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A 65-year-old woman with atrial fibrillation has been taking warfarin for several months with no problems. She visits her GP and complains that she has vaginal irritation. Her doctor diagnoses vaginal candidiasis and prescribes oral fluconazole. Later the woman notices blood in her urine on two or three occasions.
(a) Why has the woman been prescribed warfarin?
Atrial fibrillation leads to stasis of blood in the left atrium or appendage. This may result in the formation of thrombi, which can then embolize to the systemic circulation and cause stroke. Elderly patients with atrial fibrillation are at increased risk of stroke, which can be reduced by anticoagulation with warfarin.
(b) Could the fluconazole be associated with the blood in her urine?
Yes. Fluconazole inhibits the cytochrome P450 enzyme (CYP3A4) that metabolizes warfarin. This increases the anticoagulant effect of warfarin and can cause bleeding. Warfarin is one of the commonest drugs involved in drug interactions.
(c) How would you treat this patient?
The patient should stop taking fluconazole and the INR* should be checked. Since the haematuria has ceased, no immediate further action is required. However, the INR should be checked after 2 or 3 days to make sure it is falling to a suitable level.
* INR (international normalized ratio). This is the ratio of the patient’s prothrombin time to that of a standardized reference sample (normally 1). The prothrombin time is the time to clot formation following the addition of thromboplastin. It is a measure of the activity of vitamin K-dependent clotting factors and is therefore important for adjusting warfarin dosage.
(d) What methods are available for treating overdoses of warfarin?
Haemorrhage is the main adverse effect of warfarin (and other oral anticoagulants). Treatment for minor bleeds requires cessation of warfarin and administration of oral or intravenous phytomenadione (vitamin K). Major bleeding is treated with intravenous phytomenadione and dried prothrombin factors.