Coumarin derivatives combine 3 unfavorable properties which make them prone to 
potentially life threatening drug-drug interactions: (i) high protein binding; 
(ii) cytochrome P450 dependent metabolism; and (iii) a narrow therapeutic range. 
An entire list of drugs which are supposed to interact with coumarins (mostly 
with warfarin) comprises about 250 different compounds. Noteworthy are the 
interactions with cardiovascular or antilipidaemic drugs which are often 
coadministered with coumarins: amiodarone, propafenone and fibrates. 
Cardiovascular drugs which are obviously devoid or proven to be devoid of an 
interaction are angiotensin converting enzyme (ACE) inhibitors, calcium 
antagonists, beta-blockers and cardiac glycosides. There are several other drugs 
which enhance the hypoprothrombinaemic response to coumarins by various 
mechanisms: inhibitors of the elimination of the eutomer S-(-)-warfarin (e.g. 
miconazole, phenylbutazone), combined with protein binding displacement (e.g., 
sulfinpyrazone, phenylbutazone), synergistic hypoprothrombinaemia (e.g. 
cefazoline). Furthermore, bleeding complications may occur with drugs affecting 
platelet function [aspirin (acetylsalicylic acid) and several nonsteroidal 
anti-inflammatories (NSAIDs)]. Strong inducers of coumarin metabolism are 
rifampicin (rifampin) and carbamazepine. Biphasic interactions may occur where a 
drug first enhances the hypoprothrombinaemic response to a coumarin but has a 
sustained inducing effect on coumarin metabolism (e.g. phenytoin or 
sulfinpyrazone). The complex response of coumarins to concomitant drug therapy 
makes it difficult to predict the occurrence and degree of a deterioration of 
anticoagulant control in individual patients. For clinical practice, it seems 
advisable that one should monitor for changes in prothrombin time when adding or 
deleting any newly approved drug or any drug suspected (e.g. on the basis of 
this review) to cause an interaction to patients on coumarin therapy. The onset 
of the adverse prothrombin time response might be from between 1 to 2 days up to 
3 weeks (in case of phenprocoumon) after starting a concomitant drug regimen. 
With amiodarone, an adverse prothrombin time response might occur up to 2 months 
after initiating therapy. For heparins, only a drug interaction with aspirin or 
nitroglycerin seems clinically relevant due to the possibility of 
coadministration during acute cardiac events. Both drugs are shown to enhance 
the activated partial thromboplastin time response to heparin.