Warfarin Coumarins

Coumarin (4 hydroxy) brodifacoum, bromadiolone, coumatetralyl, difenacoum, flocoumafen, warfarin Coumarin (4 methyl 7 hydroxy) coumaphos m-Cresol acifluorfen, clomeprop, metolcarb o-Cresol DNOC, MCDA, MCPB, mecoprop... 

Table Vll-l-l. Properties of Heparin and Warfarin (Coumarins) (continued)...

A) Activated partial thromboplastin time reliably measures the anticoagulant effect of low-molecular-weight (LMW) heparins Cimetidine increases the anticoagulant activity of warfarin Coumarin anticoagulants reduce the activities of clotting factors 11, VII, IX, and X Heparins are safe to use in the pregnant patient... 

Exposure. Several commonly used rodentiddes rely on anticoagulants (e.g., warfarin, coumarin) to exert their effects. 

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. 

Coumarin/warfarin, given at a typical dosage of 4 to 5 mg/day, prevents the deleterious formation in the bloodstream of small blood clots and thus reduces the risk of heart attacks and strokes for individuals whose arteries contain sclerotic plaques. Taken in much larger doses, as for example in rodent poisons, Coumarin/warfarin can cause massive hemorrhages and death. 

Further work in this area showed that only one of the cou-marin rings was needed for biologic activity. Condensation of the hydroxyacetophenone, 4, with diethyl carbonate affords 4-hydroxycoumarin (2). The reaction may involve the 3-ketoester (5) cyclization of this would afford 2. Alternately, the reagent may first give the 0-acyl derivative cyclization as above will give the same product. Michael condensation of the coumarin with benzalacetone (6) affords the anticoagulant warfarin (named after its place of origin Wisconsin Alumni Research Foundation,... 

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

The two most widely used coumarins are warfarin (US, Canada, and UK) and phenprocoumon (continental Europe). The long half-life (60 h) of prothrombin means that coumarin cannot achieve therapeutic anticoagulation for at least 5 days following initiation. Thus, for patients with acute thrombosis, oral anticoagulants are usually started only when the patient is receiving a rapidly active agent, usually UFH or LMWH. 

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 term pasaon flower is used to denote many of the approximately 400 species of the herb. F saon flower has been used in medicine to treat pain, anxiety, and insomnia. Some herbalists use the herb to treat symptoms of parkinsonism. F saon flower is often used in combination with other herbs , such a valerian, chamomile, and hops, for promoting relaxation, rest and sleep. Although no adverse reactions have been reported, large doses may cause CNS depression. The use of passion flower is contraindicated in pregnancy and in patientstaking the monoamine oxidase inhibitors (MAOIs). Fission flower contains coumarin, and the risk of bleeding may be increased when used in patientstaking warfarin and pasaon flower. 

Asymmetric syntheses of warfarin <96TL8321> and the axially chiral bicoumarin, isokotanin A <96TL3015> have been reported. The former is based on a Rh-catalysed asymmetric hydrogenation of a 3-(a,P-unsaturated ketone) substituted coumarin, whilst the key steps of the latter are an asymmetric Ullmann coupling and a selective demethylation. The stereochemistry of the fused dihydrocoumarin resulting from Li/NHs reduction of... 

Matricaria recutita, known as German chamomile, is also purported to have antispasmodic properties. It is taken most often as a tea up to four times a day. Benzodiazepine, alcohol, and warfarin users should be cautioned against taking this product because it can cause drowsiness, and it contains coumarin derivatives.20... 

Dong quai No demonstrated efficacy Not recommended Structurally similar to coumarins—avoid with warfarin because INR can increase... 

Hydroxyphenol, see Hydroquinone p-Hydroxyphenol, see Hydroquinone 4-Hydroxy-3-(l-phenyl-3-oxobutyl)coumarin, see Warfarin 1 -Hydroxypropane, see 1 -Propanol 3 Hydroxypropene, see Allyl alcohol 3 Hydroxypropionic acid lactone, see p-Propiolactone... 

Competition between drugs for plasma binding sites occurs and is responsible for some of the clinically most important changes in drug distribution. Phenylbutazone and oxyphenbutazone, for example, potentiate the action of warfarin by displacement (A2) and trichloroacetic acid, a major metabolite of chloral hydrate has a similar effect (S12) and is the cause of hemorrhagic complications during coumarin therapy (A2). 

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