Carbamazepine-Induced Hepatotoxicity

( Gee Young Yun ),( Seok Hyun Kim ),( Heok Su Eun ),( Jong Seok Ju ),( Eaum Seok Lee ),( Byung Seok Lee ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Introduction: Carbamazepine is a potent anticonvulsant agent with proven efficacy in the treatment of partial and tonic-clonic seizures. An epileptic man diagnosed Lennox-Gastaut syndrome with intractable epilepsy, treated with therapeutic dosages of carbamazepine developed severe hepatitis and hepatic insufficiency. He had a positive response to withdrawal of the drug and supportive care with hepatotonics. The liver injury pattern was hepatocellular type, and the modified Roussel Uclaf Causality Assessment Method scale (RUCAM score) was 8, suggesting adverse drug reaction of carbamazepine. Herein, we report a case of hepatotoxicity secondary to carbamezepine use. Case-Report: A 43-year-old South Korean man with Lennox-Gastaut syndrome visited emergency room (ER) because of the general weakness. Blood work revealed acute liver dysfunction with aspartate aminotransferase, 1737U/L; alanine aminotransferase, 1392 U/L; and international normalized ratio, 1.83 The total bilirubin and alkaline phosphatase levels were 5.70 mg/dL, and 95U/L respectively. He had normal baseline laboratory results before increasing the dose of carbamazepine. Hepatitis A immunoglobulin M and hepatitis B surface antigen were negative, and hepatitis C RNA levels were undetectable. Hepatitis E immunoglobulin M, Cytomegalovirus immunoglobulin M, Ebstein-Barr virus viral-capsid antigen immunoglobulin M was also all negative. On the other hand, the hepatitis B surface antibody was positive. Other etiologies, including autoimmune disease, common toxins, drugs, and iron- or copper-induced insult were considered. However, anti-smooth muscle, anti-mitochondrial, and antinuclear antibodies were all negative, and the serum copper, ceruloplasmin, and 24-hour urine copper levels were in the normal ranges. He usually taked carbamazepine 600mg orally every day and increased the dose of carbamazepine to 1200mg orally every day for strict control of the epilepsy, 3 weeks ago before visiting ER. And the TDM level of the carbamazepine surpassed the normal limit. He did not report any use of alcohol or illicit drugs. The RUCAM score was 8. These findings strongly suggested drug-induced liver injury. Abdomino-Pelvic CT was performed, and it revealed that there was no biliary structure problem. As a result, carbamazepine was immediately discontinued and the patient was managed with supportive care via hepatotonics. He showed improvement of the clinical and laboratory abnormalities, with aspartate aminotransferase and alanine aminotransferase levels of 30 and 8, respectively, after 8 weeks. (Figure) Conclusion: This case report describes a 43-year-old man with epilepsy who experienced liver injury after carbamezepine administration. Usually, the mechanism of the carbamezepine-induced hepatotoxicity is explained by idiosyncratic reaction, irrelevant with dose-dependent effect. However, our case was related with the dose of the carbamazepine. Therefore, our case emphasizes that liver function tests and the TDM level of the carbamazepine should be monitored periodically after administration of carbamazepine.

Rocuronium에 의한 부분 근이완에서 Phenytoin과 Carbamazepine의 효과

이윤경 대한마취통증의학회 2007 Anesthesia and pain medicine Vol.2 No.4

Background: Phenytoin and carbamazepine may augment a neuromuscular block from nondepolarizing muscle relaxants. The potency of rocuronium is increased after the administration of an acute high dose of phenytoin. We investigated the effects of phenytoin and carbamazepine on rocuronium-induced neuromuscular blockade. Methods: Male Sprague Dawley rats (n = 80) were randomly allocated into a control group, phenytoin group, carbamazepine group, and phenytoin with carbamazepine group. The phrenic nerve was stimulated with supramaximal intensity and twitch responses were measured. After a stabilization period, 300μg rocuronium was added. After 10 minutes, in the pheytoin group of rats, phenytoin in Krebs solution was administered at a concentration of 1μg/ml (P1), 10μg/ml (P10) and 100μg/ml (P100). In the carbamazepine group of rats, carbamazepine in Krebs solution was administered at a concentration of 0.5μg/ml (C0.5), 5μg/ml (C5) and 50μg/ml (C50). In the phenytoin with carbamazepine group of rats, phenytoin simultaneously with carbamazepine was administered in Krebs solution at a phenytoin concentration of 10μg/ml (P10) and a carbamazepine concentration of 5μg/ml (C5). We measured twitch responses at 10 minutes after rocuronium administration and 10 minutes after the administration of the anticonvulsants. Results: There were significant depressions in the twitch response of rocuronium in the 100μg/ml phenytoin group of rats, 5μg/ml and 50μg/ml carbamazepine group of rats, and the 10μg/ml phenytoin with 5μg/ml carbamazepine group of rats. Conclusions: The potency of rocuronium increased with phenytoin and carbamazepine administration. Phenytoin and carbamazepine can cause recurarization perioperatively.

소아 경련 환자에서 carbamazepine과 oxcarbazepine 치료 시 환자 연령과 약물 용량과 저 나트륨 혈증의 연관성에 대한 연구

이규하,차성호,정사준 대한소아청소년과학회 2008 Clinical and Experimental Pediatrics (CEP) Vol.51 No.4

Purpose:To assess the prevalence of hyponatremia in epileptic children receiving carbamazepine or oxcarbazpine, we investigate serum sodium changes according to age, serum carbamazepine level, and daily oxcarbazepine dosage, and the prevalence of symptoms of hyponatremia. Methods:We reviewed the clinical data of the 197 children receiving carbamazepine and/or oxcarbazepine with or without antiepileptic therapy. And these were classified into the carbamazepine treated patients (group I), oxcarbazepine treated patients (group II), and carbamzepine or oxcarbazepine with other antiepileptics treated patients (group III). Potentially predictive values for development of hyponatremia were examined in each group: age, plasma level of carbamazepine and daily dosage of oxcarbazepine. We assessed the symptoms of hyponatremia. Results:The overall prevalence of hyponatremia was 20.8% (group I, II and III:17.9%, 22.6%, and 21.8%, respectively), and the prevalence in groups II and III compared with controls (P<0.03) was significantly lower. The changes of serum sodium levels relation to age were not significantly different. The changes of serum sodium levels by increasing of serum levels of carbamazepine and dosage of oxcarbazepine were statistically significant (P<0.01). Among the 41 patients who had biochemical hyponatremia, the prevalence of hyponatremic symptoms was 17.1%. Conclusion:Hyponatremia may occur relatively more frequently with oxcarbazepine or combined other antiepileptics than carbamzepine therapy only. Age of children receiving carbamazepine or oxcarbazepine was no predictive value for occurrence of hyponatremia. The patients whose serum level were less than 125 mEq/L showed more severe clinical symptoms than any other study groups. (Korean J Pediatr 2008;51:409-414) Purpose:To assess the prevalence of hyponatremia in epileptic children receiving carbamazepine or oxcarbazpine, we investigate serum sodium changes according to age, serum carbamazepine level, and daily oxcarbazepine dosage, and the prevalence of symptoms of hyponatremia. Methods:We reviewed the clinical data of the 197 children receiving carbamazepine and/or oxcarbazepine with or without antiepileptic therapy. And these were classified into the carbamazepine treated patients (group I), oxcarbazepine treated patients (group II), and carbamzepine or oxcarbazepine with other antiepileptics treated patients (group III). Potentially predictive values for development of hyponatremia were examined in each group: age, plasma level of carbamazepine and daily dosage of oxcarbazepine. We assessed the symptoms of hyponatremia. Results:The overall prevalence of hyponatremia was 20.8% (group I, II and III:17.9%, 22.6%, and 21.8%, respectively), and the prevalence in groups II and III compared with controls (P<0.03) was significantly lower. The changes of serum sodium levels relation to age were not significantly different. The changes of serum sodium levels by increasing of serum levels of carbamazepine and dosage of oxcarbazepine were statistically significant (P<0.01). Among the 41 patients who had biochemical hyponatremia, the prevalence of hyponatremic symptoms was 17.1%. Conclusion:Hyponatremia may occur relatively more frequently with oxcarbazepine or combined other antiepileptics than carbamzepine therapy only. Age of children receiving carbamazepine or oxcarbazepine was no predictive value for occurrence of hyponatremia. The patients whose serum level were less than 125 mEq/L showed more severe clinical symptoms than any other study groups. (Korean J Pediatr 2008;51:409-414)

소아복잡부분발작 및 Benign Childhood Epilepsy with Centrotemporal Spike(BCECTS)에서 Carbamazepine 또는 Valproate 단독치료시 약제선택에 관여하는 인자에 대한 연구

김영창(Young Chang Kim) 대한소아신경학회 1995 대한소아신경학회지 Vol.3 No.1

배경: 지금까지 carbamazepine과 valproate는 안전하고 모든 발작치료에 효과적인 약으로 알려져왔다. 그러나, 최근까지 valproate는 전신발작에, carbamazepine은 부분발작에 유효한 약으로 인식되어 있다. 방법:대상은 complex partial seizure와 benign childhood epilepsy with centrote-mporal spike로 처음으로 진단받은 58명으로 연령분포는 4개월에서 16세였다. 모든 환아는 carbamazepine 또는 valproate단독치료를 받았고, 혈중농도를 검사하여 용량을 조절했다. 추적관찰기간은 6개월에서 5년으로 평균 18개월이었다. 결과: 발작조절률이 carbamazepine 이 81.4%, valproate가 73.3%로 차이가 없었다. 복잡부분발작과 BCECTS에서 각각 두 항경련제의 효과를 비교해 본 결과, 복잡부분 발작에서는 두 약제간의 발작 조절률의 차이가 없었으나, BCE-CTS에서는 valproate보다 carbamazepine이 발작조절률에 있어 더욱 효과적이었다(P=0.025). 초기 발작간 뇌파소견, 치료전 발작기간 과 발작 횟수와 같은 요인들과 항경련제의 발작 조절률과는 유의한 관계는 없었다. 결론: 복잡부분발작치료에 carbamazepine과 valproate가의 효과차이는 없어 일차 선택약제로 모두 사용할 수 있으나, BCECTS환아인 경우 carbamazepine이 더욱 효과적이었다. 발작빈도 및 발작기간 등과 항경련제 선택과의유의한 관계는 없었으나, 뇌파가 focal epileptiform discha-rge를 보인 경우는 carbamazepine이 효과적이었고, Focal and generalized epileptiform disch-arge를 보인 경우는 valproate가 효과적인 경향을 보였으나 통계적인 의미는 없었다. Background : Sodium valproate and carbamazepine have been well known as safe and effective drugs for the treatment of all types of epilepsy. Until recently there has been a widely held view, however. that valproate was best for primary generalized seizures. and carbamazepine for partial seizures. Method : This study enrolled a total of 58 children with newly diagnosed as having complex partial seizures(CPS) or beni후 childhood epilepsy with centrotemporal spike(BCECTS)(age range, 4months-16years). The patients were assigned to treatment with carbamazepine or divalproex sodium as monotherapy at doses adjusted to achieve therapeutic blood level. The mean period of observation was 18 months with a range of 6 months-5years. Result : The findings suggested that both carbamazepine and valproate were equally effective in the control of partial seizures(81.4% vs 73.3%). When the analysis was repeated separately for complex partial seizure and benign childhood epilepsy with centrotemporal spike(BCECTS), no significant differences of efficacy between two drugs were found in patients with complex partial seizures, however, charbamazepine was more efficacious than valproate in patients with BCECTS (P=0.025). No correlation between initial interictal EEG findings, duration of seizures and frequency of seizures prior to treatment and seizure control rate of each drugs was found. Conclusion : Both drugs ar equally effective in the control of partial seuzres and can be prescribed as an anticonvulsant of first choice, however, carbamazepine is more efficacious than valproate in patients with BCECTS. The duration of seizures and frequency of seizures prior to treatment are not related to the choice of antiepileptic drugs, but carbamazepine tends to be effective in the paitnes with showing focal epileptiform discharges in the initial interictal EEG wheras valproate tends to be effective in the patients with having focal and generalized epileptiform discharges: however, such result is not significant statistically.

Carbamazepine과 Valproic Acid가 소아의 면역 상태에 미치는 영향

임병영(Byoung Young Lim),채수안(Soo Ahn Chae),유병훈(Byoung Hoon Yoo) 대한소아신경학회 1999 대한소아신경학회지 Vol.6 No.2

목 적 :소아에서 흔히 사용하고 있는 항경련제인 valproic acid와 carbamazepine은 혈액과 림프조직을 비롯한 여러 기관에 부작용을 초래할 수 있는 것으로 알려져 왔다. 그러나 이들 약제를 소아에서 장기간 복용시 발생할 수 있는 영향 중 소아의 면역 기능에 미치는 연구는 미미한 실정이다. 또한 지금까지 시행되었던 간질 환자를 대상으로 한 면역 상태에 관한 연구들은 다양한 연령층을 대상으로 하여 면역글로불린 변화 판정에 어려움이 있었다. 본 연구는 대상 연령을 소아 연령에 국한하여 연령으로 인한 면역 글로불린의 변이를 최소화하고, 더불어 소아 연령군의 항경련제 투여로 인한 면역글로불린의 변화를 알아보고자 이 연구를 시도하였다. 방 법 : 1997년 1월부터 1998년 6월까지 복합열성 경련 및 소아 간질로 valproic acid와 carbamazepine을 복용하고 있는 환아 30명(남자 16명, 여자 14명)을 대상으로 하였으며 치료전과 치료 10개월 후의 혈청 IgA, IgM, IgG의 변화를 비교하였다. Paired t-test를 이용하여 비교 검정하였고 면역글로불린의 변화를 p-value가 0.05 이하일 때 통계적으로 유의 하다고 판단하였다. 결 과 : 항경련제(valproic acid, carbamazepine)를 복용하고 있는 환자에서 항경련제 투여 전과 투여 10개월 후에 나타나는 혈청 면역글로블린의 변화는 다음과 같았다. 1) Valproic acid 투여 후 혈청 면역글로블린의 변화 투여 전 혈청 IgG 수치가 10.71± 3.34g/L에서 투여 10개월 후 13.36±5.36g/L으로 정상범위내에서 의미 있게 상승하였고 (p<0.05) IgA 및 IgM의 큰 변화는 없었다. 2) Carbamazepine 투여 후 혈청 면역글로블린의 변화 : 투여 전 혈청 IgG 수치가 8.42± 2.08g/L에서 투여 10개월 후 11.49±3.13g/L로 정상 범위내에서 상승을 보였고(p<0.05) IgA 및 IgM의 큰 변화는 없었다. 3) Valproic acid와 carbamazepine 병용 투여 후 혈청 면역글로블린의 변화 : 혈청 IgG 수치가 투여 전 7.64±0.99g/L에서 투여 10개월 후 10.36±1.58g/L로 valproic acid와 carbamazepine 단독 투여한 경우보다 IgG의 상승 폭이 더 컸으나 정상범위 내에서 증가하였다. IgA 및 IgM의 큰 차이는 나타나지 않았다. 결 론 : 본 연구 결과는 소아 간질 환자에서 valproic acid와 carbamazepine을 장기간 투여하였을 때 혈청 IgG가 증가하는 소견을 보였으며 혈청 IgG 증가는 소아 간질 환자 치료에 있어 항경련제 자체의 항경련 효과 외에 면역 기능의 변화로 인한 간질 치료 효과를 생각해 볼 수 있을 것이다. Purpose : Antiepileptic drug(AED) therapy has been reported to induce immunological alterations in epileptic patients. However, despite extensive studies, the accumulated data are not consistent and there is still confusion and controversy over the effects of AEDs on the immune system. This study tries to elucidate the effects of anticonvulsant on some immune parameters, and serum concentration of IgA, IgG, IgM. Methods : Thirty pediatric epileptic patients[Group A(n=12) : patients on carbamazepine, Group B(n=10) : patients on valproic acid and Group C(n=8) : patients on carbamazepine and valproic acid] were enrolled in this study and the levels of IgA, IgG, and IgM were determined before treatment and after 10 months of anticonvulsant therapy. Paired t-test was used to evaluate the data. p values<0.05 were considered significant. Results : The mean serum concentratrions of IgG was elevated in patients receiving anticonvulsants(p<0.05) but mean concentrations of IgA and IgM were not different significantly. Conclusion : Our results demonstrate that anticonvulsants elevate the serum concentrations of IgG level, suggesting that anticonvulsants may increase humoral immunity and decrease the opportunity of infectious disease, thus decreasing the convulsion.

공격적인 치료저항군 정신분열병 환자에 대한 Carbamazepine 병용투여 효과 : 이중맹검 교차연구

오동열,박강규,최재영 大韓神經精神醫學會 1994 신경정신의학 Vol.33 No.6

We studied adjunctive effects of carbamazepine to haloperidol in 15-nonresponding chronic schizophrenic patients who were suitable for John Kane criteria of nonresponding Schizophrenics and also showed aggressive behaviors before the study. We performed the study with a placebo controlled double blind cross-over design. The results were as follows : 1) There was no statistically significant difference between the carbamazepine and placebo administered groups in the changes of total BPRS scores, although carbamazepine administered group showed more improvement in total BPRS scores and some BPRS subscales. 2) Hostility improved continuously in carbamazepine administered group, besides, psychological symptoms such as anxiety, suspiciousness, hallucinatory behavior, conceptual disorganization, unusual thought content, and guilty feelings were also improved. 3) Serum prolactin concentrations were little changed in carbamazepine-placebo administered group, and in placebo-carbamazepine administered group, serum prolactin concentrations were considerably decreased at carbamazepine administration, so it is difficult to conclude a certain relationships between serum prolactin level and carbamazepine administration at present. The results suggest that adjunctive use of carbamazepine to neuroleptics maybe useful drug regimen for some case of nonresponding schizophrenics, especially carbamazepine showed some improvement in hostility score.

Stevens-Johnson Syndrome Induced by Carbamazepine Treatment in a Patient Who Previously Had Carbamazepine Induced Pruritus- A Case Report-

( Hyun Min Bae ),( Yoo Jung Park ),( Young Hoon Kim ),( Dong Eon Moon ) 대한통증학회 2013 The Korean Journal of Pain Vol.26 No.1

Stevens-Johnson syndrome (SJS) is a rare but life-threatening skin reaction disease and carbamazepine is one of its most common causes. We report a case of SJS secondary to carbamazepine in a patient with previous pruritus due to carbamazepine which was given for treatment of trigeminal neuralgia. We would like to caution all providers that carbamazepine readministration should be avoided in the patient with a previous history of SJS or adverse skin reaction. In addition, we strongly recommend gradual titration when initiating treatment with carbamazepine. (Korean J Pain 2013; 26: 80-83)

Stevens-Johnson Syndrome Induced by Carbamazepine Treatment in a Patient Who Previously Had Carbamazepine Induced Pruritus - A Case Report -

Bae, Hyun Min,Park, Yoo Jung,Kim, Young Hoon,Moon, Dong Eon The Korean Pain Society 2013 The Korean Journal of Pain Vol.26 No.1

Stevens-Johnson syndrome (SJS) is a rare but life-threatening skin reaction disease and carbamazepine is one of its most common causes. We report a case of SJS secondary to carbamazepine in a patient with previous pruritus due to carbamazepine which was given for treatment of trigeminal neuralgia. We would like to caution all providers that carbamazepine readministration should be avoided in the patient with a previous history of SJS or adverse skin reaction. In addition, we strongly recommend gradual titration when initiating treatment with carbamazepine.

Carbamazepine 치료중 저산소성 뇌손상 환자에서 발생한 Stevens-Johnson 증후군 1례

김용구,이헌정,한창수,이민수,곽동일 大韓神經精神醫學會 1997 신경정신의학 Vol.36 No.4

Carbamazepine은 정신과 영역에서 광범위하게 사용되고 있는 약물이지만, 한편으로 치명적인 부작용을 갖고 있으며, 특히 Stevens-Johnson 증후군과 같은 부작용에 대한 조기예방, 적절한 치료가 필요하다. carbamazepine을 투여 받고 있는 환자에서 생기는 어떠한 피부발진의 경우에 있어서도 담당주치의에게 즉각적인 보고를 하여, 신속한 처치와 예방을 하는 것이 중요하다. 저자들은 저산소성 뇌손상 후에 나타난 난폭한 행동 양상을 조절하기 위하여 carbamazepine으로 치료를 하던 중 발생한 Stevens-Johnson 증후군 1례를 자문의뢰 영역에서 경험하였기에, 이에 증례를 보고한다. Although carbamazepine is being widely used in treatment of a variety of psychiatric disorders, it has some serious potential risks, including Stevens-Johnson syndrome. Authors experienced in consultation a case of Sevens-Johnson syndrome due to usage of carbamazepine. The patient was treated with carbamazepine to control for aggressive behavior after a hypoxic brain damage. Authors report a case of Stevens-Johnson syndrome due to carbamazepine and also reviews related articles.

가토의 ouabain 유발 부정맥에 미치는 acebuolol 및 carbamazepine의 영향

김원준(Won Joon Kim),하정희(Jeoung Hee Ha) 대한약리학회 1987 대한약리학잡지 Vol.23 No.1

The effects of acebutolol and carbamazepine on ouabain-induced arrhythmias were investigated in rabbits. Ouabain produced ventricular arrhythmias which persisted for 7-8 min at the mean dose of 69 ± 1.3μg/kg. Ouabain arrhythmias were converted to normal sinus rhythm by administration of acebutolol or carbamazepine singly but lower dosages increased the recovery time. And then, ouabain arrhythmias were effectively converted to normal sinus rhythm and prevented by combined administration of carbamazepine and acebutolol. Each of the combined doses was ineffective when given singly. From the above results, it may be concluded that carbamazepine and acebutolol inhibited the ouabain-induced arrhythmias depending on the level of dosage and showed synergistic interaction. Adrenergic beta 1 수용체 봉쇄 약물인 acebutolol과 항 경련제로 사용되고 있는 carbamazepine은 실험적으로 ouabain유발 부정맥을 정상 심박동으로 환원시키는데 유효하다고 보고되었으나 그 상호 작용에 대해서는 밝혀진 바가 없다. 이에 본 실험에서는 가토에 ouabain 투여로 부정맥을 유발시킨 후 acebutolol과 carbamazepine을 단독 혹은 병용 투여하여 이 두 약물이 ouabain 유발 부정맥에 미치는 영향과 그 상호 작용을 규명하고자 하였다. 실험 결과 ouabain 유발 부정맥은 acebutolol 혹은 carbamazepine 단독 투여로 정상 심박동으로 환원되었으며 용량이 감소함에 따라 정상 심박동으로 회복하는데 요하는 시간이 연장되었다. 또 단독 투여시 항 부정맥 효과를 볼 수 없었던 용량을 병용 투여하였을 때 ouabain 유발 부정맥은 즉시 정상 심박동으로 환원되었으며 상기 용량의 두 약물을 병용하여 전처치함으로써 ouabain의 부정맥 유발 용량이 의의있게 증가되었다(P<0.01). 이상의 결과로 acebutolol과 carbamazepine은 ouabain 유발 부정맥을 용량 의존적으로 억제시키며 상협적인 상호작용(synergistic interaction)을 나타낸다고 사료된다.