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대한소아소화기영양학회지 : 제 12 권부록 1 호 2009 최신지견 소아청소년기의항구토제 가천의대길병원소아청소년과학교실 류 일 Antiemetics in Children and Adolescents Eell Ryoo, M.D. Department of Pediatrics, Gil Hospital, Gacheon University of Medicine and Science, Incheon, Korea In children and adolescents with acute gastroenteritis and other gastrointestinal disease, antiemetics are frequently used. But there are insufficient data about antiemetic use in children, so it should be used carefully. Despite some significant researches, treatment guidelines of ondansetron will be carefully presented through further investigation. [Korean J Pediatr Gastroenterol Nutr 2009; 12(Suppl 1): 98 102] 서 구토는소화기계의주요한증상중하나로역류, 주기성구토증후군, 반추, 다식증, 상장간막동맥증후군등과같은구토증후군, 화학요법과관련되어나타나는구토등과같이적극적치료가필요한것들과여러가지위장관질환특히급성위장관염에동반되어나타나는것으로구분할수있다. 이중일반소아과의사가가장흔히경험하는급성위장관염환자에서구토의치료는주요한관심사중의하나일뿐아니라환자의보호자입장에서구토에대한처방을요구하는것은어찌보면이해할만한일이라할수있으나아직까지이증상에대한직접적치료원칙이제시된바는없는실정 접수 :2009 년 10 월 31 일, 승인 :2009 년 11 월 6 일책임저자 : 류일, 405-760, 인천시남동구구월동 1198 번지가천대학교의과대학길병원소아청소년과학교실 Tel: 032-460-3114, Fax: 032-460-3224 E-mail: irida@medimail.co.kr 론 이다. 미국소아과학회 (AAP), 유럽소아소화기영양학회 (ESPGHAN) 등에서제시한구토증상이있는급성위장관염환자의치료원칙을살펴보면, 경증혹은중등도탈수증이있을경우경구수액제투여와함께가능한빨리다시먹일것을권장하고있으며, 항구토제투여는특별한실익이없을뿐아니라항구토제자체의부작용때문에금기시하고있다 1,2). 그러나대체적으로많은의사들은항구토제처방을하고있으며특히우리나라실정에서는이런약물처방이더욱고민스러운것이현실이다. 이에본고찰에서는급성위장관염과위식도역류증에서구토에대한치료약물들의종류와효과에대해지금까지알려진여러문헌을통해고찰해보고자한다. 본론 1952년 Wang과 Borison이처음으로연수안에화학수용체유발구역 (chemoreceptor trigger zone: CTZ) 과중심구토중추 (central vomiting center) 를규명한이후구 98

류일 : 소아청소년기의항구토제ㆍ 99 토를조절하는약물의개발뿐아니라이와관련한여러기전및이해에대한많은발전이이루어져왔다. 구토와관련한위장관운동은다른자율신경과연결된중추신경의미주신경및교감신경수출로를통해나타나므로침흘림, 호흡수의증가, 심박수의증가, 동공확장등이동반되어나타난다. 또한구토는몸운동신경 (somatomotor nerve) 을통해복막, 외늑간근, 위장, 복근, 위저부의탈장등과같은여러기관의연속적인움직임으로나타난다. CTZ에는구토를유발할수있는여러가지신경활성물질즉 dopamine, acetylcholine, vasopresin, enkephalin, angiotensin, insulin, serotonin, endorphin, substance P 등에대한수용체들이있으며, 이중 dopamine D 2 수용체가가장높은농도로존재한다. Serotonin은장점막깊은곳의 enterochromaffin 세포에서장점막의손상후이차적으로분비되는흥분성신경전달물질로가장중요하다 3). 1. 급성위장관염세계적으로급성위장관염은 5세이하의경우연간 30억 50억명의환자가발생하는것으로알려져있으며 4), 2003년연구를보면미국의경우연간 150만명이상의환자가발생하며 20만명이입원하고, 연간 300 명이사망하는것으로조사되었다 5). 또한로타바이러스백신이사용되기이전의미국통계를보면입원환자의 13% 는설사때문이며, 이들중 35% 는바이러스가원인인것으로조사되었다 6). 일반적으로영유아와소아연령층에서구토의원인을모른상태에서는항구토제를사용하지않는것이원칙이다. 특히외과적원인이나위장관의구조적원인에의해발생하는구토의경우항구토제의사용이금기로되어있다. 그러나많은논란과여러연구에도불구하고급성위장관염환자에서항구토제를사용하는것이현실이다. 이와관련하여유럽과북유럽에서 2005년한해동안위장관염환자에게사용하는항구토제의사용빈도와사용한항구토제의종류에대한조사에의하면처방된항구토제의종류는나라별로각각다른차이를보였으며항구토제를처방하는빈도는소아의경우 2 23% 에이르는것으로나타났다. 이를구체적으로살펴보면독일과캐나다에서는항히스타민제인 dimenhydrinate와 diphenhydramine을, 미국에서는 promethazine 을가장많은의사들이처방하는반면프랑스, 스페인, 이탈리아등에서는도파민수용체길항제인 domperidone을가장많이처방하는것으로나타났으며, ondansetron을처방한경우는 0 6% 로나타났다 7). 지금까지알려진항구역및항구토제로는도파민수용체특히 D 2 수용체길항제인 metoclopramide, haloperidol 등, 항히스타민제인 dimenhydrinate, diphenhydramine, promethazine, hydroxyzine 등이주로많이쓰여왔으며, 이외에항콜린약제, 5HT 3 수용체길항제, benzodiazepine, phenothiazine, corticosteroid 등이있다 (Table 1) 3). 이외에도 NK 1 수용체길항제인 palonosetron, casopitant 등과 olanzapine, gabapentin 등의약물들이화학요법과관련된구역및구토의치료에시도되고있다 8,9). 또한항암제투여로구역을유발한흰족제비연구에서 ghrelin이유용하다는보고도있다 10). 최근에는소아에서안전한것으로알려진 ondansetron에대한여러임상결과가발표됨에따라위장관염환자에서이의사용이적절한지에논란이확대되고있다. 위장관염에서주로사용하는항구토제의효과와부작용에대한고찰및메타분석에대한문헌결과, domperidone은주요한부작용은없었으나구역과구토감소가위약군에비해감소하지않았다. 또한 metoclopamide는구역과구토에효과가있다는연구결과와효과가없다는상반된연구결과가있으며부작용에대한기술역시다른결과를보인것으로조사되었다. Trimethobenzamide는위약군에비해효과가없을뿐아니라 pyrilamine-pentobarbital 보다효과가적다는보고가있으나 25년이상오래된연구결과만있다. Pyrilamine-pentobarbital 복합제는 promethazine이나 trimethobenzamide에비해구토에대한효과가좋은것으로조사되었으나부작용으로진정작용이있을뿐아니라위약군과비교한대조군연구가아니므로신뢰성이떨어진다는점이있다. Promethazine에대한연구역시위약대조군이없을뿐아니라 pyrilamine-pentobarbital 에비해효과가적다는연구결과가있으며, dexamethasone 역시대조군에비해구토를줄이지못하는것으로조사되었다. 반면 ondansetron은대조군에비해구토회수, 추가치료횟수, 정맥내수액투여필요성등이감소하는것으로조사되었고즉시입원하게되는위험도역시감소시키는것으로나타났다. 또한설사의빈도를증가

100 ㆍ대한소아소화기영양학회지 : 제 12 권부록 1 호 2009 Table 1. Antiemetics and Antinausea Drugs Chemical name Brand name in Korea Route Mechanism Uses 5-HT 3 receptor antagonist Ondansetron Ondant, Zofran, Onseran, Onfran, Ondansetron, Onsetron IV, IM, PO Chemotherapy, AGE(?) 5-HT 3 receptor blockade Granisetron Kanitron, Gratron, Kytril IV, PO Chemotherapy, postoperative Antihistamines Diphenhydramine 슬리펠 PO Dimenhydrinate Bonaling PO Anticholinergic, H 1 Motion sickness, Hydroxyzine Leuzan, Centilax, receptor PO chemotherapy-induced vomiting Adipam, Ucerax antagonism Promethazine Himazin PO Butyrophenones Domperidone Motilium, Hamidon, PO Motility disorder, GER, Gasco, etc chemotherapy Droperidol Droperidel IV D 2 receptor Cyclic vomiting, intractable Haloperidol Haldol, Serenase, etc IM, PO blockade vomiting from acute gastritis, chemotherapy, postoperative Phenothiazines Promethazine Himazine PO Chlorpromazine Chlomazine, Neomazine IV, IM, PO D 2 receptor Cyclic vomiting, acute gastritis, Perphenazine Perphenazine PO antagonism chemotherapy Substituted benzamides Metoclopramide Macperan, Maxolon, etc IV, IM, PO D 2 receptor blockade, 5-HT 3 activity Cisapride Enteric acetylcholine release Corticosteroid Dexamethasone Limethasone, Dexasolone etc. IV, IM, PO Unknown Chemotherapy-induced vomiting V: intravenous, IM: intramuscular, PO: per oral, AGE: acute gastroenteritis, GER: gastroesophageal reflux. Adapted from Pediatric gastrointestinal diseases. 4th ed. BC Decker Co, 2004 p.206. 시킨다는일부보고외에다른항구토제의주된부작용인추체외로증상은나타나지않았다 11,12). 따라서향후더많은환자를대상으로더장기간의추적관찰을통한연구혹은장기간투여에대한연구가필요하기는하지만 6개월이하의연령에서도사용가능하다는점과아직까지거의부작용에대한보고가거의없는것으로미루어약가만해결된다면구토증상의개선에주요한약물로주목받을것으로보인다. 2. 위식도역류질환 (Table 2) 영유아위식도역류에대한 metoclopramide의치료효과는각기논문별로대상환자, 약물의용량, 치료결 과가각기상이하여더많은환자를대상으로연구가필요한것으로조사되었다 13). 또한 metoclopramide는영아의 20% 이상에서중추신경계에대한효과와내분비계에영향을줄수있으므로주의해서사용해야한다. Domperidone은 75 93% 에서효과가있다는보고가있지만효과가없었다는상반되는보고도있으며효과가있다는보고의경우에도대상환자수가적어코크란연구결과효과가없는것으로알려져있다 14). Erythromycin은위배출과음식관용 (food tolerance) 증진효과가있는것으로알려져있지만위식도역류와역류증상에대한연구보고는없다. Cisapride는근육층신경얼기 (myenteric plexus) 에서 acetycholine을간접적으

류일 : 소아청소년기의항구토제ㆍ 101 Table 2. Prokinetics Chemical name Doses Side effects Metoclopramide 0.1 mg/kg/dose qid AC, HS Drowsiness, restlessness, dystonia, gynecomastia, galactorrhea Cisapride* 0.2 mg/kg/dose qid AC, HS Diarrhea, cramps, cardiac arrhythmias Erythromycin 3 5 mg/kg/dose tid-qid AC, HS Diarrhea, vomiting, cramps, antibiotic effect, pyloric stenosis Domperidone 0.3 mg/kg/day Hyperprolactinemia, dry mouth, rash, headache, diarrhea, nervousness Bethanechol 0.1 0.3 mg/kg/dose tid-qid AC, HS Hypotension, bronchospasm, salivation, cramps, blurred vision, bradycardia AC: ante cibum, GERD: gastroesophageal reflux disease, HS: hour of sleep, PC: post cibum. *Use in the United States restricted through a limited access program supervised by a pediatric gastroenterologist. Adapted from Pediatric gastrointestinal diseases. 4th ed. BC Decker Co, 2004 p.393. 로분비하여작용하며매우효과가좋은것으로알려졌으나부작용으로시장에서사라진상태이다 15,16). 결 급성위장관염을포함한소화기질환에서구토증상의치료로항구토제의사용은여러나라에서광범위하게사용되고있지만이들질환에서항구토제에대한연구는제한적이다. 따라서항구토제의사용은최소화되어야하며주의해서사용해야한다. 현재까지전향적으로비교적많이연구된항구토제로는 ondansetron이유일하지만이역시보다많은연구를통해더많은검증이필요할것으로보인다. 론 참고문헌 1) Practice parameter: the management of acute gastroenteritis in young children. American Academy of Pediatrics, Provisional Committee on Quality Improvement, Subcommittee on Acute Gastroenteritis. Pediatrics 1996; 97:424-35. 2) Guarino A, Albano F, Ashkenazi S, Gendrel D, Hoekstra JH, Shamir R, et al. European Society for Paediatric Gastroenterology, Hepatology, and Nutrition/European Society for Paediatric Infectious Diseases evidence-based guidelines for the management of acute gastroenteritis in children in Europe: executive summary. J Pediatr Gastroenterol Nutr 2008;46:619-21. 3) Sondheimer JM. Vomiting. In: Walker WA, Goulet O, Kleinman RE, Sherman PM, Shneider BL, Sanderson IR, editors. Pediatric gastrointestinal diseases. 4th ed. BC Decker Co, 2004:203-9. 4) Elliott EJ. Acute gastroenteritis in children. BMJ 2007; 334:35-40. 5) King CK, Glass R, Bresee JS, Duggan C. Managing acute gastroenteritis among children: oral rehydration, maintenance, and nutritional therapy. MMWR Recomm Rep 2003;52(RR-16):1-16. 6) Malek MA, Curns AT, Holman RC, Fischer TK, Bresee JS, Glass RI, et al. Diarrhea- and rotavirus-associated hospitalizations among children less than 5 years of age: United States, 1997 and 2000. Pediatrics 2006;117:1887-92. 7) Pfeil N, Uhlig U, Kostev K, Carius R, Schröder H, Kiess W, et al. Antiemetic medications in children with presumed infectious gastroenteritis - pharmacoepidemiology in Europe and Northern America. J Pediatr 2008;153:659-62, 662.e1-3. 8) Herrstedt J. Antiemetics: an update and the MASCC guidelines applied in clinical practice. Nat Clin Pract Oncol 2008;5:32-43. 9) Roila F, Garassino M, Fatigoni S. New anti-emetic treatments. Ann Oncol 2007;18(9 Suppl):ix43-7. 10) Rudd JA, Ngan MP, Wai MK, King AG, Witherington J, Andrews PL, et al. Anti-emetic activity of ghrelin in ferrets exposed to the cytotoxic anti-cancer agent cisplatin. Neurosci Lett 2006;392:79-83. 11) DeCamp LR, Byerley JS, Doshi N, Steiner MJ. Use of antiemetic agents in acute gastroenteritis: a systematic review and meta-analysis. Arch Pediatr Adolesc Med 2008;162:858-65. 12) Szajewska H, Gieruszczak-Białek D, Dylag M. Metaanalysis: ondansetron for vomiting in acute gastroenteritis in children. Aliment Pharmacol Ther 2007;25:393-400. 13) Hibbs AM, Lorch SA. Metoclopramide for the treatment of gastroesophageal reflux disease in infants: a systematic

102 ㆍ대한소아소화기영양학회지 : 제 12 권부록 1 호 2009 review. Pediatrics 2006;118:746-52. 14) Pritchard DS, Baber N, Stephenson T. Should domperidone be used for the treatment of gastro-oesophageal reflux in children? Systematic review of randomized controlled trials in children aged 1 month to 11 years old. Br J Clin Pharmacol 2005;59:725-9.14. 15) Vandenplas Y. Gastroesophageal reflux: medical treatment. J Pediatr Gastroenterol Nutr 2005;41(Suppl 1): S41-2. 16) Vandenplas Y, Salvatore S, Hauser B. The diagnosis and management of gastro-oesophageal reflux in infants. Early Hum Dev 2005;81:1011-24.