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WARFARIN NAD+ NADH

FIGURE 54-6 The vitamin K cycle: y-glutamyl carboxylation of vitamin K-dependent proteins. The enzyme ^-glutamyl carboxylase couples the oxidation of the reduced hydroquinone form (KH2) of vitamin Kx or K2, to )-carboxylation of Glu residues on vitamin K-dependent proteins, generating the epoxide of vitamin K (KO) and )-carboxyglutamate (Gla) residues in vitamin K-dependent precursor proteins in the endoplasmic reticulum. A 2,3-epoxide reductase regenerates vitamin KH2 and is the warfarin-sensitive step. The R on the vitamin K molecule represents a 20-carbon phytyl side chain in vitamin Kx and a 5- to 65-carbon prenyl side chain in vitamin K2.

factor IX, 24; factor X, 36; factor II, 50; protein C, 8; and protein S, 30. Because of the long half-lives of some of the coagulation factors, in particular factor II, the full antithrombotic effect of warfarin is not achieved for several days, even though the PT may be prolonged soon after administration due to the more rapid reduction of factors with a shorter t1/2, in particular factor VII.

dosage The usual adult dose of warfarin (Coumadin) is 5 mg/day for 2-4 days, followed by 2-10 mg/day as indicated by measurements of the INR. A lower initial dose should be given to patients with an increased risk of bleeding, including the elderly; age correlates with increased sensitivity to oral anticoagulants. Warfarin usually is administered orally but also can be given intravenously without dose modification. Intramuscular injection is not recommended because of the risk of hematoma formation.

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