Korean J Gastroenterol Vol. 70 No. 2, 64-71 https://doi.org/10.4166/kjg.2017.70.2.64 pissn 1598-9992 eissn 2233-6869 REVIEW ARTICLE 만성변비의약물치료 김상진, 박경식 계명대학교의과대학내과학교실 Pharmacotherapy in Patients with Chronic Constipation Sang Jin Kim and Kyung Sik Park Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea Chronic constipation is one of the most common digestive diseases frequently observed in a clinical setting. It has been known to cause considerable damage to the quality of life of patients. Despite recent developments, there are considerable limitations in the use of constipation-modulating agents in Korea. Chloride channel inhibitors, such as lubiprostone and linaclotide, have not been introduced in Korea yet, and prucalopride and several kinds of polyethylene glycol are not covered under medical insurance. This article assesses medicines that are clinically available for the management of constipation in Korea, with a brief review of agents that have recently developed around the world. (Korean J Gastroenterol 2017;70:64-71) Key Words: Constipation; Lubiprostone; Linaclotide; Prucalopride 서론 만성변비는임상현장에서매우흔히접할수있는소화기질환들가운데하나로, 잘디자인된한체계적문헌고찰에서평균유병률이 14% 정도로보고된바있으며, 1 국내연구에서의유병률은 2.6-16.5% 정도로다양하게보고되고있다. 2,3 이러한차이는연구대상이나연구방법, 진단기준등의차이에서기인하는것으로여겨진다. 국내에서도변비에대한정의는 2016년제안된로마기준 IV (ROME IV criteria) 에의해이루어지고있는데, 이기준에서는기능성변비를다음과같이정의하고있다. 1) 배변시과도하게힘을주는경우, 2) 딱딱하고덩어리진변을보는경우, 3) 대변의불완전배출이있다고느끼는경우, 4) 항문이나직장의폐쇄감을느끼는경우, 5) 배변을용이하게하기위해수조작이필요한경우등을주관적증상으로하며, 각각 의증상들은전체배변의 25% 이상에서나타나는경우를유의미한소견으로판단한다. 이와더불어 6) 배변횟수가 1주일에 3번미만인경우를객관적기준으로하여위의 6가지항목중에서 2가지이상을만족하면서묽은변은거의없고, 과민성장증후군의진단기준은충족되지않는경우를기능성변비의필요조건으로정의하였다. 다른기능성위장관질환들과마찬가지로기간기준, 즉증상의발생은 6개월전부터시작되어야하며지난 3개월동안계속된경우에기능성변비로정의할수있다. 4 실제임상현장에서는기능성변비와변비형과민성장증후군을구분하지않는경우들이많은데, 두질환간에는변비증상이라는측면에서유사한점들도있으나변비형과민성장증후군의경우복통을주증상으로하며복통의조절을치료목표로한다는점에서차이가있으며, 앞서언급한바와같이기능성변비의진단을위해서는변비형과민성장증후군의배제가필요하다. 로마기준 IV에서는평균 1주일 Received: June 17, 2017. Revised: August 4, 2017. Accepted: August 10, 2017. CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright 2017. Korean Society of Gastroenterology. 교신저자 : 박경식, 41931, 대구시중구달성로 56, 계명대학교의과대학동산의료원소화기내과 Correspondence to: Kyung Sik Park, Division of Gastroenterology, Department of Internal Medicine, Dongsan Medical Center, Keimyung University School of Medicine, 56 Dalseong-ro, Jung-gu, Daegu 41931, Korea. Tel: +82-53-250-7088, Fax: +82-53-250-7442, E-mail: seenae99@dsmc.or.kr Financial support: None. Conflict of interest: None. Korean J Gastroenterol, Vol. 70 No. 2, August 2017 www.kjg.or.kr
Kim SJ and Park KS. Pharmacotherapy in Patients with Chronic Constipation 65 에 1회이상의복통이최소 6개월전에시작되어최근 3개월간존재하며그복통이 1) 배변과관련, 2) 배변횟수의변화와동반, 3) 대변형태의변화와동반등세가지기준들가운데두가지이상을만족하는경우과민성장증후군으로진단하고, 특히대변형태가 Bristol 대변점수 1 또는 2에해당하는딱딱한변이전체배변가운데 25% 이상에서나타나며, 6 또는 7에해당하는설사형태의무른변이전체배변가운데 25% 미만에서나타나는경우변비형과민성장증후군으로진단할수있다. 4 만성변비는주관적인증상과객관적인평가를통해진단및치료적접근을하게되며, 만성변비환자들이주로호소하는증상들로는배변시과도한힘주기, 단단한대변, 복부불편감, 복부팽만감, 배변후잔변감, 배변시배출장애감등이있다. 5 또한변비환자에서는이차성변비및기질적변비의배제를위한주의깊은과정이필요한데, 자세한병력청취를통해하혈, 체중감소, 대변실금등기질적질환을시사할만한증상이나현재이환되어있는동반질환은없는지, 투약중인약제는어떤것이있는지등에대한문진이필요하다. 일반적으로변비환자들에서증상을유발하는원인을규명할수있거나변비와관련된전신질환들이있는경우를이차성변비라하며, 특히변비를유발하는여러종류의다양한약제들이있으므로이러한점들을충분히염두에두고접근할필요가있다. 이차성변비가배제되면일차성혹은원발성변비로진단할수있으며, 원발성변비는대장통과시간에따라서행형및정상통과시간형변비로구분된다. 정상통과시간형변비가운데항문배출장애가있는경우를출구폐쇄형변비라하며항문경, 골반저근실조, 배변장애등다양한이름으로명명되고있다. 자세한병력청취를통하여해당변비환자가어떤범주에속하는지판단하고, 경고증상없이변비가지속된다면경험적인약물치료를시도해볼수있으나 4-8주정도경험적약물치료에실패한경우에는대장통과시간측정, 항문직장내압검사, 풍선배출검사, 배변조영술등을포함한객관적인진단검사들을시행함으로써병태생리를고려한정확한진단이이루어져야한다. 본고에서는앞서언급한과정을거쳐진단된만성변비의치료에대하여현재임상에서실제사용되고있는약물들위주로살펴보고자하며, 국내에아직시판은되지않았지만우수한효능이입증되어조만간도입될예정인약물들에관해서도임상시험결과위주로언급하고자한다. 본론 1. 생활습관개선및섬유질섭취변비의치료를위해서는약물치료이전에변비증상을유 발할수있는약제를중단하고충분한양의식이섬유를섭취하며, 기상이후또는식사전후에규칙적으로화장실을가는기본적인생활습관의변화도중요하다. 특히배변시에발을들거나좀더낮은변기를사용하는것이도움이될수도있다. 경험적치료는식이섬유의보충부터시작하게된다. 6 식이섬유는과일류, 채소류, 곡물류등에많이함유되어있다. 불용성, 비발효성섬유질은물에잘녹지않기때문에장내세균에의해분해되지않으며몇몇과일이나채소에함유되어있는데, 특히현미나밀겨울등의통곡물에많고, 변의부피를증가시켜장관의이동과분비를촉진한다. 수용성, 발효성섬유질은대장상재균에의해발효되어상재균의성장을촉진함으로써변의부피를크게할뿐아니라, 대장내에서물, 이온과결합하여변을부드럽게하고배변의횟수와대변의양을증가시켜변비를개선시키는데, 장기간사용할경우수용성섬유질의효과가좀더우수하다. 용량이많으면복부불편감이발생하여순응도에영향을미칠수있으므로하루 15-25 g 정도를충분한양의물 (1.5-2 L) 과같이섭취할것을권장한다. 7 심한서행형변비나폐쇄성변비가있는경우에는상대적으로식이섬유의효과가적다. 8,9 하루 50 g 가량의프룬이나 15 g 가량의햄프씨드 (hempseed) 섭취가변비에효과적이었다는보고가있었는데, 주 1회이상의완전자발적배변 (complete spontaneous bowel movement, CSBM) 횟수의증가가있는경우를반응이있는것으로정의하였을때, 대조군의 8.3% 에비해햄프씨드 8주간복용자에서 43.3% 로유의하게높은반응률을보였으며특별한부작용은없었다고보고하였다. 10,11 국내에서도식이섬유의보충이특별한부작용없이변비의증상을호전시키고대장통과시간을단축시킨다는보고가있었는데, 12,13 국내의연구들은소규모단기간연구라는제한점이있기에추후장기간의대규모무작위통제연구가필요하다. 대한소화기기능성질환 운동학회에서는최근위식도역류질환, 기능성소화불량, 과민성장증후군, 만성변비등 4대기능성질환환자들에게도움이되는음식물들에관한자료를조사하여홈페이지에게재하고있으며, 의료인용과환자용으로분리하여상세히설명하고있으므로이질환들에관심이많은의료진이나환자들에게많은도움이될것으로생각한다. 14 2. 부피형성완하제앞서언급한일반적인방법에반응이없을때는완하제치료를고려하여야하는데, 변비치료에이용되는약제는기전에따라부피형성완하제, 삼투성완하제, 자극성완하제, 기타완하제등으로분류할수있다. 15 생활습관개선이나식이섬유사용만으로치료에실패한환자들을대상으로하여다음치료를결정하기위하여이루어진전향적인무작위연구는아 Vol. 70 No. 2, August 2017
66 김상진, 박경식. 만성변비의약물치료 직없으나일반적으로섬유질을농축, 추출또는합성하여제조한약물인부피형성완하제를가장먼저고려해볼수있다. 이약물들은소장에서흡수되지않고대장세균에의해서도분해되지않아수분을유지함으로써장관내대변부피가증가하면서대변양이증가하게된다. 국내시판중인약제로차전자추출물인 Mutacil (Ilyang Pharm Co., Yongin, Korea), Agio (Bukwang Pharm Co., Seoul, Korea) 등과 polycarbophil 이주성분인 Sylcon (Myungmoon Pharm Co., Seoul, Korea), Wellcon (Kuhnil Pharm Co., Seoul, Korea) 등이대표적이다. 이약제들은증상정도에따라각포장단위별 ( 포혹은정 ) 로 1-2단위씩하루 3회까지식전에충분한물과함께복용하여야한다. 이약제들은특별한부작용이드물고안전성이높아임산부에도사용할수있는장점이있으나, 장폐쇄나장협착환자에서이약제들을사용하면변의부피증가로인하여폐쇄증상이더욱심해질수있으므로사용해서는안된다. 3. 삼투성완하제부피형성완하제에효과가나타나지않는경우안정성과가격, 효능등을고려하여삼투성완하제가다음단계의치료로권장되는경우가많다. 1,9,16,17 삼투성완하제는대장내에서흡수되지않는물질로삼투압에의해대장내수분을증가시킴으로써대변을무르게하여배변을돕는데, 염류성완하제와고삼투성완하제로나눌수있다. 7 염류성완하제에는각종인산염및마그네슘염이있으며, 이전해질들은장에서거의흡수되지않아서수분의저류를일으키고장관내압력을증가시켜하제로작용한다. 일반적인성인에서의권장량은수산화마그네슘 2.4-4.8 g이며, 이역시충분한양의물과함께복용하는것이좋다. 그러나과량복용시고마그네슘혈증을일으킬수있으므로신기능부전환자와소아에서는주의하여야한다. 18 고삼투성완하제는다시비흡수성다당류완하제와합성고분자완하제로나눌수있다. 비흡수성다당류완하제에는 lactulose, lactitol, sorbitol 등이있으며, 특히 lactulose가흔히사용되는데, 이물질은갈락토오스와과당의합성이당체로혈중으로흡수되지않아서혈당을높이지않으므로당뇨병환자에서도안전하게사용할수있다. 통상적으로성인에서 15 ml씩하루 2회복용하고, 증상정도에따라용량을조절한다. 단점은대장에서장내세균에의해분해되어가스를생성하므로복부팽만이나방귀를유발할수있다는점이다. 합성고분자완하제로는 polyethylene glycol (PEG) 이대표적인데, 소장에서흡수되지않으므로수분과전해질을분비하게되고, 대변의굳기가떨어지며변의부피가늘어나이차적으로연동운동이발생한다. 19-21 대장내시경이나수술에앞 서장정결을위해사용되고있는대부분의약제들이고용량 PEG를주성분으로한다. 몇몇저용량 PEG는변비치료제로시판되고있으며 PEG 3350 (Movilax ; Pharmbio Korea Inc., Seoul, Korea), macrogel 4000 (Forlax ; Beaufour Ipsen Pharm Co., Paris, France) 등이대표적이다. 부작용으로용량의존적인복부불편감과복통등이있을수있으나 19 6개월이상의장기사용에도비교적안전하였으며, lactulose나위약군에비하여소아및성인변비환자에서우월한효과가입증되었다. 22-25 또한 PEG는소아와노인에서분변매복에대한효과적인치료제인것으로나타났다. 26,27 만성변비환자 500명이상을대상으로이루어진다수의전향적연구에서 PEG를매일투약함으로써배변횟수, 대변굳기및배변시힘주기를개선시켰다. 28 또한 PEG를 24개월이상장기간투여하여도특별한부작용없이안전하고효과적이었다는연구결과도보고되었다. 29 새로운기전의약제인 prucalopride와의비교연구도이루어졌는데, Cinca 등은주당 CSBM 횟수가 3회미만인환자 240명을대상으로하루 PEG 3,350 g 및전해질 26 g 투여 (PEG+E) 군과 prucalopride 1 mg 혹은 2 mg 투약군으로나누어 4주간투약하였고, 4주째주당 CSBM 횟수가 3회이상으로증가한환자의비율이 PEG+E 군에서 66.7%, prucalopride군에서 56.5% 였음을보고하였다. 30 이차결과변수인배변횟수및굳기, 주관적만족도등에있어서도 PEG+E군이 prucalopride군보다유의하게높았음을보고하였지만좀더대규모의연구가필요하다. 4. 자극성완하제자극성완하제는위에서언급한약제들에반응이없는경우사용하게되는데, 이들의정확한기전은확립되어있지않으나대부분수분과전해질의흡수를억제하여장내에축적되게하고, 대장의근육신경총을자극함으로써장운동을촉진하는것으로알려져있다. 임상에서흔히사용되는자극성완하제로 polyphenol 제제 (bisacodyl, phenolphthalein 등 ), anthraquinone 유도체 (cascara, aloe, senna 등 ) 등이있으며연구자들간견해의차이는있으나장기간사용시수분과전해질의손실, 지방변, 2차성고알도스테론혈증, 단백소실장증등을유발할위험성을배제할수없기때문에일반적으로수개월이내의단기간사용을권한다. 31-33 몇몇전향적연구에서는 bisacodyl 및 sodium picosulfate의임상적유용성을입증하였으며, 가장흔한부작용은복통과설사였다. 34,35 변비치료에사용되는다양한약물들의위약대비효과에대한비교를시도한메타분석에서, 주 3회이상의 CSBM 도달정도를일차평가변수로하였을때각약물은유사한효능을보였으며, 특히자극성완하제인 bisacodyl은다른약제들보다기저치대비 CSBM 증가폭에서좀더우월할것으로여겨진다. 36 The Korean Journal of Gastroenterology
Kim SJ and Park KS. Pharmacotherapy in Patients with Chronic Constipation 67 5. 생균제다수의무작위배정전향적연구를포함한한체계적문헌고찰에서생균제가배변횟수를증가시키고변의굳기를호전시키는것으로보고한바있으며, 해당연구들에서사용된균주는 Bifidobacterium lactis DN-173 010, Lactobacillus casei Shirota 그리고 Escherichia coli Nissle 1917 등이었다. 37 최근만성변비환자들의증상개선을위해새로이개발되어시판중인 VSL#3 (Sigma-Tau Health Science USA Inc., Gaithersburg, MD, USA) 의효과를분석한연구가발표되었는데, VSL#3는 Bifidobacterium longum, Bifidobacterium infantis, Bifidobacterium breve, Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus bulgaricus, Lactobacillus plantarum, Streptococcus thermophilus 등의다양한균주들을동결건조하여제조한약제이다. 이연구에서는 VSL#3 을하루 2회씩 2주단기간복용한만성변비환자에서장내세균무리의조성변화와함께변비증상이개선됨을확인하였으나, 38 현재까지장기사용에추천되는용량은하루 1회 1포이다. 이밖에도다양한종류의균주를이용한소규모연구결과들이존재하고긍정적인결과들을보고하고있으나, 다수의연구에서 prebiotics가혼합된 synbiotics의형태로투약이이루어진경우들이많으므로생균제자체의효과로보기어렵고, 아직만성변비에서생균제의작용기전이알려져있지않으며, 후속연구가부족한상황으로만성변비에서생균제의효능을단정하기는이르다고여겨진다. 6. 기타완하제및최신약물 1) 제4형세로토닌수용체 (5-Hydroxytryptamine receptor 4, 5-HT 4 receptor) 작용제 5-HT 4 receptor 작용제는연동운동을자극하고, 위장관통과시간을단축시키며, 장관에서분비를촉진시킨다. 39-41 이그룹에속하는약물들로는 cisapride, tegaserod, prucalopride 등이있으나, cisapride와 tegaserod는드물기는하지만치명적인심혈관계부작용으로인해대부분의국가에서판매되지않고있는실정이다. Prucalopride는현재시판중에있으며, dihydrobenzofurancarboxamide 유도체로다른약제들에비해 5-HT 4 receptor에좀더선택적으로작용하여효능은높이고부작용은줄인약제이다. 전향적연구들에서 prucalopride는배변횟수, 대변굳기, 배변시힘주기등대부분의만성변비증상들이호전되는것으로나타났다. 주당배변횟수가 3회미만이면서과도한힘주기, 단단하거나덩어리진변혹은불완전배변감을호소하는 1,977명의일차성변비환자들을대상으로 12주동안 prucalopride 2 mg 혹은 4 mg 을이중맹검하에투약한후일차평가변수로주당 CSBM 횟수가 3회이상으로증가한환자들의비율을측정한연구에서위약군의 11% 에비해서 prucalopride 2 mg군 23.6%, 4 mg군 24.7% 에서주당 CSBM 횟수가 3회이상으로정상화되었다. 42-44 이차평가변수인주당 CSBM 횟수가 1회이상증가한비율, 주당평균 CSBM 횟수, 대변의굳기, 첫 CSBM까지소요된시간, 구제약물필요성, 잔변감정도, 환자만족도, 배변의만족도, 삶의질향상정도등대부분의측정변수에서위약에비해유의한개선효과를보였다. 가장많은부작용은두통, 오심, 설사였으며, 대부분치료시작 24시간이내에발생하는경향을나타내었다. 42-44 이약제는최초임상시험이대부분여성에서이루어짐으로써여성변비환자에서허가를받았지만남성을대상으로이루어진임상시험이완료됨으로써현재는남성에서도급여처방이가능하다. Prucalopride 외에 5-HT 4 receptor 작용제로개발이시도되었던약물로서 quinolone 계열의 velusetrag이있는데, 2010년 4주간의무작위배정대조군연구에서효과를입증하였으나 45 추가적인연구가없는상황이다. 이에비해 prucalopride는앞서언급한 3개의대규모연구이후에도다양한지역에서추가적인무작위배정대조군연구들을통해효과를확인하였고, 46 현재에도 systemic sclerosis와연관된소화기증상치료등 47 다양한영역으로의확장을추구하고있다. 2) 제2형염소통로 (type 2 chloride channel, ClC-2) 작용제 ClC-2는장상피세포의내강측세포막에위치하며, 활성화되면 chloride와함께수분을내강으로분비하게된다. Lubiprostone 은강력한 ClC-2 작용제로서장내강내의염소및수분함량을높임으로써장통과시간을단축시키는약제이며, 미국에서는시판중이지만국내에는아직도입되어있지않다. 만성변비환자들을대상으로 lubiprostone 24 μg을 1일 2회 4주간투약하였을때주당 CSBM, 힘주기, 단단한변, 변비에대한전반적인효능평가에서유의한개선효과를나타내었다. 48 상기연구결과를토대로 lubiprostone 24 μg 1일 2회투약은만성변비치료제로미국식품의약국 (US Food and Drug Administration, FDA) 승인을받았다. 이후 Lembo 등은 248 명의환자를대상으로 48주간장기추적연구를시행하였는데, 33명 (13.3%) 의환자가약물이상반응때문에치료를중단하였고, 이약물과관련된이상반응으로구역 (19.8%), 설사 (9.7%), 복부팽만 (6.9%) 및두통 (6.9%) 등을보고하였다. 49 또한이상반응의중증도에따라서감량을허용하였음에도불구하고 48주의투약을완료한환자가 51% 에불과하였으므로, 49 이는만성변비환자에서 lubiprostone 1일 48 μg 장기간투약의내약성에대한추가연구가필요함을시사한다. 변비형과민성장증후군환자 1,171명을대상으로이루어 Vol. 70 No. 2, August 2017
68 김상진, 박경식. 만성변비의약물치료 진한 3상연구에서 lubiprostone 8 μg을 1일 2회 4주간투약하였을때복통및복부불편감에대한전반적인치료반응률이 17.9% 로, 위약의 10.1% 에비해유의한개선효과및위약과대등한안전성을보였다. 50 이환자들을대상으로 9-13개월간장기추적하였을때에도 lubiprostone의안전성및유효성이보고된바있지만, 50 중도탈락률이 40% 를상회하였고, 이상반응에의한경우를제외하면탈락사유의 50% 이상이효능부족이었다. 이는 lubiprostone이내장감각과민성을개선시키지못하는것에기인한것으로여겨진다. 최근일본에서이루어진유사한디자인의연구에서첫주의 CSBM은위약 1.3회대비 prucalopride군 3.7회로유의하게높았고, 설사 (14.5%), 구역 (14.5%) 정도의부작용을보였으나, 48주간장기추적결과설사 (37.3%), 구역 (27.3%) 등의부작용발생비율이높게나타났으며, 중도탈락자도 46명으로장기간의복용에는순응도가높지않은것으로보인다. 51 FDA는변비형과민성장증후군환자에서 lubiprostone 8 μg, 1일 2회사용을승인하였지만, 장기간처방의효용성에대하여는추가연구가필요하다. 자를대상으로하루에 1회 3 mg, 6 mg을 12주간투약하고위약군과비교하였을때 3 mg, 6 mg군모두위약군에비하여유의한 CSBM의향상이있었다. 부작용으로는설사가 3 mg 군 5.9%, 6 mg군 5.7% 정도로가장흔하게발생하였다. 56 이와같은연구결과를토대로이약제역시 FDA로부터승인을받고미국에서 Trulance (Synergy Pharm co., New York, NY, USA) 라는상품명으로시판되고있다. 4) 담즙산수송체 (bile acid transporters) 억제제 Elobixibat은비흡수성의작은분자로, 회장말단부의담즙산수송체를억제하는약제이다. 정상적으로담즙산은 95% 이상이회장말단부에서재흡수되는데, 일부재흡수되지않은담즙산은대장으로이동하여연동운동을촉진시키며, adenylate cyclase를활성화시켜대장점막의투과성을높임으로써배변을촉진하게된다. 한임상시험에서여성만성변비환자 36명을대상으로 1일 1회 2주간투약하였을때대장통과시간을단축시키고, 대변굳기, 배변횟수및과도한힘주기등의증상이개선되었다. 57 190명의만성변비환자를대상으 3) Guanylate cyclase-c (GC-C) 작용제 GC-C는장상피세포및장관신경세포에서발현된다. 장상피세포의내강측세포막에존재하는 GC-C가활성화되면세포내 cgmp 농도가상승하고, cgmp는다시이온채널인 cystic fibrosis transmembrane conductance regulator (CFTR) 를통하여중탄산염및염소배출을촉진시키며, 장관내강과체액간의전해질및삼투질농도차이에의하여세포간극을통한나트륨및수분배출이증가하게된다. 52 GC-C 작용제인 linaclotide 역시미국에서는시판중에있지만국내에는아직도입되지않았다. 변비형과민성장증후군환자 1,604명을대상으로이루어진두개의 3상연구에서 linaclotide는복통, 복부불편감, 팽만감, 과도한힘주기등의증상개선과함께배변횟수도유의하게증가시켰다. 53,54 복통및복부불편감개선은 linaclotide 290 μg을 1일 1회투약한군에서위약군과비교하여 12주투약후 37.0% 와 18.5%, 26 주투약후에는 37.2% 와 16.9% 로유의한차이를보였다. 55 이결과를바탕으로 2012년변비형과민성장증후군및만성변비를적응증으로 FDA 승인을받았다. 2015년발표된최근연구는 487명의환자를대상으로 12주간위약군 (173명), linaclotide 145 μg군 (154명), linaclotide 290 μg군 (160명) 으로나누어비교한연구인데, 위약군에서의치료반응은 7.6% 였으나 linaclotide 145 μg군 15.7%, 290 μg군에서는 16.4% 로위약군에비하여유의한차이가있었다. 또다른 GC-C 작용제인 plecanatide에대한대규모 3상연구결과가최근발표되었는데, 이연구에서는 1,394명의환 Table 1. Summary of Management in Patients with Constipation Classification by mechanism Life style change Trial of regular defecation Dietary fiber Bulk-forming laxatives Psyllium Polycarbophil Osmotic laxatives Salts laxatives Magnecium salts Hyperosmolar laxatives Nonabsorbable polysaccharides Lactulose Lactitol Synthetic polymer PEG Stimulant laxatives Anthraquinone Aloe Senna Polyphenol or Diphenylmethane Phenophthalein Bisacodyl Probiotics Others 5-HT 4 agonist Type 2 chloride channel activator Guanylate cyclase-c agonist Bile acid uptake inhibitor Examples Brown rice, Bran Mutacil, Agio Sylcon, Wellcon Magmil Duphalac, Ctri-lactitol Forlax, Movilax HT, hydroxytryptophan; PEG, polyethylene glycol. a Not commercially available in Korea. Alaxyl (Senna+psyllium) Dulcolax, Duolax VSL#3, Mutaflor Prucalopride (Resolor ) a Lubiprostone (Amitiza ) a Linaclotide (Linzess ) a Plecanatide (Trulance ) a Elobixibat (under clinical trial) a The Korean Journal of Gastroenterology
Kim SJ and Park KS. Pharmacotherapy in Patients with Chronic Constipation 69 로이루어진 2상연구에서는위약, elobixibat 5 mg, 10 mg, 15 mg군으로무작위배정한후 8주간 1일 1회투약하였는데, 10 mg 및 15 mg 투약군에서위약군과비교하여첫주부터배변횟수및변비증상을개선시켰고, 8주간의투약기간전반에걸쳐효과가지속되었다. 가장흔한부작용은복통과설사였으며, 용량의존적이었다. 58 현재이약제의유효성및안전성을검증하는 3상연구가진행중에있어결과가기대된다. 결 론 본고에서는만성변비의임상진료에서흔히쓰이는치료약제및개발중인변비치료약제전반에관하여살펴보았으며, 이는 Table 1에요약하였다. Lubiprostone, linaclotide, plecanatide 등변비가발생하는병태생리를고려하여최근에개발된약제들이현재까지국내에는도입되지않고있으며, prucalopride나비교적효능이우수한몇몇 PEG 약제들이시판되고는있으나의료보험적용이되지않음에따른비용문제등국내의진료실정에서적절한변비치료약제의사용에는많은제한이있다. 현재는국내의료자원의배분이악성종양이나혈관성질환등의중증질환에치우쳐있는경향이있으나, 만성변비또한환자의삶의질에심각한장애를초래할수있으므로이러한점들을극복하기위한많은노력이필요하리라여겨진다. REFERENCES 1. Suares NC, Ford AC. Prevalence of, and risk factors for, chronic idiopathic constipation in the community: systematic review and meta-analysis. Am J Gastroenterol 2011;106:1582-1591. 2. Jeong JJ, Choi MG, Cho YS, et al. Chronic gastrointestinal symptoms and quality of life in the Korean population. World J Gastroenterol 2008;14:6388-6394. 3. Jun DW, Park HY, Lee OY, et al. A population-based study on bowel habits in a Korean community: prevalence of functional constipation and self-reported constipation. Dig Dis Sci 2006;51: 1471-1477. 4. Mearin F, Lacy BE, Chang L, et al. Bowel disorders. Gastroenterology 2016;150:1393-1407.e5. 5. Johanson JF, Kralstein J. Chronic constipation: a survey of the patient perspective. Aliment Pharmacol Ther 2007;25:599-608. 6. Moayyedi P, Quigley EM, Lacy BE, et al. The effect of fiber supplementation on irritable bowel syndrome: a systematic review and meta-analysis. Am J Gastroenterol 2014;109:1367-1374. 7. Lembo A, Camilleri M. Chronic constipation. N Engl J Med 2003; 349:1360-1368. 8. Bharucha AE, Pemberton JH, Locke GR 3rd. American Gastroenterological Association technical review on constipation. Gastroenterology 2013;144:218-238. 9. Ford AC, Moayyedi P, Lacy BE, et al. American College of Gastro- enterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol 2014;109 Suppl 1:S2-S26; quiz S27. 10. Attaluri A, Donahoe R, Valestin J, Brown K, Rao SS. Randomised clinical trial: dried plums (prunes) vs. psyllium for constipation. Aliment Pharmacol Ther 2011;33:822-828. 11. Cheng CW, Bian ZX, Zhu LX, Wu JC, Sung JJ. Efficacy of a Chinese herbal proprietary medicine (hemp seed pill) for functional constipation. Am J Gastroenterol 2011;106:120-129. 12. Kim JY, Kim OY, Yoo HJ, et al. Effects of fiber supplements on functional constipation. Korean J Nutr 2006;39:35-43. 13. Kim TI, Park SJ, Choi CH, Lee SK, Kim WH. Effect of ear mushroom (auricularia) on functional constipation. Korean J Gastroenterol 2004;44:34-41. 14. Food guide for the patients with functional gastrointestinal diorders. [Internet]. Seoul: The Korean Society of Neurogastroenterology and Motility; 2017 May 25 [cited 2017 Jun 15]. Available from: http://www.ksgm.org/ 15. Bouras EP, Tangalos EG. Chronic constipation in the elderly. Gastroenterol Clin North Am 2009;38:463-480. 16. Lederle FA, Busch DL, Mattox KM, West MJ, Aske DM. Cost-effective treatment of constipation in the elderly: a randomized double-blind comparison of sorbitol and lactulose. Am J Med 1990; 89:597-601. 17. Chey WD. The role of food in the functional gastrointestinal disorders: introduction to a manuscript series. Am J Gastroenterol 2013;108:694-697. 18. Xing JH, Soffer EE. Adverse effects of laxatives. Dis Colon Rectum 2001;44:1201-1209. 19. Klauser AG, Voderholzer WA, Heinrich CA, Schindlbeck NE, Müller-Lissner SA. Behavioral modification of colonic function. Can constipation be learned? Dig Dis Sci 1990;35:1271-1275. 20. Hobbis IC, Turpin G, Read NW. Abnormal illness behaviour and locus of control in patients with functional bowel disorders. Br J Health Psychol 2003;8(Pt 4):393-408. 21. Ashraf W, Park F, Lof J, Quigley EM. An examination of the reliability of reported stool frequency in the diagnosis of idiopathic constipation. Am J Gastroenterol 1996;91:26-32. 22. Voskuijl W, de Lorijn F, Verwijs W, et al. PEG 3350 (transipeg) versus lactulose in the treatment of childhood functional constipation: a double blind, randomised, controlled, multicentre trial. Gut 2004;53:1590-1594. 23. Attar A, Lémann M, Ferguson A, et al. Comparison of a low dose polyethylene glycol electrolyte solution with lactulose for treatment of chronic constipation. Gut 1999;44:226-230. 24. Chaussade S, Minić M. Comparison of efficacy and safety of two doses of two different polyethylene glycol-based laxatives in the treatment of constipation. Aliment Pharmacol Ther 2003;17: 165-172. 25. Dipalma JA, Cleveland MV, McGowan J, Herrera JL. A randomized, multicenter, placebo-controlled trial of polyethylene glycol laxative for chronic treatment of chronic constipation. Am J Gastroenterol 2007;102:1436-1441. 26. Culbert P, Gillett H, Ferguson A. Highly effective new oral therapy for faecal impaction. Br J Gen Pract 1998;48:1599-1600. 27. Chen CC, Su MY, Tung SY, Chang FY, Wong JM, Geraint M. Vol. 70 No. 2, August 2017
70 김상진, 박경식. 만성변비의약물치료 Evaluation of polyethylene glycol plus electrolytes in the treatment of severe constipation and faecal impaction in adults. Curr Med Res Opin 2005;21:1595-1602. 28. Ford AC, Suares NC. Effect of laxatives and pharmacological therapies in chronic idiopathic constipation: systematic review and meta-analysis. Gut 2011;60:209-218. 29. Migeon-Duballet I, Chabin M, Gautier A, et al. Long-term efficacy and cost-effectiveness of polyethylene glycol 3350 plus electrolytes in chronic constipation: a retrospective study in a disabled population. Curr Med Res Opin 2006;22:1227-1235. 30. Cinca R, Chera D, Gruss HJ, Halphen M. Randomised clinical trial: macrogol/peg 3350+electrolytes versus prucalopride in the treatment of chronic constipation -- a comparison in a controlled environment. Aliment Pharmacol Ther 2013;37:876-886. 31. Ikarashi N, Baba K, Ushiki T, et al. The laxative effect of bisacodyl is attributable to decreased aquaporin-3 expression in the colon induced by increased PGE2 secretion from macrophages. Am J Physiol Gastrointest Liver Physiol 2011;301:G887-G895. 32. Schang JC, Hémond M, Hébert M, Pilote M. Changes in colonic myoelectric spiking activity during stimulation by bisacodyl. Can J Physiol Pharmacol 1986;64:39-43. 33. Frexinos J, Staumont G, Fioramonti J, Bueno L. Effects of sennosides on colonic myoelectrical activity in man. Dig Dis Sci 1989; 34:214-219. 34. Mueller-Lissner S, Kamm MA, Wald A, et al. Multicenter, 4-week, double-blind, randomized, placebo-controlled trial of sodium picosulfate in patients with chronic constipation. Am J Gastroenterol 2010;105:897-903. 35. Kamm MA, Mueller-Lissner S, Wald A, Richter E, Swallow R, Gessner U. Oral bisacodyl is effective and well-tolerated in patients with chronic constipation. Clin Gastroenterol Hepatol 2011;9:577-583. 36. Nelson AD, Camilleri M, Chirapongsathorn S, et al. Comparison of efficacy of pharmacological treatments for chronic idiopathic constipation: a systematic review and network meta-analysis. Gut 2016 Jun 10. pii: gutjnl-2016-311835. [Epub ahead of print] 37. Chmielewska A, Szajewska H. Systematic review of randomised controlled trials: probiotics for functional constipation. World J Gastroenterol 2010;16:69-75. 38. Kim SE, Choi SC, Park KS, et al. Change of fecal flora and effectiveness of the short-term VSL#3 probiotic treatment in patients with functional constipation. J Neurogastroenterol Motil 2015; 21:111-120. 39. Prather CM, Camilleri M, Zinsmeister AR, McKinzie S, Thomforde G. Tegaserod accelerates orocecal transit in patients with constipation-predominant irritable bowel syndrome. Gastroenterology 2000;118:463-468. 40. Bouras EP, Camilleri M, Burton DD, Thomforde G, McKinzie S, Zinsmeister AR. Prucalopride accelerates gastrointestinal and colonic transit in patients with constipation without a rectal evacuation disorder. Gastroenterology 2001;120:354-360. 41. Grider JR, Foxx-Orenstein AE, Jin JG. 5-hydroxytryptamine4 receptor agonists initiate the peristaltic reflex in human, rat, and guinea pig intestine. Gastroenterology 1998;115:370-380. 42. Tack J, van Outryve M, Beyens G, Kerstens R, Vandeplassche L. Prucalopride (resolor) in the treatment of severe chronic constipation in patients dissatisfied with laxatives. Gut 2009;58: 357-365. 43. Quigley EM, Vandeplassche L, Kerstens R, Ausma J. Clinical trial: the efficacy, impact on quality of life, and safety and tolerability of prucalopride in severe chronic constipation--a 12-week, randomized, double-blind, placebo-controlled study. Aliment Pharmacol Ther 2009;29:315-328. 44. Camilleri M, Kerstens R, Rykx A, Vandeplassche L. A placebo-controlled trial of prucalopride for severe chronic constipation. N Engl J Med 2008;358:2344-2354. 45. Goldberg M, Li YP, Johanson JF, et al. Clinical trial: the efficacy and tolerability of velusetrag, a selective 5-HT4 agonist with high intrinsic activity, in chronic idiopathic constipation - a 4-week, randomized, double-blind, placebo-controlled, dose-response study. Aliment Pharmacol Ther 2010;32:1102-1112. 46. Yiannakou Y, Piessevaux H, Bouchoucha M, et al. A randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy, safety, and tolerability of prucalopride in men with chronic constipation. Am J Gastroenterol 2015;110:741-748. 47. Vigone B, Caronni M, Severino A, et al. Preliminary safety and efficacy profile of prucalopride in the treatment of systemic sclerosis (SSc)-related intestinal involvement: results from the open label cross-over PROGASS study. Arthritis Res Ther 2017;19:145. 48. Johanson JF, Morton D, Geenen J, Ueno R. Multicenter, 4-week, double-blind, randomized, placebo-controlled trial of lubiprostone, a locally-acting type-2 chloride channel activator, in patients with chronic constipation. Am J Gastroenterol 2008;103: 170-177. 49. Lembo AJ, Johanson JF, Parkman HP, Rao SS, Miner PB Jr, Ueno R. Long-term safety and effectiveness of lubiprostone, a chloride channel (ClC-2) activator, in patients with chronic idiopathic constipation. Dig Dis Sci 2011;56:2639-2645. 50. Johanson JF, Drossman DA, Panas R, Wahle A, Ueno R. Clinical trial: phase 2 study of lubiprostone for irritable bowel syndrome with constipation. Aliment Pharmacol Ther 2008;27:685-696. 51. Fukudo S, Hongo M, Kaneko H, Takano M, Ueno R. Lubiprostone increases spontaneous bowel movement frequency and quality of life in patients with chronic idiopathic constipation. Clin Gastroenterol Hepatol 2015;13:294-301.e5. 52. Vaandrager AB. Structure and function of the heat-stable enterotoxin receptor/guanylyl cyclase C. Mol Cell Biochem 2002;230: 73-83. 53. Chey WD, Lembo AJ, Lavins BJ, et al. Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, doubleblind, placebo-controlled trial to evaluate efficacy and safety. Am J Gastroenterol 2012;107:1702-1712. 54. Rao S, Lembo AJ, Shiff SJ, et al. A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol 2012;107:1714-1724; quiz p.1725. 55. Quigley EM, Tack J, Chey WD, et al. Randomised clinical trials: linaclotide phase 3 studies in IBS-C - a prespecified further analysis based on European Medicines Agency-specified endpoints. Aliment Pharmacol Ther 2013;37:49-61. 56. Miner PB Jr, Koltun WD, Wiener GJ, et al. A randomized phase III The Korean Journal of Gastroenterology
Kim SJ and Park KS. Pharmacotherapy in Patients with Chronic Constipation 71 clinical trial of plecanatide, a uroguanylin analog, in patients with chronic idiopathic constipation. Am J Gastroenterol 2017;112: 613-621. 57. Wong BS, Camilleri M, McKinzie S, Burton D, Graffner H, Zinsmeister AR. Effects of A3309, an ileal bile acid transporter inhibitor, on colonic transit and symptoms in females with functional constipation. Am J Gastroenterol 2011;106:2154-2164. 58. Chey WD, Camilleri M, Chang L, Rikner L, Graffner H. A randomized placebo-controlled phase IIb trial of a3309, a bile acid transporter inhibitor, for chronic idiopathic constipation. Am J Gastroenterol 2011;106:1803-1812. Vol. 70 No. 2, August 2017