Chun BJ Moon JM Kim SH N-acetylcysteine Glucuronide 45%-55% Renal excretion Glutathione(+) Cysteine and Mercapturic acid Acetaminophen Figure 1. Aceta

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1 pissn: eissn: Focused Issue of This Month 응급해독제 아세트아미노펜중독의해독제 : 아세틸시스테인 전병조 1 문정미 1 김승호 2* 1 전남대학교, 2 연세대학교의과대학응급의학교실 Antidote for acetaminophen poisoning: N-acetylcysteine Byeong Jo Chun, MD 1 Jeong Mi Moon, MD 1 Seung Ho Kim, MD 2* Department of Emergency Medicine, 1 Chonnam National University School of Medicine, Gwangju, 2 Yonsei University School of Medicine, Seoul, Korea *Corresponding author: Seung Ho Kim, edksh@yumc.yonsei.ac.kr Received September 30, 2013 Accepted October 14, 2013 N-acetylcysteine (NAC) is widely recognized as the antidote of choice for acetaminophen overdose. Acetaminophen is a commonly used analgesic and antipyretic agent, and its use is one of the most common causes of poisoning worldwide. Acetaminophen toxicity may occur acutely when supratherapeutic amounts are ingested purposefully or unintentionally. Liver failure may occur in severe toxicity. However, if treated early, patients with acetaminophen poisoning generally recover uneventfully. Acetaminophen is metabolized to N-acetyl-p-benzoquinone imine (NAPQI), which is detoxified by conjugation with glutathione. In overdose, hepatic stores of glutathione are depleted and NAPQI binding to hepatocytes induces cell death and hepatic necrosis. NAC replenishes hepatic glutathione and may also act as a glutathione substitute, combining directly with the toxic metabolite. Intravenous NAC is indicated in patients who present with a history of acetaminophen overdose within the previous 8 to 10 hours, patients unable to tolerate oral NAC, and patients who present with evidence of fulminant hepatic failure. However, caution should be used in patients who have experienced previous hypersensitivity or anaphylactoid reactions to intravenous NAC, as well as in patients with asthma. The most common anaphylactoid reactions include rash, flushing, and bronchospasm. Adults should receive 150 mg/kg administered for 45 minutes, followed by 50 mg/kg administered for 4 hours, followed by 100 mg/kg administered for 16 hours. The total dose is 300 mg/kg delivered over 21 hours. Additionally, caution should always be used when intravenous NAC is prescribed and the amount of diluent is calculated. Monitoring of patients with a should include repeated neurologic and hemodynamic assessment. Keywords: Acetaminophen; Hepatotoxicity; Antidotes; Acetylcysteine; Anaphylactoid reaction 서 론 아세트아미노펜은전세계적으로널리사용되고있는해열 진통제이지만의사의처방전없이구매가가능하기때문에자살을목적으로과량을복용하는경우가증가하 고있다 [1]. 미국독극물통제센터협회 (American Association of Poison Control Centers) 는 2011년도연보를통해성분이밝혀진약물중독환자 123만여명중 30.8% 가아세트아미노펜을포함한진통제이었으며 1,158명의사망환자중복합성분과단일제제의아세트아미노펜에의한경우 c Korean Medical Association This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 대한의사협회지 1067

2 Chun BJ Moon JM Kim SH N-acetylcysteine Glucuronide 45%-55% Renal excretion Glutathione(+) Cysteine and Mercapturic acid Acetaminophen Figure 1. Acetaminophen metabolism. NAPQI, N-acetyl-p-benzoquinone imine; CYP450, cytochrome P450. 가 11.2% 이었다고보고하였다 [2]. 국내의중독환자발생빈도에관련된공식자료는없지만최근 2개년동안 12개응급의료센터에내원한중독환자빈도분석에의하면 20세이하의연령에서아세트아미노펜에중독된경우가가장많았다 [3]. 더불어지난 6월식품의약품안전처에서소아용해열 진통제에규정량이상의아세트아미노펜이함유되어판매를금지시킨경우가있었고, 8월에는미국 Food and Drug Administration (FDA) 에서아세트아미노펜이함유된진통제가발진, 수포등심각한피부반응을일으킬수있다는조사결과를발표하면서관심이재조명되고있다 [4,5]. 성인에서 140 mg/kg 이상의아세트아미노펜을복용한경우는간에서대사물질인 N-acetyl-p-benzoquinone imine (NAPQI) 에의해간기능부전이발생할수있다 [6]. N-acetylcysteine (NAC) 은아세트아미노펜과량복용후 8시간이내에투여하면 NAPQI의독성을감소시켜간손상을예방할수있기때문에아세트아미노펜중독환자에서효과적인해독제로알려져있다 [6-8]. 그러나치료용량또는초과용량으로사용한환자에서심각한이상반응들이보고되고있기때문에사용에주의를기울일필요가있다. 본특집에서는아세트아미노펜중독환자의해독제로사용되고있는 NAC 의작용기전과투여방법, 이상반응, 응급처치등에대한이해를통하여 NAC의효과적이고안전한처방에도움을제공하고자한다. 5% 5%-10% NAPQI (CYP450 2E1) 35%-45% Gluathione(-) Liver cell damage Sulfate 아세트아미노펜중독 1. 간독성기전과아세틸시스테인역할경구를통해체내에들어온아세트아미노펜은 1-2시간후혈중최고농도에도달하며, 4시간후대부분흡수되며생체이용률은 98% 에이른다 [9]. 반감기는 2-4시간이며신생아나간경화환자에서반감기는증가한다 [10]. 간에서 glucuronyl transferase와 sulfotransferase에의해 90% 가 glucuronide 또는 sulfate와결합하여비독성대사물형태로신장을통해배설되고, 5-10% 는주로 cytochrome P450 (CYP) 2E1에의해중간활성대사체인 NAPQI 를생성하지만이것의대부분은 gluta-thione과결합하여비독성대사산물인 cysteine 또는 aceta-minophenmercaptate으로변환되어신장을통해배설된다 (Figure 1) [11,12]. 과량흡수된아세트아미노펜은간이나신장에독성을미치는데이는 NAPQI에의한것으로증가된 NAPQI를해독하기위한 glutathione이부족할경우에발생한다. 알코올중독자, 영양결핍자, 후천성면역결핍증환자와같이 glutathione 저장량이부족하거나항경련제와항결핵제를동시에투여받아 CYP2E1 활성이증가된환자, 아세트아미노펜을장기간복용한환자등에서간손상발생가능성이높다 [13]. 체내에투여된 NAC은 NAPQI가간단백질에결합하는것을길항적으로억제하고, 항산화제인 glutathione 생성을증가시키며, sulfate 전구물질로작용하여산화과정을통한 NAPQI 형성을직접저하시켜아세트아미노펜에의한간손상을예방하는것으로알려져있다 [6-8,14]. 2. 임상양상간손상을제외하고아세트아미노펜에의한타장기손상은드물게발생한다. 음독초기에간에서젖산 (lactic acid) 대사를억제하여대사성산증이동반될수있고신장에존재하는 CYP2E1와프로스타글란딘합성효소에의하여 NAPQI 1068 아세트아미노펜중독의해독제 : 아세틸시스테인

3 N-acetylcysteine for acetaminophen poisoning 특 집 생성, 허혈과체액손실등으로신독성이나타날수있으며전격성간부전 (fulminant hepatic failure) 을보인환자에서심장독성에의한심전도변화와췌장염이발생한경우도있다 [15,16]. NAC 치료를받지않은환자에서심각한간독성이나타날경우사망률은 58-80% 에이른다 [17]. 아세트아미노펜에의한전격성간부전의치료는 NAC 투여, 응고장애와산증교정, 뇌부종치료등이포함된다. 동맥혈 ph가 7.3 미만, PT가 100초이상, creatinine이 300 μg/l 이상, grade 3 이상의뇌병증 (encephalopathy) 이지속되는환자는간이식도치료방법으로고려되어야한다 [18]. 사망률을낮추기위해서는아세트아미노펜에의한독성의조기진단과치료가중요하지만초기임상증상은비특이적으로나타나조기진단에어려움이있다. 아세트아미노펜중독후치료를받지않은환자의임상경과는 4단계로구분된다. 1) 1단계 (0-24시간) 아세트아미노펜에노출된후 24시간이내에는무증상이거나오심, 식욕부진, 구토, 권태감과같은소화기계증상을호소한다. 간독성으로진행되는환자에서도이기간동안에는증상이나타나지않을수있다. 혈청간기능효소검사치도정상범위에있다. 그러나과량복용한환자의경우에서간독성징후없이의식저하와대사성산증이나타날수있다 [19]. 2) 2단계 (2-3일) 음독후 2-3일사이에는간손상정도에따라임상양상이다양하게나타날수있다. 간손상으로우상복부통증과혈청 aspartate aminotransferase (AST), alanine aminotransferase (ALT) 가증가하며빌리루빈상승, 혈액응고지연등의소견과함께신기능저하, 췌장염등이동반될수있다. 이단계에서바로 4단계로진행해특별한치료없이후유증을남기지않고회복되는경우도있다. 3) 3단계 (3-4일) 간독성이최고조에이르는시기로전격성간부전으로진행될수있으며젖산산증 (lactic acidosis), 응고장애, 급성신부전, 뇌병증, 저혈당증, 췌장염등이올수있으며혈청 AST, ALT가 3,000 IU/L 이상으로증가할수있다. 간부전정도와예후는 AST, ALT 보다혈액응고지연, 저혈당, 동맥혈 ph의정도에의해결정된다. 심각한간부전이나타난환 자는출혈, 급성호흡부전, 뇌부종, 패혈증등으로과량복용후 3-5일사이에사망할수있다 [17]. 4) 4단계 (7일이후 ) 3 단계의전격성간부전에서회복한환자는음독후 7일이지나면서후유증을남기지않고회복되기시작한다. 조직학적소견은수개월까지지속될수있으나검사실소견은대부분 4일후부터회복되기시작하여 7-10일사이에정상화된다. 3. 진단및치료 1) 아세트아미노펜의혈중농도와 Rumack-Matthew nomogram 아세트아미노펜에의한급성중독은노출시간 4시간이내로정의하며간독성을유발할수있는최저용량은보고에따라다르지만성인에서 mg/kg, 소아에서 150 mg/kg 이상복용했을경우이다 [20]. 그러나복용량을이용한독성발생예측은노출용량을정확히알수있는경우에한하며그외경우에는혈중아세트아미노펜농도를측정하여간독성발생을예측해야한다. 측정된아세트아미노펜혈중농도는 Rumack-Matthew nomogram을이용해치료계획을세울수있다. 미국과유럽등에서주로사용되는 normogram은간독성진단의민감도를증가시키기위해노출후 4시간째의아세트아미노펜독성농도결정점을 150 μg/ml 으로하향조정하여 Rumack-Matthew nomogram과평행한치료선 (treatment line) 을만들었다 (Figure 2) [21]. 결정점을 150 μg/ml으로하향조정한후치료선이하의혈중아세트아미노펜농도를보인환자에서간독성발생은현저히낮아졌으나 NAC의투여경우가증가하여 NAC에의한이상반응비율은증가하였다 [22]. Nomogram은아세트아미노펜복용후 4시간부터 24시간까지의혈중농도에근거하여적용할수있으며사망이나임상적간독성발생가능성보다 AST, ALT의상승가능성에의미를두고만들어졌다 [23]. 4시간이내의혈중농도는아세트아미노펜음독여부진단에도움이되며, 100 μg/ml 이하일경우심각한음독가능성을배제할수있고시간경과후추가검사가필요하다 [24]. 24시간이후에는아세트아미노펜의대사가진행되 대한의사협회지 1069

Chun BJ Moon JM Kim SH Acetaminophen plasma concentration (μg/ml) 500 400 300 200 150 100 90 80 70 60 50 40 30 20 10 9 8 7 6 5 4 3 2 Rumack-Matthew line Treatment line Treatment should be

4 Chun BJ Moon JM Kim SH Acetaminophen plasma concentration (μg/ml) Rumack-Matthew line Treatment line Treatment should be administered if level is above solid line Hours positingestion Figure 2. The Rumack-Matthew nomogram (from Wikipedia. Rumack-Matthew nomogram [Internet]. San Francisco: Wikimedia foundation, according to the Creative Commons Attribution License) [21]. 어측정하기어렵기때문에간기능검사와임상증상을참고하여간독성이나타난경우는 NAC 치료를시작하거나지속해야한다. 노출시간을알수없을때는노출후 8시간이내로보고혈중농도가결정점이상일경우 NAC 치료를시작해야한다. 노출된지 8시간이전에 AST와 ALT가상승한환자는노출시간이정확하지않을가능성과타질환에의해상승했을가능성을고려해야한다. 타약제와병용노출일경우는혈중아세트아미노펜농도를측정해 NAC 치료의기준으로삼고, 타약제에의한증상을주의하여관찰한다. 국내에서생산되는일부아세트아미노펜제제의경우 diphenhydramine 성분이섞여있기때문에항콜린성증상, 환각, 환청, 진전, 경련등의증상이추가로나타날수있다. 2) 위장관정화아세트아미노펜중독시치료는위장관정화, 해독제인 NAC 투여및대증요법등을시행한다. 아세트아미노펜은신속하게위장관에서흡수되고효과적인해독제가있기때문에아세트아미노펜만음독한경우위세척필요성은크지않다. 그러나지속유리형약물이나위장관내흡수를저하시키는약물을병용한경우와음독후조기내원한경우에는위세척을고려할수있다. 아세트아미노펜에노출된후 2시간이내투여된활성탄이효과적이지만금기증이없다면경구를통해복용된아세트아미노펜은 4시간에걸쳐흡수되므로음독 4시간이내에내원한환자도활성탄투여의대상이될수있다 [25]. 활성탄이경구로투여된 NAC을흡수하여 NAC의효과를저하시킬가능성때문에활성탄사용에논란이있었으나활성탄은음독후 4시간이내에투여되고 NAC은음독후 8시간이내에투여되기때문에병행하여치료가가능하다. 반복적인활성탄투여가필요할경우, 즉다른제제와함께복용했거나지속유리형아세트아미노펜제제를음독한환자에게는정맥을통해 NAC을투여하거나, NAC은위장관에서신속히흡수되기때문에활성탄과동시에투여되지않는다면의미있는상호작용을피할수있기때문에경구를통해 NAC을투여할때는 NAC과활성탄투여간격을 1-2시간정도로유지해줄것을권장하고있다 [26]. 혈액투석은노출된후 24 시간이상경과되고간손상이진행된환자에서 NAC 과병행하여시행할경우효과가있다는보고가있다 [27]. 3) 아세틸시스테인투여방법아세트아미노펜의독성대사체인 NAPQI가생성되고이를해독하는 glutathione이고갈될때까지는일정시간이소요된다. 임상적으로아세트아미노펜음독후혈중농도검사등을위해시간이지연되더라도 8시간이내에 NAC이투여된다면환자의예후에큰영향을미치지는않는다고알 1070 아세트아미노펜중독의해독제 : 아세틸시스테인

5 N-acetylcysteine for acetaminophen poisoning 특 집 Table 1. Recommended dose for the administration of N-acetylcysteine for acetaminophen poisoning Method used Oral route Total dose 1st dose 2nd dose Intravenous route Total dose Recommend dose 1,330 mg/kg of N-acetylcysteine, during 72 hours 140 mg/kg 70 mg/kg every 4 hours for 17 doses 300 mg/kg of N-acetylcysteine, during 21 hours 1st dose 150 mg/kg IV infusion in 200 ml 5% dextrose for 1 hour 2nd dose 50 mg/kg IV infusion in 500 ml 5% dextrose for 4 hours 3rd dose 100 mg/kg IV infusion in 1,000 ml 5% dextrose for 16 hours IV, intravenous. 려져있다. 지연투여된 NAC의효과에대한연구에서아세트아미노펜을음독하고 16-24시간경과후내원한환자에게 NAC을투여하여간손상, 뇌부종, 사망률등을감소시켰다는보고도있다 [28]. NAC의경구투여방법은부하용량으로 140 mg/kg를투여하고이후매 4시간마다 70 mg/kg 씩 17차례, 총 72시간투여한다. NAC의불쾌한냄새와맛으로구역감과구토가심한환자에게는주스에섞어마시거나비위관을통해투여할수있고진토제인 metaclopromide 또는 ondansetron 등을사용할수있다 [8]. 경구투여후 1시간이내에구토한경우는반드시재투여해야한다 [29]. 정맥투여는 150 mg/kg을 5% 포도당액 200 ml에희석하여처음 1시간동안정맥주사한후, 50 mg/kg을 5% 포도당액 500 ml에희석하여 4시간동안정맥주사하고, 이후 16시간동안 100 mg/kg을 5% 포도당액 1,000 ml에희석해서정맥주사하여총투여량은 300 mg/kg을초과하지않도록한다 (Table 1). 첫부하용량의속도는 1980년대이후 15분으로권장되었다가부작용발생빈도가주입속도와관계된다는임상보고들에의해 2006년이후부터 1시간으로연장하여투여할것을권장하고있다 [30]. 국내에서생산되는 NAC 제제는 20% 희석액으로 4 ml 바이알당 800 mg의 NAC을함유하는것이주를이루고있지만초과용량의 NAC이투여되어사망한경우를보고한상당수에서용량계산과기록, 혼합비율실수가원인이었기때문에 NAC을사용할경우는반드시용량을확인해야한다 [30]. 4) 아세틸시스테인의경구요법과정맥요법비교 NAC 투여경로에따른효과에대해서논란은있지만아세트아미노펜음독후간부전이나타나지않은환자를대상으로 8시간이내에치료를시작하였고, 경구투여후구토를하지않았다면경구와정맥요법에따른간독성발생률차이는없는것으로보고되고있다 [31,32]. 경구요법은문맥순환에의해간내 NAC 농도를높게유지할수있는장점이있지만의식저하환자에서흡입의위험성과구토로 NAC 치료와흡수가지연될수있으며치료기간이정맥요법에비해길다는단점이있다. 또한먹기힘든 NAC 특유의고약한냄새가있기때문에상태가양호하고협조가잘되는환자를대상으로선택할수있다. 이에반해정맥요법은빠른시간내에혈중최고농도에도달시킬수있고, 높은혈중농도를유지하여간, 신장, 뇌등주요장기에쉽게 NAC이도달할수있으며, 치료자가의도한용량을목표시간내에비교적정확히투여할수있다는장점이있다. 의식이저하된환자와전격성간부전, 임신중인환자, 경구로 NAC 섭취를못하는환자가정맥투여의대상이될수있지만이상반응발생빈도와정도가경구요법보다높게보고되고있어주의를요한다 [33]. 아세틸시스테인이상반응 1. 독성동력학과발생기전 NAC은경구투여시위장관에서빠르게흡수되지만간초회-통과효과 (liver first-pass effect) 대사량이많기때문에생체이용률은 10-30% 로낮으며분해되지않은 NAC의분포용적도 0.5 L/kg로낮다. 간에서탈아세틸화 (diacetylation) 된뒤 cysteine 을생성하거나산화되어 diacetylcysteine을생성한다 [29]. 정맥투여된 NAC의평균배설반감기는성인과신생아의경우각각 5.6시간과 11시간으로보고되었으며간기능이저하된환자는반감기가더길어질수있다. Amphotericin B, tetracycline, erythromycin, ampicillin sodium 등은 NAC의효능을불활성화시킬수 대한의사협회지 1071

6 Chun BJ Moon JM Kim SH 있기때문에함께사용할경우주의해야한다 [34]. NAC에의한이상반응발생기전은명확하지않다. 치료용량에서발생한이상반응은대부분정맥을통해첫번째용량을투여한후 10-45분사이에발생하였고, 이상반응이발생한환자에서측정한혈중히스타민농도가이상반응발생시점과비슷한추이로상승했으며, 이상반응의정도가심할수록히스타민농도가높게나타나체내히스타민분비와관련있는아나필락시스양반응 (anaphylactoid reaction) 이원인일것이라는주장이설득력있어보인다 [35]. 그러나치료를시작하고 2-3일경과후치료용량의 10배이상을초과투여받은환자에서도심각한이상반응이발생한다고보고되고있어투여용량과도관계가있을것으로보인다. 부작용유발인자에대한연구에서다른약제에아나필락시스양반응이있었거나천식의과거력, 혈중아세트아미노펜농도가낮을수록이상반응발생빈도는높게나타났다 [36]. 혈중아세트아미노펜농도가 NAC의이상반응발생에관여하는기전에대해서는아세트아미노펜이아나필락시스양반응을억제시키는역할을할것이라는가설만제기되고있어추가연구가필요한부분이다. 2. 임상양상 NAC을경구및정맥으로투여하였을경우에이상반응발생빈도는 10-60% 까지보고되고있다 [35]. 경구투여는주로오심, 구토, 설사등소화기계증상이주로발생하며심각한합병증은초래하지않는것으로알려져있다. 이에반해정맥투여는아나필락시스양반응을일으킬수있는데대부분홍반 (erythema), 발진 (rash), 구토등경한증상을보이지만드물게기관지수축에의한호흡곤란, 경련, 부정맥, 저혈압, 쇼크등생명을위협하는독성반응을일으킬수있다. 27세남성이 6시간간격으로 5 g의 NAC을 3일동안경구복용후고열과발진, 관절부종등혈청병 (serum sickness) 이발생하여투약중단후회복되었으며, 8,480 mg/kg의 NAC을 3일동안경구와정맥으로투여받은 3세남아에서전격성간염이발생하였다 [37]. 17세여아는아세트아미노펜음독후경구를통해치료용량의 NAC을투여받고 sulfhemoglobinemia가발생하였고, 천식환자에서경구치료 용량의 NAC을투여후기관지수축이발생했다는보고도있다 [38,39]. 의료진의용량계산실수로초과용량의 NAC 을투여받고사망한증례보고들도있다. 만성폐쇄성폐질환 (chronic obstructive pulmonary disease) 과 C형간염을가진 53세남자는계획된용량의 10배인 126,000 mg의 NAC을정맥투여받은후급성심근경색이발생해사망하였으며, 30개월여아는 2,450 mg/kg의 NAC을정맥투여받은지 5시간후부터중첩성간질 (status epilepticus) 이발생하여뇌부종 (cerebral edema) 과저산소뇌증 (hypoxic encephalopathy) 으로사망하였다 [40,41]. 또한 21세여성은아세트아미노펜을음독후 NAC을투여받던중, NAC 100 mg/kg/hr 용량으로 27시간동안총 150 g을정맥으로투여받고경련과뇌부종으로사망하였다 [42]. 3. 치료선택적인해독제는없다. 다량의 NAC 중독환자는기도와호흡, 순환기계안정이필요하며심전도와활력징후를주의깊게관찰해야한다. 활성탄은소화관에서 NAC의흡수를지연시키기때문에경구를통해과량복용한환자에게투여해야한다. 구역감이나구토가심한경우에는 metoclopramide, ondansetron 등의항구토제를투여할수있다. 삼킬수있는환자에게는 5 ml/kg에서최대 200 ml까지물을마시게하여희석시킬수있으며경련발생시 benzodiazepine과 phenytoin, propofol 등으로조절한다 [8]. 체액을보충하고저혈압으로인한쇼크가동반된경우는승압제를투여해야하고호흡기계증상과신경계증상이심할경우기도확보와호흡보조치료를하며필요시기관내삽관을시행한다. 아나필락시스양반응으로저혈압이지속될경우는 epinephrine과항히스타민제, 스테로이드등을사용할수있다 [35]. 고열과젖산산증 (lactic acidosis), 횡문근융해증 (rhabdomyolysis) 등이지속될경우뇌파검사를시행하면서신경근차단제 (neuromuscular blocking drugs) 사용을고려해볼수있다. 정맥투여시이상반응이발생하면 NAC 투여를중단하고대증적치료를시행하며, 증상이호전될경우는혈역학과신경학적증상을주의깊게관찰하면서 NAC의재투여를시도해야한다 [43] 아세트아미노펜중독의해독제 : 아세틸시스테인

7 N-acetylcysteine for acetaminophen poisoning 특 집 4. 예방 가능하다면이상반응이적은경구요법을선택하고정맥 요법을선택했을경우는이상반응을예방하기위해노력해야한다. 정맥요법의첫번째투여량에의한이상반응을줄이기위해서는주입속도를 1시간동안서서히투입하면서투입후지속적인모니터링을시행하고, 예방적항히스타민제와분무형베타차단제를투여할수있으며, NAC의피부반응검사도고려될수있다. 과량투여에의한이상반응을줄이기위해서는환자체중을고려한정확한용량계산과정확한기록, 정확한배합이필요하다 [35]. 5. 임산부에게아세틸시스테인투여임산부의아세트아미노펜중독에의한간독성발생예측은비임산부와동일하며임산부에대해 NAC의유해성이증명되지않았기에 NAC 치료가필요한경우에는임신여부와관계없이일반성인과같은치료지침에따라투여해야한다. NAC의 FDA 임산부안전성등급은 B이다 [44]. 결 론 간독성을일으킬수있는아세트아미노펜중독에대해서는비교적잘알려진반면선택적해독제로사용되는 NAC의유해성은잘알려지지않았다. 아세트아미노펜중독의해독제로사용되고있는 NAC이지만, NAC이직접적으로인체에유해한이상반응을일으킬수있기때문에사용에주의를기울여야할것으로본다. 특히아세트아미노펜중독환자에게 NAC을정맥용법으로투여할경우, 치료용량과초과용량모두에서생명을위협할수있는심각한이상반응이발생할수있기때문에첫번째용량이투여되는동안집중관찰을시행하고, 투여해야할용량의정확한계산과반복확인을거쳐서의도하지않은상황을미연에방지해야할것으로생각된다. 핵심용어 : 아세트아미노펜 ; 간독성 ; 해독제 ; 아세틸시스테인 ; 아나필락시스양반응 REFERENCES 1. Lee WM. Acetaminophen and the U.S. Acute Liver Failure Study Group: lowering the risks of hepatic failure. Hepatology 2004;40: Bronstein AC, Spyker DA, Cantilena LR Jr, Rumack BH, Dart RC Annual report of the American Association of Poison Control Centers National Poison Data System (NPDS): 29th annual report. Clin Toxicol (Phila) 2012;50: Kim HJ, Kim YW, Kim H, Park CB, So BH, Lee KR, Lee KW, Lee KW, Lee SW, Lee JY, Cho GC, Cho J, Chung SP. Comparison between emergency patient poisoning cases and the Tox-Info System Database. J Korean Soc Clin Toxicol 2012; 10: Kim J. Tylenol syrups for children recalled. The Korea Times Apr US Food and Drug Administration. FDA warns of rare acetaminophen risk [Internet]. Silver Spring: US Food and Drug Administration; 2013 [cited 2013 Nov 12]. Available from: Mitchell JR, Jollow DJ, Potter WZ, Gillette JR, Brodie BB. Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. J Pharmacol Exp Ther 1973;187: Prescott LF, Park J, Ballantyne A, Adriaenssens P, Proudfoot AT. Treatment of paracetamol (acetaminophen) poisoning with N-acetylcysteine. Lancet 1977;2: Chung SP, Kim SH, Lee HS. Acetaminophen poisoning. J Korean Soc Clin Toxicol 2008;6: McGilveray IJ, Mattok GL, Fooks JR, Jordan N, Cook D. Acetaminophen II. A comparison of the physiological availabilities of different commercial dosage forms. Can J Pharm Sci 1971; 6: Bannwarth B, Netter P, Lapicque F, Gillet P, Pere P, Boccard E, Royer RJ, Gaucher A. Plasma and cerebrospinal fluid concentrations of paracetamol after a single intravenous dose of propacetamol. Br J Clin Pharmacol 1992;34: Xu JJ, Hendriks BS, Zhao J, de Graaf D. Multiple effects of acetaminophen and p38 inhibitors: towards pathway toxicology. FEBS Lett 2008;582: Patten CJ, Thomas PE, Guy RL, Lee M, Gonzalez FJ, Guengerich FP, Yang CS. Cytochrome P450 enzymes involved in acetaminophen activation by rat and human liver microsomes and their kinetics. Chem Res Toxicol 1993;6: Mitchell JR, Jollow DJ, Potter WZ, Davis DC, Gillette JR, Brodie BB. Acetaminophen-induced hepatic necrosis: I. role of drug metabolism. J Pharmacol Exp Ther 1973;187: Ekins BR, Ford DC, Thompson MI, Bridges RR, Rollins DE, Jenkins RD. The effect of activated charcoal on N-acetylcysteine absorption in normal subjects. Am J Emerg Med 1987; 5: 대한의사협회지 1073

8 Chun BJ Moon JM Kim SH 15. Mazer M, Perrone J. Acetaminophen-induced nephrotoxicity: pathophysiology, clinical manifestations, and management. J Med Toxicol 2008;4: Lee JY, Gil HW, Yang JO, Lee EY, Hong SY. A case of acute renal failure induced by acetaminophen intoxication. Korean J Med 2011;80: Makin A, Williams R. The current management of paracetamol overdosage. Br J Clin Pract 1994;48: Lee WM. Acute liver failure. Dallas: Cambridge University Press; Flanagan RJ, Mant TG. Coma and metabolic acidosis early in severe acute paracetamol poisoning. Hum Toxicol 1986;5: Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics 1975;55: Wikipedia. Rumack-Matthew nomogram [Internet]. San Francisco: Wikimedia Foundation [cited 2013 Nov 12]. Available from: Smilkstein MJ, Douglas DR, Daya MR. Acetaminophen poisoning and liver function. N Engl J Med 1994;331: Prescott LF, Illingworth RN, Critchley JA, Proudfoot AT. Intravenous N-acetylcysteine: still the treatment of choice for paracetamol poisoning. Br Med J 1980;280: Rumack BH, Peterson RC, Koch GG, Amara IA. Acetaminophen overdose: 662 cases with evaluation of oral acetylcysteine treatment. Arch Intern Med 1981;141(3 Spec No): Dart RC, Erdman AR, Olson KR, Christianson G, Manoguerra AS, Chyka PA, Caravati EM, Wax PM, Keyes DC, Woolf AD, Scharman EJ, Booze LL, Troutman WG; American Association of Poison Control Centers. Acetaminophen poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila) 2006;44: Buckley NA, Whyte IM, O Connell DL, Dawson AH. Activated charcoal reduces the need for N-acetylcysteine treatment after acetaminophen (paracetamol) overdose. J Toxicol Clin Toxicol 1999;37: Daly FF, Fountain JS, Murray L, Graudins A, Buckley NA; Panel of Australian and New Zealand clinical toxicologists. Guidelines for the management of paracetamol poisoning in Australia and New Zealand: explanation and elaboration: a consensus statement from clinical toxicologists consulting to the Australasian poisons information centres. Med J Aust 2008; 188: Prescott LF. Paracetamol: past, present, and future. Am J Ther 2000;7: Heard KJ. Acetylcysteine for acetaminophen poisoning. N Engl J Med 2008;359: Hayes BD, Klein-Schwartz W, Doyon S. Frequency of medication errors with intravenous acetylcysteine for acetaminophen overdose. Ann Pharmacother 2008;42: Chae HJ, Rhee NG, Kim HJ, You JS, Chung SP, Lee HS. Oral vs. Intravenous administration of N-acetylcysteine in the acetaminophen poisoning. J Korean Soc Clin Toxicol 2012;10: Perry HE, Shannon MW. Efficacy of oral versus intravenous N-acetylcysteine in acetaminophen overdose: results of an open-label, clinical trial. J Pediatr 1998;132: Bebarta VS, Kao L, Froberg B, Clark RF, Lavonas E, Qi M, Delgado J, McDonagh J, Arnold T, Odujebe O, O Malley G, Lares C, Aguilera E, Dart R, Heard K, Stanford C, Kokko J, Bogdan G, Mendoza C, Mlynarchek S, Rhyee S, Hoppe J, Haur W, Tan HH, Tran NN, Varney S, Zosel A, Buchanan J, Al-Helial M. A multicenter comparison of the safety of oral versus intravenous acetylcysteine for treatment of acetaminophen overdose. Clin Toxicol (Phila) 2010;48: Zyoud SH, Awang R, Syed Sulaiman SA, Sweileh WM, Al-Jabi SW. Incidence of adverse drug reactions induced by N-acetylcysteine in patients with acetaminophen overdose. Hum Exp Toxicol 2010;29: Pakravan N, Waring WS, Sharma S, Ludlam C, Megson I, Bateman DN. Risk factors and mechanisms of anaphylactoid reactions to acetylcysteine in acetaminophen overdose. Clin Toxicol (Phila) 2008;46: Sandilands EA, Bateman DN. Adverse reactions associated with acetylcysteine. Clin Toxicol (Phila) 2009;47: Mohammed S, Jamal AZ, Robison LR. Serum sickness-like illness associated with N-acetylcysteine therapy. Ann Pharmacother 1994;28: Lu HC, Shih RD, Marcus S, Ruck B, Jennis T. Pseudomethemoglobinemia: a case report and review of sulfhemoglobinemia. Arch Pediatr Adolesc Med 1998;152: Bailey B, McGuigan MA. Management of anaphylactoid reactions to intravenous N-acetylcysteine. Ann Emerg Med 1998;31: Elms AR, Owen KP, Albertson TE, Sutter ME. Fatal myocardial infarction associated with intravenous N-acetylcysteine error. Int J Emerg Med 2011;4: Bailey B, Blais R, Letarte A. Status epilepticus after a massive intravenous N-acetylcysteine overdose leading to intracranial hypertension and death. Ann Emerg Med 2004;44: Heard K, Schaeffer TH. Massive acetylcysteine overdose associated with cerebral edema and seizures. Clin Toxicol (Phila) 2011;49: Marzullo L. An update of N-acetylcysteine treatment for acute acetaminophen toxicity in children. Curr Opin Pediatr 2005; 17: Wilkes JM, Clark LE, Herrera JL. Acetaminophen overdose in pregnancy. South Med J 2005;98: 아세트아미노펜중독의해독제 : 아세틸시스테인

9 N-acetylcysteine for acetaminophen poisoning 특 집 Peer Reviewers Commentary 아세트아미노펜은해열 진통제로서널리사용되고있으며, 의사의처방전없이도약국에서쉽게구매할수있어치료목적외의과량섭취로인하여중독환자가늘어나고있는실정이다. 최근에는일반인뿐만아니라청소년들사이에서도정서적으로불안한상태에서과량의아세트아미노펜을복용하고응급실에내원하는경우가많고, 이로인하여간손상까지보일수있어서사회적으로염려되는바가크다. 본논문은아세트아미노펜의대사과정및중독에의한간손상의기전과 NAC 의해독기전에대하여간결하면서도쉽게이해할수있도록기술하였다. 아세트아미노펜중독을진료하는것이부담스러울수있는일선진료현장에서아세트아미노펜중독의치료를위하여 NAC 의투여용량, 투여경로, 부작용및기타주의점등에대한핵심적인내용을자세히기술함으로 NAC 의사용에좀더친숙해지고, 일선진료에서아세트아미노펜중독환자치료의지침이될수있을것으로생각된다. [ 정리 : 편집위원회 ] 자율학습 2013 년 11 월호정답 ( 족부무지외반증의예방및치료 ) 대한의사협회지 1075

대한임상독성학회지 2012:10(2):97~102 Volume 10, Number 2, December, 2012 Journal of The Korean Society of Clinical Toxicology 원 저 Acetaminophen 중독환자에서 N-Acetyl

대한임상독성학회지 2012:10(2):97~102 Volume 10, Number 2, December, 2012 Journal of The Korean Society of Clinical Toxicology 원 저 Acetaminophen 중독환자에서 N-Acetylcysteine 투여경로에따른치료효과및부작용비교 연세대학교의과대학응급의학교실 채효주 이누가