O

Acenocoumarol Anisindione

FIGURE 54-5 Structural formulas of the oral anticoagulants. 4-Hydroxycoumarin and indan-1,3-dione are the parent molecules from which the oral anticoagulants are derived. The asymmetrical carbon atoms in the coumarins are shown in blue.

minimal structural requirement for activity. This carbon is asymmetrical in warfarin (and in phenprocoumon and acenocoumarol). The enantiomers differ in anticoagulant potency, metabolism, elimination, and interactions with other drugs. Commercial preparations of these anticoagulants are racemic mixtures. No advantage of administering a single enantiomer has been established.

mechanism of action The oral anticoagulants are antagonists of vitamin K (see below). Coagulation factors II, VII, IX, and X and the anticoagulant proteins C and S are synthesized mainly in the liver and are biologically inactive unless 9-13 of the amino-terminal glutamate residues are carboxylated to form the Ca2+-binding y-carboxyglutamate (Gla) residues. This reaction of the descarboxy precursor protein requires CO2, O2, and reduced vitamin K, and is catalyzed by y-glutamyl carboxylase in the rough endoplasmic reticulum (Figure 54-6). Carboxylation is directly coupled to the oxidation of vitamin K to its corresponding epoxide.

Therapeutic doses of warfarin decrease by 30-50% the total amount of each vitamin K-depend-ent coagulation factor made by the liver; in addition, the secreted molecules are undercarboxylated, resulting in diminished biological activity (10-40% of normal). Congenital deficiencies of the procoagulant proteins to these levels cause mild bleeding disorders. Oral anticoagulants have no effect on the activity of fully carboxylated molecules in the circulation. Thus, the time required for the activity of each factor in plasma to reach a new steady state after therapy is initiated or adjusted depends on its individual rate of clearance. The approximate half-lives (in hours) are: factor VII, 6;

Warfarin Sodium

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