Coumarin anticoagulants hepatic

Chemistry and pharmacokinetics The coumarin anticoagulants (eg, warfarin) are small, Upid-soluble molecules that are readily absorbed after oral administration. They cross the placental barrier readily and are potentially dangerous to the fetus. Warfarin is highly bound to plasma proteins (> 99%), and its elimination depends upon metabolism by hepatic cytochrome P450. 

Drug-drag interactious Coumarin anticoagulants The addition of ophthalmic erythromycin for conjunctivitis in a 77-year-old woman taking warfarin reportedly caused an increase in INR [79" ]. This could have been due to systemic absorption of erythromycin followed by hepatic enzyme inhibition. Neither the dose of erythromycin nor the serum concentration was reported. 

The principal adverse reaction to warfarin is hemorrhage. Prolonged therapy with the coumarin-type anticoagulants is relatively free of untoward effects. Bleeding may be observable (e.g., skin, mucous membranes) or occult (e.g., gastrointestinal, renal, cerebral, hepatic, uterine, or pulmonary). Rarer untoward effects include diarrhea, small intestine necrosis, urticaria, alopecia, skin necrosis, purple toes, and dermatitis. 

Rare adverse effects of fibrates include rashes, gastrointestinal symptoms, myopathy, arrhythmias, hypokalemia, and high blood levels of aminotransferases or alkaline phosphatase. A few patients show decreases in white blood count or hematocrit. Both agents potentiate the action of coumarin and indanedione anticoagulants, and doses of these agents should be adjusted. Rhabdomyolysis has occurred rarely. Risk of myopathy increases when fibrates are given with reductase inhibitors. The use of fenofibrate with rosuvastatin appears to minimize this risk. Fibrates should be avoided in patients with hepatic or renal dysfunction. There appears to be a modest increase in the risk of cholesterol gallstones. 

The anticoagulant coumarins show certain structural similarities to vitamin K and probably as anti-metabolites their effects are manifested as a vitamin K depletion. As in vitamin K deficiency, the administration of warfarin depressed the synthesis of factor Vll in the liver. The action of this coumarin or lack of vitamin K is specific. These treatments have no general effect on hepatic protein synthesis, reducing only the synthesis of factor VII. Furthermore, the effect was only reversed by the administration of vitamin K [421], These changes occur mo coumarins have no effect on blood clotting when added in vitro. 

Dicoumarol, warfarin and tromexan (67) have been shown to be metabolised by hepatic microsomal enzymes. These enzymes can be increased by phenobarbital and with the rapid metabolism of the anticoagulant its effect is reduced [451]. In contrast, phenyramidol inhibits the metabolism of coumarin and hence prolongs the duration of the anticoagulant response [445]. In the rat, the major metabolites of these compounds are 7-hydroxylated derivatives (68) [460— 462]. In man, besides the alteration of the ring [463], side-chain hydroxylation also occurs (69) in the rabbit, de-esterification proceeds rapidly (70) (see Figure 3.9). 

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