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Carbamazepine overdose after exposure to simethicone : a case report Ozlem GUNEYSEL, MD; Ozge ONUR, MD; Arzu DENIZBASI, Assoc Prof. Marmara University, School of Medicine Department of Emergency Medicine Corresponding author: Dr Ozlem GUNEYSEL Marmara Universitesi Hastanesi Acil Servis Tophanelioglu C Yurtacan S No 13-15 Altunizade –USKUDAR/ISTANBUL TURKEY e-mail : [email protected] Fax : +90216 326 95 78 Phone : +90532 221 13 68 E-mail adresses: OG: [email protected] OO: [email protected] AD: [email protected] 1 Abstract Introduction Carbamazepine is an anticonvulsant drug and is also used as a treatment for patients with manic-depressive illness, post herpetic neuralgia, or phantom limb pain. The drug itself has many drug interactions. Simethicone is an antifoaming agent and known as an inert material. There is no known drug interaction with carbamazepine. Case presentation A 45 year old male patient with a medical history of epilepsy presented to our emergency room with complaints of vertigo, gait disturbance, dizziness, slurred speech, and diplopia. He was using Carbamazepine 400 mg three times /day for four years and Keppra twice daily for one year. No other drugs were reported except a history of two days Simethicone usage. Carbamazepine serum level was 34.2 µg/ml (4-11 µg/ml). Patient was taken to the neurology inpatient unit with a diagnosis of carbamazepine intoxication. Carbamazepine was withdrawn. Intravenous hydration and cardiac monitorization were done. After 36 hours his serum carbamazepine level was normalized and neurological exam was intact. Conclusion The mechanism is unknown but a risk of overdose must be taken under consideration during prescribing simethicone to a patient who is using carbamazepine. 2 Background Carbamazepine is an anticonvulsant drug, received approval for use as an antiepileptic agent in the United States in 1974. It is also used as a treatment for patients with manic-depressive illness, post herpetic neuralgia, or phantom limb pain. Therapeutic plasma concentration is 4- 12 mg/L. It is approximately 75-80% protein bound. Carbamazepine is oxidized by hepatic microsomal enzymes to produce its active metabolite, carbamazepine 10, 11- epixode. In terms of drug interactions, carbamazepine induces the metabolism of other anticonvulsant drugs. Inhibitors of hepatic microsomal enzymes such as erythromycin, clarithromycin, and cimetidine increase carbamazepine levels [1]. Simethicone is an antifoaming agent that acts by altering the surface tension of mucus-entrapped gas bubbles in the digestive tract, allowing them to coalesce and disperse [2]. It is excreted unchanged in the feces; it is not absorbed [3]. There is no known drug interaction with carbamazepine. We present a case of carbamazepine overdose after exposure to simethicone. After cessation of simethicone therapy normal drug levels of carbamazepine were obtained again with standard dose of the drug. Case presentation A 45 year old male patient with a medical history of epilepsy presented to our emergency room with complaints of vertigo, gait disturbance, dizziness, slurred speech, and diplopia. He was using Carbamazepine (Karazepin®) 400 mg three times /day for four years and Keppra® twice daily for one year. No other toxin, alcohol, herbal products, drugs were reported except a history of two days Simethicone (Metsil®) usage. He had a blood pressure (BP) of 115/70 mmHg, pulse rate (PR) of 88 beats/min, respiratory rate (RR) of 18 breaths /min. The patient had a normal mental status and was able to give a reliable history. He denied trauma, extra drug dosage or suicidal attempt. In his neurological examination, pathological findings were bilateral nystagmus, dysarthria, diplopia, ataxic walking. He had a serum carbamazepine level reported as 10.5 µg/ml (reference range: 4-11) two days before, confirmed in neurology outpatient clinic. The initial laboratory findings were as follows: Hematocrit,41.5, prothrombin time, 12.3 sec (reference range,11-13), INR, 1.02 , creatinine, 0.97 mg/dl (0.5-1.10 mg /dl); glucose, 102 mg/dl (70-110mg/dl); serum alanine aminotransferase (ALT), 16 U/L (10–37 U/L); aspartate aminotransferase (AST), 17 U/L (10–40 U/L); alkaline phosphatase (ALP), 238 U/L (0–270 U/L); γ-glutamyltransferase (GGT), 46 U/L (7–49 U/L); total bilirubin, 0.54 mg/dL (0.2–1.0 mg/dL); carbamazepine serum level, 34.2 µg/ml (4-11 µg/ml). Cranial computed tomography (CT) scan was normal. Patient was taken to the neurology inpatient unit with a diagnosis of carbamazepine intoxication. Carbamazepine was withdrawn. Intravenous hydration and cardiac monitorization were done. After 36 hours his serum carbamazepine level was normalized (level at 24 hours: 17.6, level at 36 hours: 11.4) and neurological exam was intact. In control visit he was warned about simethicone. There is no problem since 6 months. 3 Discussion Carbamazepine (CBZ) is one of the most commonly prescribed drugs for the prevention of partial seizures as well as for treatment of generalized tonic-clonic seizures and trigeminal neuralgia [4]. The most important interactions affecting the disposition of CBZ are those resulting in the induction of its metabolism. Clinically, a variety of drug interactions between CBZ and co-administered drugs have been reported. The actions of most drugs that affect CYP3A4 by inhibition or induction manifest as drug interactions with CBZ [5,6]. However, there has been no demonstration of simethicone and carbamazepine interaction until now. Simethicone has been used as an adjunct in the treatment of various clinical conditions in which gas retention may be a problem including dyspepsia, infant colic, peptic ulcer, irritable colon. It also appears to be helpful as an adjunct to various procedures such as colonoscopy and bowel radiography [7]. It is a mixture of liquid dimethylpolysiloxanes which have antifoaming activity. It acts in the stomach and intestines by altering surface tension of gas and mucus bubbles enabling them to coalesce. It is reported as physiologically inert, no toxic effects are reported in ingestion [8]. Because of its availability, CBZ is a drug commonly involved in accidental and intentional overdoses. The American Association of Poison Control Centers reported a total number of 18.201 CBZ overdoses from 1999 to 2001. This led to 18 deaths [9]. Acute CBZ toxicity presents with cardiac, respiratory, and neurological effects. Neurological signs include loss of consciousness, seizures, ataxia, choreoathetosis, myoclonus, motor restlessness, mydriasis, and nystagmus [10]. Most of these signs were positive in our patient. In this case we present a CBZ toxicity due to simultaneous intake of simethicone. Both drugs are widely used, but there has been no studies searching effect of simethicone on the pharmacokinetics of CBZ up to date. Due to simethicone is an inert material, we could not explain the mechanism of action. But there was no other factor for such a patient receiving CBZ for four years, no adverse events were reported by him until the use of simethicone. This patient’s directory follow-up was excellent. Conclusion A risk of overdose must be taken under consideration during prescribing simethicone to a patient who is using CBZ. 4 Competing interests The authors declare they have no competing interests. Authors’ contributions OG identified the relevant case, conducted the literature search and wrote the discussion OO wrote the case presentation AD involved in conception of the article and revising it critically for important intellectual data before final approval All authors read and approved the final manuscript Consent : Written informed consent was obtained from the patient for publication of this case report. 5 References 1. Carbamazepine intoxication. [http://www.emedicine.com/emerg/topic77.htm] 2. Voepel-Lewis TD, Malviya S, Burke C et al. Evaluation of simethicone for the treatment of postoperative abdominal discomfort in infants. J of Clin Anest 1998; 10(2): 91-94. 3. SIMETHICONE, Pertinent data on File, Bilim Pharmaceuticals; Istanbul / Turkey. 4. Kim KA, Oh SO, Park PW. Effect of probenecid on the pharmacokinetics of carbamazepine in healthy subjects. Eur J Clin Pharmacol. 2005; 61(4):275-80. 5. Spina E, Pisani F, Perucca E. Clinically significant pharmacokinetic drug interactions with carbamazepine.An update. Clin Pharmacokinet. 1996; 31(3):198-214. 6. Rambeck B, Specht U, Wolf P. Pharmacokinetic interactions of the new antiepileptic drugs. Clin Pharmacokinet. 1996; 31(4):309-24. 7. McNally PR, Maydonovitch CL, Wong RK. The effect of simethicone on colonic visibility after night-prior colonic lavage. A double-blind randomized study. J Clin Gastroenterol. 1989; 11(6):650-2. 8. FAO/WHO Exp. Comm. Food Add., Tech. Rep. Ser. World Health Org. No. 648, 1980. 9. Askenazi DJ, Goldstein SL, Chang IF. Management of a severe carbamazepine overdose using albumin-enhanced continuous venovenous hemodialysis. Pediatrics. 2004; 113(2):406-9 10. Stremski ES, Brady WB, Prasad K, et al. Pediatric carbamazepine intoxication. Ann Emerg Med. 1995; 25(5):624-30. 6