Vitamin K antagonist

I6I C. Warfarin baits need contain only 0 025% active principle, and rats are killed after ingesting about 5 doses the bait can be left down and the risk of acute toxicity to man or domestic animals is not serious. In common with other coumarin derivatives, warfarin reduces the clotting power of blood and death is caused by haemorrhages initiated by any slight injury. Warfarin is a vitamin K antagonist, and large oral doses of the vitamin can be given as an antidote. 

Therapeutic Function Anticoagulant, Vitamin K antagonist Chemical Name 3-(Q -acetonyl-p-nitrobenzyl)-4-hydroxycoumarin Common Name Nicoumalone Structural Formula ... 

Vitamin K. Figure 1 The vitamin K cycle, w indicates where warfarin or other vitamin K antagonist inhibit the cycle. 

Application of vitamin K-antagonistic anticoagulants like warfarin gave no clearcut results concerning bone density or a changed risk for bone fractures. 

Dicoumarol is found in sweet clover and can cause hemorrhaging in cattle because of its anticoagulant action. It acts as a vitamin K antagonist and has served as a model for the development of warfarin and related anticoagulant rodenticides. 

Warfarin and the second-generation superwarfarins are ARs that have a structural resemblance to dicoumarol and vitamin K. They act as vitamin K antagonists, thereby retarding or stopping the carboxylation of clotting proteins in the hepatic endoplasmic reticulum. The buildup of nonfunctional, undercarboxylated clotting proteins in the blood leads eventually to death by hemorrhaging. 

Ansell J, Hirsh J, Poller L, et al. The pharmacology and management of the vitamin K antagonists The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004 126 204S-233S. 

In the future, this test may be replaced by the proteins induced by vitamin K antagonists absence (PIVKA) concentrations in serum. PIVKAs are coagulation factor precursors, normally not detectable in blood but released into the... 

Racemic warfarin (65), a vitamin K antagonist, has been used for decades both as an oral anticoagulant in man and as a rodenticide. The metabolism of this drug has been found to be substrate-enantioselective 9S-warfarin is considered as more active than the 9R-antipode. In mammalian systems, warfarin undergoes a stereoselective reduction of the ketonic side chain [176,177], affording mainly the 9R,llS-alcohol (71), but the major biotransformation route involves substrate-enantioselective aromatic hydroxylations at 4 -, 6-, 7- or 8-positions... 

At the required dosage, the resins cause diverse gastrointestinal disturbances. In addition, they interfere with the absorption of fats and fat-soluble vitamins (A, D, E, K). They also adsorb and decrease the absorption of such drugs as digitoxin, vitamin K antagonists, and diuretics. Their gritty texture and bulk make ingestion an unpleasant experience. 

Vitamin K (phylloquinone) and similar substances with modified side chains are involved in carboxylating glutamate residues of coagulation factors in the liver (see p. 290). The form that acts as a cofactor for carboxylase is derived from the vitamin by enzymatic reduction. Vitamin K antagonists (e. g., coumarin derivatives) inhibit this reduction and consequently carboxylation as well. This fact is used to inhibit blood coagulation in prophylactic treatment against thrombosis. Vitamin K deficiency occurs only rarely, as the vitamin is formed by bacteria of the intestinal flora. 

Toxicology. Pindone is a vitamin K antagonist and causes inhibition of prothrombin formation, which results in hemorrhage. 

Warfarin acts as a vitamin K antagonist and suppresses the hepatic formation of prothrombin and of factors VII, IX, and X, causing a markedly reduced prothrombin activity of the blood.Warfarin also causes dilatation and engorgement of blood vessels and an increase in capillary fragility. The two effects can combine to produce hematomas, severe blood... 

Drugs that may interact with lepirudin and increase the risk of bleeding include thrombolytics (eg, tPA, streptokinase) and coumarin derivatives (vitamin K antagonists). 

Vitamin K antagonists, such as dicoumarol (8.61, a natural product) and warfarin (8.62), are used as anticoagulants in human therapy (thrombosis, atherosclerosis) and as rat poisons that lead to internal bleeding and death in rodents. Heparin, a polysaccharide consisting of 2-0-sulfonated glucuronic acid and 2-N,6-0-disulfonated glucosamine, is also a widely used anticoagulant, but its effect is connected not with Vitamin K but with enzyme inhibition. 

Figure 17.1 The coagulation cascade., Site of action of vitamin K antagonists LMWH, low molecular weight heparin.

Costedoat-Chalumeau N, Amoura Z, Aymard G, Sevin O, Wechsler B, Du Cacoub PLT, Diquet B, Ankri A, Piette JC. Potentiation of vitamin K antagonists by high-dose intravenous methylprednisolone. Ann Intern Med 2000 132(8) 631-5. 

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