Pendlimari R, Anaparthy R, Sugumar A. Drug interaction presenting as acute abdomen. World J Gastrointest Pharmacol Ther 2010; 1(1): 40-42 [PMID: 21577294 DOI: 10.4292/wjgpt.v1.i1.40]
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Rajesh Pendlimari, MBBS, Division of Colon & Rectal Surgery, Mayo Clinic, 200 First street SW, Rochester, MN 55905, United States. firstname.lastname@example.org
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Rajesh Pendlimari, Division of Colon & Rectal Surgery, Mayo Clinic, Rochester, MN 55905, United States
Rajeswari Anaparthy, Division of Internal Medicine, Mayo Clinic, Rochester, MN 55905, United States
Aravind Sugumar, Division of Gastroenterology & Hepatology, Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN 55905, United States
ORCID number: $[AuthorORCIDs]
Author contributions: Pendlimari R and Sugumar A designed the research; Pendlimari R did the background search and drafted the manuscript; Anaparthy R and Sugumar A reviewed and edited the manuscript.
Correspondence to: Rajesh Pendlimari, MBBS, Division of Colon & Rectal Surgery, Mayo Clinic, 200 First street SW, Rochester, MN 55905, United States. email@example.com
Telephone: +1-507-2669164 Fax: +1-507-2841794
Received: December 8, 2009 Revised: January 20, 2010 Accepted: January 27, 2010 Published online: February 6, 2010
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.
Warfarin is the most widely used anticoagulant drug in north America, because it can be taken orally and it has excellent bioavailability. 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 (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.
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.
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.
Warfarin exerts its effects by lowering the active vitamin K required for the activation of clotting factors II, VII, IX and X. 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. 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. 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. Intramural hematomas can be a fatal complication in elderly patients with abdominal pain and a supra therapeutic INR. 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, measurable serum concentrations have been demonstrated following mucosal application. It is hypothesized that in the elderly ,vaginal atrophy maybe responsible for increased uptake. The rates of warfarin-related hospitalization for bleeding is substantially lower for patients who report receiving medication instructions from a physician, nurse or pharmacist.
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.
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.
Peer reviewer: Carolina Ciacci, MD, Professor, Department of Clinical and Experimental Medicine, University Federico II, Naples, Italy
S- Editor Li LF L- Editor Hughes D E- Editor Yang C
Sutcliffe FA, MacNicoll AD, Gibson GG. Aspects of anticoagulant action: a review of the pharmacology, metabolism and toxicology of warfarin and congeners.Rev Drug Metab Drug Interact. 1987;5:225-272.
Wells PS, Holbrook AM, Crowther NR, Hirsh J. Interactions of warfarin with drugs and food.Ann Intern Med. 1994;121:676-683.
Bettler S, Montani S, Bachmann F. [Incidence of intramural digestive system hematoma in anticoagulation. Epidemiologic study and clinical aspects of 59 cases observed in Switzerland (1970-1975)].Schweiz Med Wochenschr. 1983;113:630-636.
Hirsh J, Dalen J, Anderson DR, Poller L, Bussey H, Ansell J, Deykin D. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range.Chest. 2001;119:8S-21S.
O'Reilly RA, Goulart DA, Kunze KL, Neal J, Gibaldi M, Eddy AC, Trager WF. Mechanisms of the stereoselective interaction between miconazole and racemic warfarin in human subjects.Clin Pharmacol Ther. 1992;51:656-667.
Salazar JA, Poon I, Nair M. Clinical consequences of polypharmacy in elderly: expect the unexpected, think the unthinkable.Expert Opin Drug Saf. 2007;6:695-704.
Jacobs LG. Warfarin pharmacology, clinical management, and evaluation of hemorrhagic risk for the elderly.Cardiol Clin. 2008;26:157-167, v.
Polat C, Dervisoglu A, Guven H, Kaya E, Malazgirt Z, Danaci M, Ozkan K. Anticoagulant-induced intramural intestinal hematoma.Am J Emerg Med. 2003;21:208-211.
Wooltorton E. Drug advisory: the interaction between warfarin and vaginal miconazole.Can Med Assoc J. 2001;165:938.
Pemberton MN, Oliver RJ, Theaker ED. Miconazole oral gel and drug interactions.Br Dent J. 2004;196:529-531.
Devaraj A, O'Beirne JP, Veasey R, Dunk AA. Interaction between warfarin and topical miconazole cream.BMJ. 2002;325:77.
Silingardi M, Ghirarduzzi A, Tincani E, Iorio A, Iori I. Miconazole oral gel potentiates warfarin anticoagulant activity.Thromb Haemost. 2000;83:794-795.
Thirion DJ, Zanetti LA. Potentiation of warfarin's hypoprothrombinemic effect with miconazole vaginal suppositories.Pharmacotherapy. 2000;20:98-99.
Marco M, Guy AJ. Retroperitoneal haematoma and small bowel intramural haematoma caused by warfarin and miconazole interaction.Int J Oral Maxillofac Surg. 1998;27:485.
Ezsiás A, Wojnarowska F, Juniper R. Topical use of miconazole antifungal oral gel on warfarinized patients: a word of caution.Dent Update. 1997;24:421-422.
Jimenez J. Abdominal pain in a patient using warfarin.Postgrad Med J. 1999;75:747-748.
Benziger DP, Edelson J. Absorption from the vagina.Drug Metab Rev. 1983;14:137-168.
Daneshmend TK. Systemic absorption of miconazole from the vagina.J Antimicrob Chemother. 1986;18:507-511.
Metlay JP, Hennessy S, Localio AR, Han X, Yang W, Cohen A, Leonard CE, Haynes K, Kimmel SE, Feldman HI. Patient reported receipt of medication instructions for warfarin is associated with reduced risk of serious bleeding events.J Gen Intern Med. 2008;23:1589-1594.