Coumarin anticoagulants

Booth NL, Nikolic D, van Breemen RB, Geller SE, Banu-var S, Shuhnan LP, Farnsworth NR. Confusion regarding anticoagulant coumarins in dietary supplements. Clin Pharmacol Ther 2004 76 511-16. 

The seeds of Dipteryx odorata (Dutch tonka bean) and Dipteryx oppositofolia (EngUsh tonka bean) are said to yield 1-3% of the non-anticoagulant coumarin, which is covered in a separate monograph. 

Anthoxanthum odoratum (sweet vernal grass) contains anticoagulant coumarins, which cause bleeding in cattle that consume the grass. 

Trade names Aldocumar Coumadin (Bristol-Myers Squibb) Coumadine Marevan Waran Warfilone Indications Thromboembolic disease, pulmonary embolism Category Anticoagulant Coumarin Half-life 1.5-2.5 days (highly variable)... 

Booth, N.L., D. NikoUc, R.B. van Breemen, et al. 2004. Confusion regarding anticoagulant coumarins in dietary supplements. Clin. Pharmacol. Ther. 76(6) 511-516. 

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. 

The anticoagulant action of coumarins resembles the Symptoms observed in vitamin K deficiency [436], and clinical observations on the reversibility of the coumarin effect by adequate amounts of vitamin K also indicate a competition between these compounds. However, this concept may represent an over-simplification because no single enzyme system has been identified where such a metabolite—anti-metabolite antagonism takes place [437]. It has been suggested that vitamin K and the anticoagulant coumarins exert their action in the liver cell at different levels [438]. They may interact with the regulation of the synthesis of vitamin K-dependent factors [439,440]. 

Coum rinic Acid Compounds. These synthetic phyUoquinone derivatives and congeners have been employed as anticoagulants since the isolation of 3,3 -methylenebis(4-hydroxy-2H-l-benzopyran-2-one) [66-76-2] (bis-4-hydroxycoumarin or dicoumarol) (1) from spoiled sweet clover in 1939. The ingestion of the latter was responsible for widespread and extensive death of bovine animals at that time. The parent compound for the synthesis of many congeners is 4-hydrocoumarin, which is synthesized from methyl salicylate by acetylation and internal cyclization. The basic stmctures of these compounds are shown in Figure 2, and their properties Hsted in Table 6 (see Coumarin). 

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. 

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,... 

Most oral anticoagulants are coumarin derivatives that act via vitamin K antagonism ([2] Fig. 2). Vitamin K... 

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. 

Coumarin is also widely used for long-term anticoagulation in chronic atrial fibrillation (particularly to avoid cardioembolic strokes), to prevent DVT or PE in patients with chronic hypercoagulability (e.g., congenital AT or protein C deficiency), or to prevent... 

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