Phenprocoumon Coumarins

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. 

Bishydroxycoumarin (dicoumarol) is a natural occurring anticoagulant found in sweet clover. A number of coumarin derivatives have been synthesized as anticoagulants, warfarin, phenprocoumon and acenocoumarol being most frequently used. The nonpolar carbon substituent at the 3 position required for activity is asymmetrical. The enantiomers differ in both pharmacokinetic and pharmacodynamic properties. The coumarins are marketed as racemic mixtures. 

The coumarin anticoagulants include dicumarol, warfarin sodium (coumadin sodium), warfarin potassium (Athrombin-K), acenocoumarol (Sintrom), and phenprocoumon (Liquamar). The inanedione derivatives are phenindione (Hedulin), diphenadione (Dipaxin), and anisindi-... 

The coumarin anticoagulants include dicumarol, warfarin sodium (coumadin sodium), warfarin potassium (Athrom-bin-K), acenocoumarol (Sintrom), and phenprocoumon (Liquamar). The inanedione derivatives are phenindione (Hedulin), diphenadione (Dipaxin), and anisindione (Miradon). The pharmacological properties of oral anticoagulants are identical qualitatively, but their pharmacokinetic parameters and their toxicities vary. Racemic warfarin sodium is the most widely used anticoagulant. Antithrombotic drugs are used clinically either to prevent the formation of blood clots within the circulation (anticoagulant) or to dissolve a clot that has already formed (thrombolytic). 

The substituents at position 3 greatiy affect the pharmacokinetic and toxicoiogicai properties of warfarin and its derivatives (Tabie 31.1) (24). Dicoumaroi is not compieteiy absorbed in the gastrointestinai tract, often is associated with gastrointestinai discomfort, and is very rareiy used ciinicaiiy. Today, the oniy coumarin used in the United States is warfarin, but phenprocoumon and acenocomumaroi are used in Europe. 

The coumarins, warfarin, phenprocoumon and acenocoumarol, are racemic mixtures of S- and 7 -enantiomers. The 5-enantiomers of these... 

Similar advice applies to acenocoumarol and phenprocoumon, and probably also other coumarins. Some recommend an initial reduction in acenocoumarol dose of 50% when amiodarone is added, whereas others recommend that the INR should be closely monitored, and the dose of acenocoumarol only reduced in response to an increase in INR. ... 

Co-trimoxazole modesitly inhibits the metabolism of A warfarin, and a number of case reports show that the anticoagulant effects of the coumarins warfarin, acenocoumarol, and phenprocoumon are increased by co-trimoxazole. Case reports surest that sul-fafurazole, sulfadoxine, and sulfamethizole may have similar effects. Two cohort studies have suggested that trimethoprim alone is associated with an increased risk of overanticoagulation, but this was less than that for co-trimoxazole in one of these studies. Anecdotal evidence su ests that the indanedione phenindione might not interact with co-trimoxazole, but in one study sul-faphenazole increased the effect of phenindione. 

Not fully understood. Sulfamethoxazole is a known inhibitor of the cytochrome P450 isoenzyme CYP2C9, by which S-warfarin in predominantly metabolised. The finding that co-trimoxazole caused a modest 22% increase in S-warfarin levels supports this mechanism. Acenocoumarol and phenprocoumon are also metabolised by CYP2C9 and might be expected to be similarly affected. Plasma protein binding displacement has been suggested as a mechanism, but on its own it does not provide an adequate explanation because the interaction is sustained. Sulfonamides can drastically reduce the intestinal bacterial synthesis of vitamin K, but this is not normally an essential source of the vitamin unless dietary sources are exceptionally low, see also Coumarins + Antibacterials , p.365. 

The interaction between co-trimoxazole and coumarin anticoagulants is well documented and well established. The incidence appears to be high. If bleeding is to be avoided the INR should be well monitored and the warfarin, acenocoumarol, or phenprocoumon dosage should be reduced. Anecdotal evidence suggests that co-trimoxazole may not interact with the indanedione phenindione, but note that sulfaphenazole did, so some caution is still appropriate. 

Controlled studies have shown no interaction between pioglitazone and warfarin or phenprocoumon, or between rosiglitazone and warfarin. This suggests that coumarin dose adjustments are unlikely to be needed when these antidiabetics are used. 

The manufacturers of capecitabine also report that this interaction has occurred with the coumarins including phenprocoumon. ... 

Voriconazole is a known inhibitor of the cytochrome P450 isoenzymes CYP2C9 and CYP3A4, by which the coumarins (phenprocoumon, acenocoumarol and warfarin) are metabolised. The manufacturers advise close monitoring of the prothrombin time in any patient on a coumarin anticoagulant who is given voriconazole. Dose adjustments of the coumarin should be made accordingly. ... 

The interaction between warfarin and benzbromarone or benziodarone is established and elinieally important. If benzbromarone is added to warfarin monitor prothrombin times and be alert for the need to reduce the dosage by about one-third to prevent over-anticoagulation. Information about other coumarins is limited, but what is known about the mechanism of action suggests that acenocoumarol and phenprocoumon would also be predicted to interact, and this has been shown for benziodarone and acenocoumarol or phenprocoumon, in a few patients. The limited evidence suggesting an interaction with some indanediones also suggests that some caution is appropriate with these drugs as well. 

The anticoagulant effects of phenprocoumon and warfarin can be reduced by colestyramine, especially if the coumarin is given at the same time. An isolated report describes unexpected sensitivity to warfarin in a patient taking colestyramine, which was attributed to a possible reduction in vitamin K absorption with colestyramine. Colestipol did not alter the absorption or effect of phenprocoumon or warfarin and colesevelam did not alter the pharmacokinetics of warfarin. 

The interaction between warfarin and cimetidine is well documented, well established and potentially clinically important. Its effects are generally modest, but rarely, patients have shown a marked interaction. Because of this unpredictability, and to avoid bleeding, the response should be monitored well in every patient when cimetidine is first added, being alert for the need to reduce the warfarin dosage. The onset of the interaction appears rapid effects have been seen within days, and even as early as 24 hours. The effect of low non-prescription doses of cimetidine on warfarin do not appear to have been studied. Acenocoumarol is reported to in-teraet similarly, and there is one case of phenindione being affected. Expect other coumarins and indanediones to behave in the same way, with the possible exception of phenprocoumon, which was not affected in one study. 

Randomised, placebo-controlled (1982, 1983) 20 patients Stable acenocoumarol (8 patients) or phenprocoumon (12 patients) 500 mg four times daily for 3 weeks (10 patients) placebo (10 patients) Average increase in thrombotest lue of about 20 seconds (14% increase), which necessitated a reduction in coumarin dose in 5 patients 8,9... 

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