety of green vegetables, particularly broccoli, in large amounts can act as an antagonist to the effects of anti-coagulant therapy (D Arcy, 1993) in warfarin overdose, vitamin K is used to normalize the INR. 

AD MacNicoll, AK Nadian, MG Townsend. Inhibition by warfarin of fiver microsomal vitamin K-reductase in warfarin-resistant and susceptible rats. Biochem Pharmacol 33(8) 1331—1336, 1984. 

Yuan HY, Chen JJ, Lee MT, etal. A novel functional VKORCl promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Genet 2005 14(13) 1745-5L... 

Schelleman H, Limdi NA, Kimmel SE. Ethnic differences in warfarin maintenance dose requirement and its relationship with genetics. Pharmacogenomics 2008 9(9) 1331 6. 

---