Dicoumarol interaction

CI2. Cucinell, S. A., Conney, A. H., Sansor, M., and Bums, J. J., Drug interactions in man lowering effect of phenobarbital on plasma levels of dicoumarol and diphenylhydantoin. Clin. Pharmacol. Thcr. 6, 420-429 (1965). 

Dicoumarol is an artefactual coumarin formed by putrefaction of ensiled sweet clover and has been employed as an anticoagulant because it inhibits quinone reductase activity and, therefore, the function of vitamin K in the way of synthesising coagulation factors. Given that quinones are involved in redox systems affecting mitogenic kinase cascades, dicoumarol was studied for its interaction with some of these enzymes. In fact dicoumarol prevented the activation of SAPK and of nuclear factor-xB (NF-kB) [59]. 

Munday R, Smith BL, Munday CM. Effects of buty-lated hydroxyanisole and dicoumarol on the toxicity of menadione to rats. Chem Biol Interact 1998 108 155-70. 

The interaction with HSA of drugs such as phenylbutazone and its analogues (319), dicoumarol (320), warfarin, 4-hydroxy-coumarin or... 

A number of studies and case reports suggest that allopurinol does not alter the pharmacokinetics or pharmacodynamics of warfarin. Nevertheless, a few case reports suggest that allopurinol might have increased the effect of warfarin. Two cases have also been reported with phenprocoumon. Allopurinol increased the half-life of dicoumarol in some healthy subjects, but there do not appear to be any reports of a clinically significant interaction. 

Not understood. One study showed that norethandrolone did not alter the metabolism of dicoumarol, and did not alter the plasma levels of vitamin-K dependent clotting factors. However, a more recent study of oxandrolone and warfarin shows a pharmacokinetic basis for this interaction. ... 

There is some evidence that the absorption of dicoumarol may be increased by magnesium hydroxide, but there is no direct evidence that this is clinically important. Aluminium hydroxide does not interact with either warfarin or dicoumarol, and magnesium hydroxide does not interact with warfarin. 

The documentation for the interaction between anticoagulants and oral chloramphenicol is very sparse and poor (the best being the pharmacokinetic report about dicoumarol) so that this interaction is by no means adequately established. There would therefore appear to be little reason for avoiding concurrent use, but it would seem prudent to monitor prothrombin times if oral chloramphenicol is started in patients taking a cou-marin, being alert for the need to reduce the anticoagulant dosage. 

Dicoumarol inhibits the metabolism of tolbutamide and increases its effects cases of hypoglycaemic coma have been reported. Chlorpropamide may be affected similarly. Although isolated cases of interactions (raised prothrombin times, bleeding or hy-poglycaemia) have been seen in patients taking sulfonylureas and coumarins, in general, no important interaction appears to occur. There also appears to be no interaction between phenindione and tolbutamide. 

Dicoumarol appears to increase the effects of tolbutamide by inhibiting its metabolism by the liver. This may also be true for chlorpropantide. The increase in the anticoagulant effects of dicoumarol by tolbutamide may, in part, be due to a plasma protein binding interaction. In the case of phenprocoumon there seem to be several different mutually opposing processes going on, which cancel each other out. There is no clear explanation for most of these interactions. 

Jahnchen E, Meinertz T, Gilfrich H-J, Groth U. Phaimacokinetic analysis of die interaction between dicoumarol and tolbutamide in man. EurJClin Pharmacol 916) 10, 349-56. 

Information is very sparse and limited to dicoumarol and warfarin, but the interaction seems to be established. Be alert for other coumarins to behave similarly. Anticipate the need to alter the anticoagulant dosage if ethchlorvynol is started or stopped. The benzodiazepines may be a useful non-interacting alternative to ethchlorvynol, see Coumarins + Benzodiazepines and related drugs, p.391. 

The interactions of clofibrate with dicoumarol, warfarin and phenindione are established, clinically important and potentially serious. Severe bleeding (fatal in some instances) has been seen. The incidence of the interaction is reported to be between 20 and 100%, but it would be prudent to assume that all patients will be affected. Dosage reduetions of one-third to one-half may be needed to avoid the risk of bleeding. Monitor the INR and adjust the dose accordingly. Information about other eoumarins and indanediones is lacking but it would be prudent to assume that they will interact with clofibrate in a similar way. 

The rate of absorption of dicoumarol can be increased by food. Two reports describe antagonism of the effects of warfarin by icecream, and another report attributes an increase in prothrombin time to the use of aspartame. However, the most common food-warfarin interaction is that due to foods containing vitamin K... 

Not understood. One suggestion for the interaction between food and dicoumarol is that food may cause prolonged retention of dicoumarol in the upper part of the gut, leading to increased tablet dissolution and increased absorption. 

Quinidine did not alter the anticoagulant effect of warfarin in a study in patients, nor in a retrospective analysis of patient data. However, isolated reports of increased warfarin effects and bleeding have been reported, although these stem from over 35 years ago, and nothing further seems to have been reported, su esting that an interaction is unlikely. Quinidine did not alter the half-life of phenprocoumon in healthy subjects. A small decrease in the effects of dicoumarol and warfarin has also been reported with quinidine, which was attributed to changes in haemodynamic factors following cardioversion. 

Information about interactions between anticoagulants and tricyclic antidepressant is limited, patchy and inconclusive. It appears that amitriptyline and nortriptyline do not alter the half-life of warfarin, but might increase that of dicoumarol. A greater fluctuation in anticoagulant control was noted in two analyses, one with warfarin and one with phenprocoumon. However, these were uncontrolled studies, and the findings need confirming in a randomised study. Moreover, there do not appear to be any... 

None of these interaetions has been extensively studied nor are they well established, but what is known suggests that the use of dicoumarol with phenytoin should be avoided or monitored very closely. Serum phenytoin levels and anticoagulant control should be well monitored if acenoeou-marol, phenprocoumon or warfarin is given with phenytoin. Dosage adjustments may be needed to accommodate any interactions. Information about other anticoagulants (apart from phenindione, which had no effect... 

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