Warfarin vitamin

Warfarin Vitamin Kj Stimulates coagulation factor synthesis... 

Failure of certain individuals to respond to normal doses of a drug, e.g. resistance to warfarin, vitamin D, may be said to constitute a form of natural tolerance (see Pharmacogenetics p. 122). 

In the presence of warfarin, vitamin K epoxide cannot be reduced back to the active hydroquinone, but accumulates, and is excreted as a variety of conjugates. If enough vitamin K is provided in the diet, the quinone can be reduced to the active... 

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. 

In contrast to heparin, the coumarinic acid anticoagulants are inactive in vitw ]6k.e heparin they are active in vivo. The phenylindanedione-type compounds (7) (36) and warfarin (2) produce their in vivo inhibitory effect on the coagulation system by competitively antagonizing the normal activity of vitamin (8) (37—44). 

The isoprene-derived molecule whose structure is shown here is known alternately as Coumarin and warfarin. By the former name, it is a widely prescribed anticoagulant. By the latter name, it is a component of rodent poisons. How can the same chemical species be used for such disparate purposes The key to both uses lies in its ability to act as an antagonist of vitamin K in the body. 

Anticoagulants. Figure 2 Coumarin (Warfarin) and the vitamin K cycle. Abbreviations glu, glutamate gla, y-carboxyglutamate. (Modified from [2], with permission from Chest.)... 

Maintenance doses widely vary among patients (e.g., from 1 to 20 mg/day for warfarin), and are influenced by diet (variable vitamin K intake) and medications that affect coumarin metabolism (decreased drug clearance e.g., cotrimoxazole, amiodarone, erythromycin increased clearance e.g., barbiturates, carbamaze-pine, rifampin). Thus, regular monitoring is needed... 

The pharmacological and/or adverse effects of a drug can be reversed by co-administration of drugs which compete for the same receptor. For example, an opioid receptor antagonist naloxone is used to reverse the effects of opiates. Drugs acting at the same site with opposite effects also can affect each other, e.g. the reduction in the anticoagulant effect of warfarin by vitamin K. 

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. 

All anticoagulants interfere with the clotting mechanism of the blood. Warfarin and anisindione interfere with the manufacturing of vitamin K-dependent clotting factors... 

The effects of warfarin may increase when administered with acetaminophen, NSAIDs, beta blockers, disulfiram, isoniazid, chloral hydrate, loop diuretics, aminoglycosides, cimetidine, tetracyclines, and cephalosporins. Oral contraceptives, ascorbic acid, barbiturates, diuretics, and vitamin K decrease the effects of warfarin. Because die effects of warfarin are influenced by many drugp, die patient must notify die nurse or die primary healdi care provider when taking a new drug or discontinuing... 

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. 

FIGURE 11.3 Action of warfarin and related rodenticides on the vitamin K cycle. 

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. 

The anticoagulant rodenticides warfarin and superwarfarins are toxic because they have high affinity for a vitamin K binding site of hepatic microsomes (Chapter 11, Section 11.2.4). In theory, an ideal biomarker would... 

Vitamin K is the cofactor for the carboxylation of glutamate residues in the post-synthetic modification of proteins to form the unusual amino acid y-carboxygluta-mate (Gla), which chelates the calcium ion. Initially, vitamin K hydroquinone is oxidized to the epoxide (Figure 45-8), which activates a glutamate residue in the protein substrate to a carbanion, that reacts non-enzymically with carbon dioxide to form y-carboxyglut-amate. Vitamin K epoxide is reduced to the quinone by a warfarin-sensitive reductase, and the quinone is reduced to the active hydroquinone by either the same warfarin-sensitive reductase or a warfarin-insensitive... 

Prothrombin and several other proteins of the blood clotting system (Factors VII, IX and X, and proteins C and S) each contain between four and six y-carboxygluta-mate residues which chelate calcium ions and so permit the binding of the blood clotting proteins to membranes. In vitamin K deficiency or in the presence of warfarin, an abnormal precursor of prothrombin (preprothrombin) containing little or no y-carboxyglutamate, and incapable of chelating calcium, is released into the circulation. 

Treatment of pregnant women with warfarin can lead to fetal bone abnormalities (fetal warfarin syndrome). Two proteins are present in bone that contain y-carboxygluta-mate, osteocalcin and bone matrix Gla protein. Osteocalcin also contains hydroxyproHne, so its synthesis is dependent on both vitamins K and C in addition, its synthesis is induced by vitamin D. The release into the circulation of osteocalcin provides an index of vitamin D stams. 

For activity, factors II, VII, IX, and X and proteins C and S require vitamin K-dependent y-carboxylation of certain glutamate residues, a process that is inhibited by the anticoagulant warfarin. 

Warfarin exerts its anticoagulant effect by inhibiting the production of the vitamin K-dependent coagulation factors... 

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