A 70-year old woman was transferrred to hospital for rehabilitation six week following the amputation of her left leg below the knee.On hospital day 4, warfarin sodium (Coumadin) 5 mg daily was added to the regimen, and daily PTs were ordered. Heparin therapy was discontinued on day 12, at which time the PT was 18,9 sec (control 11,4 sec). With the warfarin sodium therapy of 4-5 mg daily, the PT was subsequently stabilized in the 20-24 sec range, equivalent to calculated prothrombin ratios (PR) of 1,73 to 2,28. On hospital day 47, the patient experienced what was thought to be a partial seizure, which the became generalized. Treatment with phenytoin 250 mg given orally every eight hours was initated for a total of four doses and then followed by a maintenance dosage of 200 mg at bedtime. Despite reductions in the warfarin dose, the PR increased to a peak of 2,44 on hospital day 53, at which time the serum phenytoin concentrations was 8,4 Ág/ml. Thereafter, the PR decreased, ranging from 1,39 to 1,58, although the warfarin dose had been increased to 5 mg daily. On hospital day 71, based on a trough serum phenytoin concentration of 5,2 Ág/ml, the phenytoin dose was increased to 200 mg twice daily. To elevate the PR to the therapeutic range, the warfarin dose was also increased to 7,5 mg alternating with 5 mg daily, and four days later the PR was 1,83.After initiating phenytoin on hospital day 47, the patients PR appeared to increase for six days, after which it declined to less than that observed before the initiation of phenytoin.

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

A 74-year old man had a right occipital infarction and a right frontal infarction. In view of the recurrent strokes and embolic focus in the right carotid he was commenced on warfarin in May 1989. He was eventually discharged from hospital on 6 mg/day of warfarin with an INR of 2,36 (therapeutic range 2,5 - 4,0). No other medications were introduced and the warfarin dose was controlled to give a ratio between 2 and 3. He was readmitted 5 months later having 3 generalized tonic/clonic seizures. A cerebral computed tomographic (CT) scan showed no change from before and phenytoin was started with a loading dose of 300 mg intravenously; he was maintained on 300 mg/day. His hepatic and renal function were normal. The admission INR was 2,87 and he was contined on 6 mg warfarin/day. Seven days after admission he suddenly became pale and hypotensive after a generalized tonic/clonic seizure. He had abdominal tenderness attributed to a spontaneous retroperitoneal haemorrage, which was confirmed by an abdominal CT scan. The INR was 10,41 and phenytoin level 10 mg/l (therapeutic range 10-20). No other drugs had been introduced. He was resuciated with fresh frosen plasma and intravenous fluid. His general condition improved, only to deteroiate again 3 days later, complicated by cardiac arrest from which he did not recover despite cardiopulmonary resuciation.

Phenytoin has been reported to have major interactions with warfarin. Phenytoin induces warfarin's metabolism. However, there are many case reports which provide conflicting conclusions. Here, we report a case of a 65-year-old man with mechanical heart valve on chronic warfarin therapy who experienced persistent fluctuations of INR and bleeding secondary to probable warfarin-phenytoin interactions. The patient's anticoagulation clinic visits prior to hospitalization were thoroughly evaluated and we continued to follow-up the case for 3 months post-hospitalization. The reported interaction could be reasonably explained from the chronology of events and the pattern of INR fluctuations whenever phenytoin was either added or discontinued from his drug regimen. < copyright > Springer 2005

The effect of bishydroxycoumarin, phenprocoumon, warfarin and phenindione on the metabolism of diphenylhydantoin (DPH) and tolbutamide has been studied in 54 patients. The half-lives of DPH and tolbutamide in blood following i.v. injections were studied in 33 patients before and after one week of anticoagulant treatment. Bishydroxycoumarin increased the mean half-life values of DPH from 8.8 to 37.4 hours and of tolbutamide from 4.9 to 17.5. Phenprocoumon prolonged DPH half-life from a mean value of 9.9 to 14.0 hours but did not change the tolbutamide half-life. Warfarin and phenindione did not affect DPH or tolbutamide half-lives. Steady state concentration studies in 21 patients showed a rise in serum DPH during bishydroxycoumarin and phenprocoumon treatment but not during treatment with warfarin and phenindione. A rise in serum tolbutamide was noted during treatment with bishydroxycoumarin. These findings suggest that bishydroxycoumarin inhibits the betabolism of DPH and tolbutamide and that phenprocoumon inhibits DPH metabolism. No effect on DPH and tolbutamide metabolism could be demonstrated following administration of warfarin and phenindione

Two patients were stabilized on maintenance doses of warfarin and had significant elevations of their prothrombin times when phenytoin was added to their regimen. In one case the patient had been receiving 2,5 mg warfarin 5 days a week and 5 mg of warfarin 2 days a week. Prothrombin times were never greater than 21 seconds, with a control time of 12 seconds. Phenytoin, 300 mg daily, was added for arrythmia control, and enven though warfarin was decreased to 2,5 mg daily the patient`s prothombin time was 32 seconds (control value, 12 seconds) within a month. Phenytoin therapy was discontinued, and the patient`s prothrobin time was again controlled on his former warfarin regimen.