Drug interaction presenting as acute abdomen

Abstract

Warfarin is the most common oral anticoagulant prescribed around the world. Adverse drug interactions with warfarin are a huge problem especially in the elderly and in patients who take multiple medications. Most adverse drug interactions involve concomitantly prescribed oral or intravenous medications. Occasionally, topical or mucosally absorbed drugs can interact, leading to fluctuations in warfarin levels with adverse consequences. In this case report, we describe a case of intestinal intramural hematoma, a rare but known consequence of a supra therapeutic international normalized ratio (INR). The supra therapeutic INR was a consequence of mucosally absorbed miconazole, prescribed for vaginal candidiasis. We wish to highlight this rare and potentially fatal drug interaction, along with the need for frequent INR monitoring when new drugs are added or removed in patients taking warfarin.

Key Words: Warfarin; Intramural hematoma; Miconazole; Drug interactions; International normalized ratio; Supra therapeutic

INTRODUCTION

Warfarin is the most widely used anticoagulant drug in north America, because it can be taken orally and it has excellent bioavailability[1]. Oral anticoagulants are commonly used to prevent as well as treat deep venous thrombosis and pulmonary embolism. In addition to this indication, they are being increasingly prescribed to prevent thromboembolic events in patients with atrial fibrillation and prosthetic heart valves.

Warfarin achieves its anticoagulant effect by inhibiting the activation of vitamin K-dependent clotting factors. The potential for warfarin to adversely interact with other drugs, resulting in fluctuations in the anticoagulant effect, is widely recognized[2] (Table 1). This is a major problem with warfarin especially in the elderly who are often on multiple medications due to concomitant comorbid conditions.

Table 1 Commonly used drugs in clinical setting that potentiate warfarin effects[2].

Category	Drugs
Antibiotics	Co-trimoxazole, erythromycin, isoniazid, fluconazole,
	miconazole, metronidazole, ciprofloxacin, itraconazole
	and tetracycline
Cardiac drugs	Amiodarone, clofibrate, propafenone, propranolol,
	and sulfinpyrazone, quinidine, simvastatin, and
	acetylsalicylic acid
Others	Phenylbutazone, piroxicam, acetaminophen,
	dextropropoxyphene, cimetidine, omeprazole, alcohol
	(only if concomitant liver disease was present), chloral
	hydrate, disulfiram, phenytoin, tamoxifen, anabolic
	steroids, and influenza vaccines

Intestinal intramural hematoma is an infrequent but potentially fatal complication of anticoagulant usage. The incidence of spontaneous intestinal intramural hematoma among patients on warfarin was reported as 1 in 2500[3].

CASE REPORT

A 72 years old Hispanic female presented to our emergency room with severe intermittent abdominal pain in the periumbilical region for five days which quickly became continuous, relieved only with narcotics. She had nausea and melena but no vomiting. The patient had undergone a mechanical mitral valve replacement in 1986 and was on warfarin for anticoagulation. Additionally, she was on levothyroxine, candesartan, digoxin, furosemide and metoprolol for multiple medical comorbidities for a number of years. She was prescribed miconazole 1% topical cream for vaginal candidiasis a week before presentation. Prior to that, her anticoagulation was stable for many years and she did not have any documented adverse drug interactions. Initial physical examination revealed tachycardia and mild diffuse abdominal tenderness, but no rigidity. Laboratory investigations were remarkable for international normalized ratio (INR) > 13, hemoglobin (HB) of 12.2 g/dl and heme-occult positive brown stool. An X-ray of the abdomen revealed a normal bowel gas pattern. She was admitted and managed conservatively with intravenous fluids, nil per oral and pain control with morphine. Six units of fresh frozen plasma were transfused and vitamin K (10 mg sc) was given.

A day into her hospitalization, the abdominal pain worsened and was associated with multiple episodes of vomiting and melena. Repeat physical examination was notable for rebound tenderness and orthostatic hypotension. Laboratory investigations revealed an INR of 6 and HB of 8.2 g/dL. She was transfused two units of packed red blood cells and a CT scan of the abdomen revealed numerous fluid filled loops of small bowel, which were edematous and thickened. She rapidly became tachycardic, hypotensive and only had a partial response to fluid resuscitation. The patient then underwent an emergency exploratory laparotomy. Intra-operatively 20 cm of jejunum was resected as it appeared devitalized. Histopathology revealed a large intramural hematoma. She made an uneventful recovery from surgery and was discharged home with relevant education on warfarin.

DISCUSSION

Warfarin exerts its effects by lowering the active vitamin K required for the activation of clotting factors II, VII, IX and X[4]. Both effectiveness and safety are monitored by blood INR levels. Miconazole, a broad spectrum anti-fungal agent potentiates the effect of warfarin by inhibiting hepatic microsomal cytochrome P-450 enzymes[5]. Polypharmacy is major problem in the elderly population and heightens the chance of a drug-drug interaction[6,7]. Intramural hematoma is a rare but well documented complication of warfarin toxicity[8]. Adverse drug interactions have been reported between miconazole and warfarin but most of these involve miconazole as an oral formulation or gel and it is conceivable that most of the absorption is via the oral mucosa[9-15].

The usual presentation of an intestinal intramural hematoma is that of an acute abdomen. Melena or hematochezia is uncommon but may be present[8]. Intramural hematomas can be a fatal complication in elderly patients with abdominal pain and a supra therapeutic INR[16]. Ultrasound and CT scan of the abdomen are often diagnostic and form an important part of the initial evaluation. Most patients can be managed conservatively with hemodynamic support and gentle reversal of anticoagulation. Surgery in the form of bowel resection may be needed in severe cases.

Physicians should exercise caution when prescribing drugs for patients on warfarin. A high index of suspicion should be present when a patient on warfarin presents with unexplained abdominal symptoms. Although, miconazole is poorly absorbed from the vagina[17], measurable serum concentrations have been demonstrated following mucosal application[18]. It is hypothesized that in the elderly ,vaginal atrophy maybe responsible for increased uptake[9]. The rates of warfarin-related hospitalization for bleeding is substantially lower for patients who report receiving medication instructions from a physician, nurse or pharmacist[19].

Addition/deletion of medications in patients who are stably anticoagulated on warfarin must prompt more frequent checks until a new steady state is reached. Intramural hematoma should be considered in the differential diagnosis of any patient with abdominal pain who is receiving concurrent warfarin therapy.

CONCLUSION

We wish to highlight that fact that intestinal intramural hematoma, a rare and potentially fatal condition, is seen in patients with abdominal pain and a supratherapeutic INR. Patients receiving warfarin need frequent INR checks when any new medications (including topical) are added or removed until a new steady state is achieved.