Clinically Important Drug Interactions with Anticoagulants

Abstract

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.

Bosentan treatment in patients with primary pulmonary hypertension receiving nonparenteral prostanoids

“…Anaemia was not a problem in the present study population. Anticoagulation with the oral anticoagulant phenprocoumon was altered in the majority of patients, probably due to the induction by bosentan of cytochrome P 450 -dependent metabolism [26,27]. Thus close monitoring of the INR is indispensable in patients undergoing anticoagulation therapy with phenprocoumon as long as they receive bosentan.…”

Main comedications associated with major bleeding during anticoagulant therapy with coumarins

“…Most information on drug interactions with coumarin anticoagulants is based on case reports and smallscale experiments [1,4,7,18]. This is an unsatisfactory basis on which to make recommendations for anticoagulant therapy.…”

Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors

“…3,6,11 Warfarin is highly bound to serum albumin, which in combination with its extensive cytochrome P450 (CYP) metabolism and narrow therapeutic range makes warfarin susceptible to drug interactions. 12 An asymmetric carbon in the warfarin molecule gives rise to the enantiomeric forms S-and R-warfarin. 13 Both enantiomers are eliminated extensively via hepatic metabolism with a low extraction ratio.…”