대한내과학회지 : 제 88 권제 1 호 2015 http://dx.doi.org/10.3904/kjm.2015.88.1.1 특집 (Special Review) - Laxatives 제대로알기 전통적완하제 1 부산대학교의과대학내과학교실, 2 순천향대학교의과대학소화기연구소, 3 이화여자대학교의학전문대학원내과학교실, 4 계명대학교의과대학내과학교실, 5 전남대학교의과대학내과학교실, 6 단국대학교의과대학내과학교실, 7 울산대학교의과대학소화기내과학교실, 8 원광대학교의과대학내과학교실및소화기질환연구소, 9 서울대학교의과대학내과학교실, 10 성균관대학교의과대학내과학교실 이봉은 1 ㆍ이태희 2 ㆍ김성은 3 ㆍ박경식 4 ㆍ박선영 5 신정은 6 ㆍ정기욱 7 ㆍ최석채 8 ㆍ홍경섭 9 ㆍ홍성노 10 ; 대한소화기기능성질환ㆍ운동학회변비및항문직장기능연구회 Conventional Laxatives Bong Eun Lee 1, Tae Hee Lee 2, Seong-Eun Kim 3, Kyung Sik Park 4, Seon-Young Park 5, Jeong Eun Shin 6, Kee Wook Jung 7, Suck Chei Choi 8, Kyoung Sup Hong 9, Sung Noh Hong 10 ; and Constipation Research Group of the Korean Society of Neurogastroenterology and Motility 1 Department of Internal Medicine, Pusan National University School of Medicine, Busan; 2 Institute for Digestive Research, Soonchunhyang University College of Medicine, Seoul; Department of Internal Medicine, 3 Ewha Womans University School of Medicine, Seoul; 4 Keimyung University School of Medicine, Daegu; 5 Chonnam National University Medical School, Gwangju; 6 Dankook University College of Medicine, Cheonan; 7 Department of Gastroenterology, University of Ulsan College of Medicine, Seoul; 8 Department of Internal Medicine and Digestive Disease Research Institute, Wonkwang University School of Medicine, Iksan; Department of Internal Medicine, 9 Seoul National University College of Medicine, Seoul; 10 Sungkyunwan University School of Medicine, Seoul, Korea Based on published guidelines on the management of chronic constipation, secondary causes should be excluded and then patients should be told to increase their dietary fiber intake to 20-25 g per day. If these measures do not improve the symptoms, conventional laxatives are generally the next choice. Although there is limited evidence for the efficacy of these older laxatives due to a lack of well-designed clinical trials, most clinicians agree that they are effective at relieving the symptoms of constipation. Conventional laxatives include bulk-forming, osmotic, and stimulant laxatives. Bulking laxatives consist of fiber such as psyllium, cellulose, and bran. Osmotic laxatives are classified into sugar-based laxatives and polyethylene glycol. Bisacodyl and sodium picosulfate are stimulant laxatives. Understanding their mechanisms of action, efficacy, and side effects might improve the quality of life of patients suffering from chronic constipation. (Korean J Med 2015;88:1-8) Keywords: Constipation; Laxatives Correspondence to Tae Hee Lee, M.D., PhD. Institute for Digestive Research, Soonchunhyang University College of Medicine, 53 Daesagwan-ro, Yongsan-gu, Seoul 140-743, Korea Tel: +82-2-709-9691, Fax: +82-2-709-9696, E-mail: iman0825@naver.com Copyright c 2015 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution - 1 - Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
- The Korean Journal of Medicine: Vol. 88, No. 1, 2015 - 서론만성변비는유병률이지역인구의 14% 로보고된흔한질환이고 [1] 생명과연계된중증질환은아니지만증상으로인한불편감이삶의질저하로이어질수있기때문에식생활습관에대한환자교육과적절한약제의사용이중요하다. 만성변비환자가내원하면기질적인질환및이차적인원인에대한평가가이루어지며, 변비증상완화를위한첫단계로생활습관및식생활개선이시도된다. 하지만증상호전이없는경우에는약제투여가필요하며, 적절한약제를선택하고병합하기위해서는각약제의작용기전및부작용을알고효과를예측하는것이필요하다. 본고에서는만성변비의일차치료약제로전통적으로사용되고있는부피형성완하제, 삼투성완하제, 자극성완하제에대한내용을정리하였다. 본론부피형성완하제 (bulk forming laxatives) 부피형성완하제는식이섬유를이용하여만든약제로소장에서흡수되지않고장내수분을흡수하여장관내대변부피및대변량을증가시켜대장통과시간을단축시키고대변을부드럽게하여변이쉽게배출될수있도록도와준다 [2]. 부피형성완하제에는차전자 (psyllium, ispaghula, plantago seed), 해초, 한천 (agar), 카라야 (karaya, plant gums), 메틸셀룰 로오스 (methylcellulose) 유도체및칼슘폴리카르보필 (calcium polycarbophil) 등이있으며, 국내에서주로사용중인약제를표 1에정리하였다 [3]. 아락실 과같은부피형성완하제의일부는센나 (senna) 와같은자극성완하제가복합되어있으므로주의해서처방해야하며, 장기간사용은피하는것이바람직하다. 변비환자에서하루평균 20-25 g 정도의식이섬유섭취가권장되는데 [4], 특히정상통과형변비 (normal transit constipation) 환자에게효과적이며일상에서식이섬유를충분히섭취하지못하는환자에서도부피형성완하제가유용할것으로생각된다. 부작용이거의없어임산부를비롯한변비환자에서안전하게사용할수있다. 부작용으로는장내세균에의해대사되어이산화탄소나수소와같은가스를형성하여복부팽만감이나다량의방귀를유발할수있으므로장협착이나장폐쇄환자에서는증상을악화시킬수있어주의가필요하다. 약제로인한복부불편감을줄이고복용순응도를높이기위해서는 1-2주정도의기간동안적정용량까지점차적으로약제를증량하고, 충분한양의물과함께복용시키는것이중요하다. 복용후약제의효능이 12-72시간후에나타나므로몇주정도의시간이소요될수있음을환자에게설명하는것이필요하다. 우리나라변비혹은변비우세형과민성장증후군환자에게 psyllium이주성분인아기오 18 g을매일 3주간투여했을때변비와관련된증상이호전되고대장통과시간도단축되었다 [5]. 삼투성완하제인락툴로오스 (lactulose) 와마그네 Table 1. Bulk forming laxatives Contents Drugs Detailed contents (/1 pack or tablet) Daily recommended dose Adverse effects Psyllium Mutacil Psyllium 3.25 g/4 g 1 P one to three times Abdominal cramps, constipation, diarrhea, esophageal or bowel obstruction Agio Psyllium 4.08 g/6 g 1-2 P once or twice Alaxyl Psyllium 2.17 g + Senna 0.47 g/4 g 1-2 P once or twice Calcium polycarbophil Sylcon Wellcon Calcium polycarbophil 625 mg 2 T one to four times Abdominal fullness P, pack; T, tablet. Contraindications Hypersensitivity to psyllium or any component of the formulation, fecal impaction, gastrointestinal obstruction - 2 -
- Bong Eun Lee, et al. Conventional laxatives - Table 2. Osmotic laxatives Contents Drugs Daily recommended dose Adverse effects Contraindications Saline laxatives Magnesium hydroxide Hyperosmolar laxatives Lactulose Lactitol PEG a Single: Magmil, Manomil, Marogel, et al (500 mg/t) Combination with Aloe: Madinol, Maroel, Maelline, Magnol, et al (MGO 500 mg/t) Duphalac-easy Syr. (15 ml/p), Monilac-S Syr. (500 ml/b) Potalac Syr. (10 ml/p), Potalac Powd. (20 g/p) Forlax Powd. (PEG4000 10 g/p), Dulcolax balance Powd. (PEG4000 10 g/p), Mylax Powd. (PEG3350 17 g/p) Movilax Powd. (PEG3350 + electrolytes 13.125 g/p) 1-2 g in 1 or 2 divided doses 1-2 g in 1 or 2 divided doses Hypermagnesemia 15-45 ml Abdominal discomfort, abdominal distention, belching, cramping, diarrhea (excessive 15-30 ml (10-20 g) dose), flatulence, nausea, vomiting 10-20 g Abdominal bloating, cramping, diarrhea, flatulence, nausea Hypersensitivity to magnesium or any component of the formulation, renal impairment, neuromuscular diseases Patients requiring a low galactose diet Hypersensitivity to PEG or any component of the formulation T, tablet; MGO, magnesium hydroxide; Syr., syrup; P, pack; B, bottle; Powd.; powder; PEG, polyethylene glycol. a PEG is so metabolically inert that is less likely to cause gastrointestinal-related adverse effects than the lactulose or lactitol. 슘염제제 (magnesium sulafate) 와의비교연구에서도 ispaghula 를복용한군에서배변의형태가좋아지고대장통과시간이단축되었으며, 대변지림, 복부통증및설사등의부작용이적었다 [6]. 차전자를제외한부피형성완하제는효과를뒷받침할연구결과는충분하지않으나많이사용되고있으며, 그중합성섬유소인칼슘폴리카르보필은차전자와의교차연구에서복용 3주동안배변의빈도, 형태, 용이성정도에서동일한효과를보여주었다 [7]. 국내변비치료에관한임상진료지침에서부피형성완하제는변비의치료에효과적이라고제시하고있다 ( 권고수준 : 높음, 증거수준 : 높음 ) [2]. 삼투성완하제 (osmotic laxatives) 삼투성완하제는삼투성의활성이온이나분자로서장관에서흡수되지않고삼투압에의해체내수분을장관내로이동하게하여장내수분을증가시켜배변을용이하게도와주는효과적인변비치료제이다. 약제투여시수분의손실을 막고균형을유지하기위해서수분을충분히섭취하는것이중요하다. 삼투성완하제는크게염류성완하제 (salts laxatives) 와고삼투성완하제 (hyperosmolar laxatives) 로나뉜다 (Table 2). 염류성완하제 (saline laxatives) 염류성완하제는마그네슘염과나트륨염으로나뉘며, 마그네슘염에는수산화마그네슘, 구연산마그네슘, 황산마그네슘등이있고, 나트륨염으로는인산나트륨이있다. 염류성완하제는복용 30분-3시간후비교적빠르게효과가나타난다. 수산화마그네슘이대표적으로처방되는마그네슘염제제로성인의일반권장량은하루 2.4-4.8 g이다. 마그네슘염의경우과량복용시고마그네슘혈증을일으킬수있어신기능부전환자에서는사용하지않는것이바람직하며, 소아에서투여시에도주의가필요하다. 마그네슘염제제의경우도알로에 (aloe) 와같은자극성완하제와복합된약제가많이시판되고있으므로성분을확인한후처방해야한다. 인산나트륨은고인산혈증, 저칼슘혈증, 저칼륨혈증등을일으 - 3 -
- 대한내과학회지 : 제 88 권제 1 호통권제 653 호 2015 - 킬수있고드물게급성인산신병증을유발할수있어서현재는거의사용되고있지않다 [8,9]. 염류성완하제에대한위약대조군연구는거의없으나, 복용이편하고복용후불편감이거의없어많이사용되고있다. 국내임상진료지침에서마그네슘제제는변비의치료에효과적이라고제시하였으며 ( 권고수준 : 높음, 증거수준 : 낮음 ), 경도또는중등도의변비환자에서장기간효과적으로투여할수있겠다 [2]. 고삼투성완하제 (hyperosmolar laxatives) 고삼투성완하제는크게비흡수성다당류완하제와합성고분자 (synthetic macromolecule) 인폴리에틸렌글리콜 (polypethyleneglycol, PEG) 로분류된다. 비흡수성다당류완하제에는락툴로오스 (lactulose), 락티톨 (lactitol), 소르비톨 (sorbitol), 글리세린 (glycerine) 등이있다. 락툴로오스는갈락토오스 (galactose) 와과당 (fructose) 의합성이당체로소장에서흡수되지않고대장에서세균에의해대사되어대장을자극하는산을생성하고장내삼투압과산도를높여변에수분을축적시키고변을부드럽게하는효과가있다. 대장에서세균에의해발효되는과정에서장내가스를형성하기때문에복부팽만이나방귀를일으킬수있다. 하지만그외중대한부작용이없는안전한약제로장기간복용이가능하며노인, 소아및임산부에게도안전하게처방할수있다. 혈중으로흡수되지않기때문에당뇨병환자의변비치료에도유용한데맛이달아서복용을어려워하는환자도있다. 성인에서하루일반권장량은 15-60 ml로복용 24-48시간이후에효과가나타나게되며, 초기적은양으로시작하여점차적으로약제를증량하는것이설사와같은부작용을예방할수있다. 락툴로오스는만성변비환자 150명에대한두개의무작위대조군연구 [10,11] 와 opiate와연관되어발생한 57명의변비환자에대한무작위대조군연구 [12] 에서배변횟수의정상화와대변굳기의호전을보였다. 우리나라의소규모단기간연구에서도변비환자에게 7일간락툴로오스를투여했을때대장통과시간이빨라지고변비증상이개선되었다 [13]. 비흡수성다당류완하제는우리나라에서임상적으로널리사용되고있으며, 국내임상진료지침에서비흡수성다당류완하제는변비의치료에효과적이라고제시하였다 ( 권고수준 : 높음, 증거수준 : 높음 ) [2]. 합성고분자인 PEG는대장내시경의전처치약제로널리사용되고있는약제로변비치료제로서는 PEG 3350 ( 마이락 스산, 모비락스산 ) 과 macrogel 4000 ( 폴락스산, 둘코락스발란스산 ) 이국내에서시판되고있다. PEG는장내세균에의해대사되지않기때문에비흡수성다당류완하제보다헛배부름이나방귀증세가덜하며, 매우안전하게사용할수있는약제로장기간복용이가능하고노인, 소아및임산부에게도처방이가능하다. 드물게과량복용시전해질및수분저류가일어날수있으므로신장및심장기능이저하된경우에는사용에주의가필요하다. 복용후 1-4일째효과가나타나며하루 13-39 g으로용량을조절할수있다. 500명이상의만성변비환자를대상으로한 9개의잘설계된연구 [12,14-21] 에서 PEG 투여는배변횟수, 대변굳기, 배변시힘주기를개선시키고다른하제를중단하게할수있었으며, 6개월동안투여해도부작용이없었음을보고했다. PEG와락툴로오스의효과를비교한 137명의변비환자를대상으로했던무작위대조군시험에서는 PEG가배변횟수, 배변시힘주기, 환자만족도, 부작용등에서더나았음을보고하였으며 [22], 10개의위약대조군연구를종합하여분석한 Cochrane systematic review에서도 PEG가락툴로오스보다더나은효과를보였다 [23]. 우리나라소아변비환자를대상으로 6개월이상 PEG를투여했을때심각한부작용은관찰되지않았다 [24]. 국내임상진료지침에서 PEG는변비의치료에효과적이라고제시하였다 ( 권고수준 : 높음, 증거수준 : 높음 ) [2]. 자극성완하제 (stimulant laxatives) 자극성완하제의작용기전은정확하게알려져있지는않지만대장내에서수분및전해질의흡수를억제하고대장의근육신경총을자극하여장운동을촉진하는것으로알려져있다. 자극성완하제로는디하이드로콜린산 (dehydrocholic acid), 피마자기름 (castor oil), 도큐세이트 (docusate) 와같은계면활성제 (surfactant laxatives) 와센나나알로에, 카스카라 (cascara) 와같은안트라퀴논 (anthraquinone) 제제, 페놀프탈레인 (phenolphthalein) 이나비사코딜 (bisacodyl) 과같은폴리페놀 (polyphenol) 등이있다 (Table 3) [3]. 성분에따라작용시간이다양하며비사코딜의경우복용 6-12시간 ( 좌약은 15-60분 ), 안트라퀴논제제는복용 8-12시간이내에작용이나타난다. 효과를입증할만한임상연구가부족하며대부분의자극성완하제가복합제제로시판되고있어약제별효과와적절한용량및용법이불분명하다. 그럼에도불구하고배변활동이 - 4 -
- 이봉은외 9 인. 전통적완하제 - Table 3. Stimulant laxatives Contents Drugs Daily recommended dose Adverse effects Single Bisacodyl Dulcolax (5 mg/t) 10-15 mg every night Abdominal cramp (mild), electrolyte disturbance (metabolic acidosis or alkalosis, hypocalcemia), nausea, rectal irritation (burning), vertigo, vomiting Disodium picosulfate Crown picorak (7.5 mg/t) Contraindications Hypersensitivity to bisacodyl or any component of the formulation, abdominal pain or obstruction, nausea or vomiting 5-7.5 mg every night Nausea, vomiting Hyperensitivity to sodium picosulfate or any component of the formulation, gastrointestinal obstruction Castor oil 15-30 ml Abdominal cramps, diarrhea, nausea, electrolyte disturbance, hypotension Combination Bisacodyl, docusate Dulcolax-S, Duolax, et al (bisacodyl 5 mg/t) 10 mg every night Bisacodyl, docusate, dehydrocholic acid, casanthranol Bisacodyl, docusate senna Visacool, Mayqueen S, et al (bisacodyl 4 mg/t) Bicogreen S (bisacodyl 5 mg/t) Cascara, et al Dyrax Syr. (cascara 0.8 g/10 ml) T, tablet; Syr., syrup. 1 tablet one to three times 5-10 mg every night 5-10 ml twice 활발한아침에배변을유도할목적으로대부분의약제가취침전복용할것을권고하고있다. 일반적으로부피형성완하제나삼투성완하제에효과가없거나불충분한변비환자에서단기간간헐적으로투여되고있는데일부에서전해질불균형, 복통, 오심, 팽창감등의부작용이발생할수있으며, 장기간사용하거나남용시대장흑색증, 대사성알칼리증, 전해질이상, 뇨산혈증및고알도스테론증등의합병증이생길수있다. 과거연구에서자극성완하제가장신경계에손상을가져올수있다고하였지만 [25,26], 실제적으로자극성완하제사용이대장의구조적혹은기능적손상을일으킨다는보고는없었다. 최근미국소화기학회에서는장기간사용을금지할직접적인이유는없다고언급하면서 [27] 자극성완하제의장기사용을이전보 다는허용하고있다. 하지만현재까지도안전성에대한자료가불충분하기때문에장기간유지요법으로서의일차약제가아닌급성증상완화를위해적절하게사용하는것이바람직하겠다. 자극성완하제는많은변비환자들이약국이나비의료기관에서임의로쉽게접할수있어올바른약제사용에대한환자교육이필요하다. 자극성완하제에대한무작위대조군시험은없으며, 환자군을대상으로한규모가작은증례중심의연구들로주로보고되었다. 계면활성제는대변연화제라고도불리며, 이중도큐세이트는대변의표면장력을낮춰대변을부드럽게하고소장과대장에서수분흡수를증가시켜장내액체에의해대변종괴를이동시킨다. 부작용은거의없으나다른하제에비해효과가다소떨어지며, 우리나라에서는비사코딜, - 5 -
- The Korean Journal of Medicine: Vol. 88, No. 1, 2015 - Table 4. Summary of conventional laxatives Type Drugs Onset of action (hr) Daily recommended dose Proposed mode of action Bulk forming Psyllium Calcium polycarbophil Methylcellulose 12-72 Titrate up to 20 g Titrate up to 20 g Luminal water binding increases stool bulk and reduces consistency Osmotic Saline laxative Luminal water binding, Increase Magnesium salts 0.5-3 2.4-4.8 g fluid excretion by creating an osmotic gradient Hyperosmolar laxative Poorly absorbed sugar 24-48 15-60 ml Polyethelene glycol (PEG) 24-96 13-39 g Stimulant hr, hour. Surfactant laxative Docusate Dehydrocholic acid Castor oil Anthraquinones Senna Aloe Cascara Polyphenol Bisacodyl Sodium picosulfate 8-12 6-12 4-6 15-30 ml 187 mg 325 mg (or 5 ml) 5-10 mg 5-15 mg Act locally to stimulate colonic motility Decrease water absorption from large intestine 센나등과함께복합성분으로만들어진약제가대부분이다. 비사코딜은위약에비해급성변비치료에있어서배변횟수와대변굳기에서호전을보이며부작용은유사했고 [28], 주로상행결장의운동을촉진시켜효과를나타낸다 [29]. 소디움피코설페이트 (sodium picosulfate) 는 triarylmethane 계열의약제로대장내시경의전처치약제로도사용되고있으며복용 4-6시간후에비사코딜과유사한작용을나타낸다. 만성변비환자에서 4주간투약했을때위약에비해배변횟수와삶의질이향상되었다 [30]. 변비환자를대상으로비사코딜과소디움피코설페이트를 4주간투약하면서효과를비교한연구에서두약제는동등한효과를보여주었다 [31]. 자극성완하제의효과를보고한국내연구는아직없다. 자극성완하제의효과에대한임상적근거는부족하나부피형성완하제및삼투성완하제에반응이없는일부변비환자와급성변비증상의완화에효과적일것으로생각되며, 국내임상진료지침에서자극성하제는일부변비환자의치료에도움을준다고제시하였다 ( 권고수준 : 낮음, 증거수준 : 중등도 ) [2]. 결론전통적완하제는변비환자에서약제선택시우선적으로투여되는약제이다. 일반적으로부작용이거의없어안전한부피형성완하제가먼저투여되며, 이에효과가없거나불충분하면삼투성완하제로전환하거나병합하여사용한다. 최근연구에따르면 PEG가락툴로오스에비해복부팽만및방귀와같은부작용은적으면서더나은효과를보였는데, 환자의증상및약제의특성을고려하여적절하게사용해볼수있겠다. 자극성완하제는부피형성완하제및삼투성완하제에반응이없는일부변비환자와급성변비증상의완화에효과적일것으로보인다. 전통적완하제에대한요약을표 4에정리하였다. 각약제의작용기전및이에따른효과와부작용에대해숙지하여변비환자의삶의질개선을위한적절한약제투여를위한노력이필요하다. 중심단어 : 변비 ; 완하제 - 6 -
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