대한내과학회지 : 제 80 권제 5 호 2011 특집 (Special Review) - 흔한하부장관의기능성질환 변비의치료 고신대학교의과대학내과학교실 박무인 Treatment of Constipation Moo In Park Department of Internal Medicine, Kosin University College of Medicine, Busan, Korea Constipation is a common gastrointestinal disease affecting approximately 16.5% of the population in Korea. Systemic diseases such as hypothyroidism or colon cancer and drugs can cause constipation in some patients with constipation, there is no obstructive mucosal or structural cause in the vast majority of patients with constipation. Evaluation for secondary causes of constipation is needed to provide appropriate management. Once secondary causes have been excluded, constipation may be classified into normal or slow transit constipation, evacuation disorder of the spastic or flaccid varieties, or both. Treatment of chronic constipation based on the underlying pathophysiology is generally successful. The aims of this review are to discuss the management of functional constipation based on guidelines for the treatment of constipation published in Korean Journal of Gastroenterology in 2011: lifestyle changes; bulking agents and stool softeners; osmotic agents; stimulant laxatives; prokinetics; biofeedback and surgical treatments. Exercise and dietary fiber are helpful in some patients with constipation. Laxatives including bulking agents, stool softeners, osmotic agents, stimulant laxatives have been found to be more effective than placebo at relieving symptoms of constipation. New enterokinetic agents such as 5-hydroxytryptamine-4 receptor agonists, intestinal secretagogues, and peripheral opioid antagonists could be effective in patients with constipation who cannot get adequate relief from current laxatives. Biofeedback could relieve symptoms in selected patients with constipation due to pelvic floor dyssynergia. Surgical treatments can be helpful in some patients with refractory constipation. (Korean J Med 2011;80:510-523) Keywords: Constipation; Drugs; Treatment 서론만성변비는서구의경우성인의 2-27% 에서볼수있으며 [1-3] 우리나라에서도 16.5% 정도의유병률을보이는아주흔한질환이다 [4]. 남성보다여성에서더흔하며 [5] 65세이상의노인에서는운동의저하, 식이의변화, 복용약물의증가, 위장관기능의변화와동반질환혹은장신경계의변성등으로인하여유병률이 30-40% 정도로증가한다 [6]. 또한변비환자들은심각한삶의질의저하를호소한다 [7]. 만성변비환자의대부분은기질적원인이없는특발성이며드물게다양한이차적인원인들에의해서변비가유발된다. 여러전신질환혹은약물복용등이변비의원인이될수있다. 변비를일으키는전신질환으로는당뇨병, 갑상선기능저하증, 고칼슘혈증을초래하는질환등이있다. 파킨슨병, 다발경화증, 척추병등의신경질환도변비를일으키며우울증, 정신분열증등의정신질환도변비의원인이된다. 마약성진통제, 항콜린제, 제산제, 칼슘차단제등여러약물들도변비를유발할수있다 [2]. - 510 -
- Moo In Park. Treatment of constipation - 원인규명이가능한이차성변비나기질성변비가배제되면원발성혹은일차성변비로진단할수있으며원발성변비는대장통과시간과항문직장기능검사 (anorectal function test) 등의배변과관련된대장과항문직장의운동생리검사를통하여크게세가지형으로분류할수있다. 배변장애형변비, 정상통과시간형변비, 서행성변비로나눌수있는데항문직장의배변기구가정상적으로작동하지않는배변장애형은항문직장의배변기구가정상적으로작동하지않는형인항문경 (anismus) 과골반저근실조 (pelvic floor dyssynergia) 로불리는연축형 (spastic) 배변장애와과도한회음부하강 (descending perineum syndrome) 으로분류되는비연축형 (flaccid) 이있다. 대장항문의운동생리검사에서이상소견이없는경우는대장통과시간에따라정상통과시간형과서행형변비로구분된다 [2]. 이러한배변병태생리학적인분류에따라치료방침이달라지며이러한분류에의거하여맞춤치료를하면대개만족스러운치료효과를본다 [8]. 배변장애형변비는바이오피드백을비롯한행동요법으로치료하게되며배변장애가동반되지않은정상통과시간형변비와서행성변비는약물치료를한다. 그렇지만, 특발성만성변비환자를치료하는단계적접근법은아직확립되어있지않아서의료기관마다진단과치료적접근법이상이하며일반적인치료에반응하지않는심한난치성변비는여전히존재한다. 본고에서는만성특발성변비의치료에대하여 2011년에대한소화기학회지에발표된변비치료에관한임상진료지침 [9] 을참고하여비약물적치료, 약물치료, 행동요법과수술적요법으로나누어기술하고자하며최근에개발된새로운약제에대해서도소개하고자한다. 비약물적치료만성변비환자가처음으로내원하게되면우선기질적원인을배제한다음운동을포함한환자교육, 식이섬유의섭취등을포함한식이의변화등을통하여치료를시도하게된다. 환자교육일단환자를안심시키고정상적인배변습관에관하여간단하게설명해준다. 하제등을자가로투약하여온환자에게는과도한사용을자제시키고수분과식이섬유의섭취를 증가시킨다. 환자에게아침식사후규칙적으로배변을시도하도록교육시킨다. 생활양식의변화운동을포함한육체적활동이변비환자의일부에서증상을호전시킨다고알려져왔지만 [10-12], 연구대상이나운동강도에따라서다양한결과를보이며 [13] 운동이위장관운동에미치는영향에대한연구결과도서로상이하다 [14-21]. 우리나라의임상진료지침에서는 운동이일부변비환자에서증상을호전시키는데도움을줄수있다 고제시하고있다 [9]. 식이섬유식이섬유는대장에서상재균에의해발효되며상재균의성장을유발하여변괴를크게하고, 대장내에서물, 이온과결합하여변을부드럽게하고부피를크게함으로써배변의횟수와대변의양을증가시켜변비를개선시킨다. 변비증상을완화시키기위해서하루에약 20-25 g 정도의식이섬유를섭취하도록권장하고있다 [2]. 하지만식이섬유가변비치료에분명한도움을준다는증거는많지않다. 우리나라의임상진료지침에서는 식이섬유는대변의양을증가시키고장의통과시간을단축시키는데도움을줄수있다. 고제시하고있다 [9]. 식이섬유의변비치료에대한효과는미미하지만쉽게시행할수있고부작용이적고값이저렴하므로초기치료로시도해볼만하다. 약물치료환자에대한교육, 생활양식의변화와식이섬유섭취의증가등에호전되지않으면약물치료를시도하는데약제사용에대한표준화된원칙은없는실정이다. 미국의 Mayo Clinic에서최근에제시한알고리듬에의하면식이섬유의섭취를증가시켜보고변비의증상이개선되지않으면여러가지하제를투여하게된다. 이러한치료에반응이없으면대장통과시간, 항문직장기능검사 (anorectal function test) 와배변조영술을시행하여기능성변비를아형으로분류하여적절하게치료하게된다 (Fig. 1) [8]. 변비치료에이용되는하제는부피형성하제, 삼투성하제, 자극성하제, 기타하제등으로나눌수있으며네가지작용기전이있는데각각의약제는한가지이상의작용기전을 - 511 -
- 대한내과학회지 : 제 80 권제 5 호통권제 609 호 2011 - Figure 1. Algorithm for managing patients with chronic constipation [8]. 가진다 (Table 1). 장관내의물과결합하거나, 점막에서의흡수와분비를변화시키거나, 세균총을증가시키거나, 장점막을자극하여장운동을증가시키는등의기전으로나눌수있다. 하제종류에따른치료효과를살펴보고자한다. 부피형성하제 부피형성하제에는차전자씨 (psyllium, isphagula, plant seed), 해초, 한천 (agar), 카라야 (karaya, plant gums), 메틸셀룰로우스 (methylcellulose) 유도체및폴리카보필 (polycarbophil) 등이있다. 부피형성하제는소장에서흡수되지않고대장세균에의해서도분해되지않아수분을함유할수있다. 수분유지에의해장관내대변부피가증가하면대변량이증가하고대변이부드러워져서쉽게배출된다. 하제의일부는장내세균에의해대사되어이산화탄소나수소와같은가스를형성한다. 이로인해복부팽만감이나다량의방귀를유발한다. 충분한양의물과함께복용하는것이중요하며장협착이나장폐쇄환자에서는증상을악화시킬수있으므로투여해서는안된다. 부피형성하제들간의효과차이에대한연구는거의없다. 변비환자에서 psyllium은위약 [22-24] 과 docusate [25] 에비하여대변양을증가시켰다. 또한변비의증상들인복통, 배변시힘주기, 배변통과불완전배출감등도호전시켰다. 8 주이상관찰한연구는없지만임상경험에의하면 psyllium 의효과는장기간지속되는것으로보인다. 우리나라의변비혹은변비우세형과민성장증후군환자에서이루어진개방형연구에서 psyllium이주성분인아기오 18 g을매일 3주동안투여하였을때변비와관련된증상이호전되고대장통과시간도단축되었다 [26]. Psyllium을제외한메틸셀룰로우스와폴리카보필에대한연구는거의없지만임상경험은충분하여효과적이면서안전하게투여할수있다고알려져있다. 다만우리나라에서시판되고있는부피형성하제중일부는센나 (senna) 와같은자극성하제와합성된종류가있으므로이러한약제는장기복용을피하는것이좋다. 우리나라의임상진료지침에서는 부피형성하제는변비의치료에효과적이다. 라고제시하고있다 [9]. 즉, 부피형성하제는장기간투약하면서관찰한연구는없지만변비의치료에효과적이라고말할수있다. 삼투성하제삼투성하제는삼투성의활성이온이나분자로서장관에서흡수되지않고장관내에서수분을저류시켜배변을용이하게한다. 염류성하제와고삼투성하제로나눌수있다. 염류성하제염류성하제에는마그네슘염과나트륨염이있다. 마그네슘염은수산화마그네슘, 구연산마그네슘, 황산마그네슘등이있고나트륨염으로는인산나트륨이있다. 마그네슘이온은장에서거의흡수되지않아서수분의저류효과로장관내압이증가하여하제로작용한다. 과량복용시고마그네슘혈증을일으킬수있어신기능부전환자와소아에서는주의하여투여해야한다. 성인의일반적인권장량은수산화마그네슘 2.4 g 내지 4.8 g이며충분한양의물과함께복용해야한다. 64명의변비환자에서수산화마그네슘 20 ml 투여군과부피형성하제와 sorbitol을병합투여한군을비교하였는데수산화마그네슘군이병합투여군에비하여배변횟수와대변굳기정도가더나았다 [27]. 우리나라에는변비환자를대상으로한마그네슘제제의효과에관한연구는없지만, 변비환자에게널리사용되고있는실정이다. 최근에대장내시경검사의전처치시변비환자에서 PEG (polyethylene glycol) 에수산화마그네슘을추가하여 PEG 단독투여군보다대장정결도가더나아졌다는보고가있다 [28]. - 512 -
- 박무인. 변비의치료 - Table 1. Medications for chronic constipation Classification by mechanism Examples Usual adult dose Bulk-forming laxatives Uncleaned rice (Brown rice) Bran Psyllium Mutacil, Agio Titrate up to-20 g Seaweed (Tangle) Agar Karaya, plant gums Methylcellulose derivatives Titrate up to-20 g Polycarbophil Sylcon Titrate up to-20 g Osmotic laxatives Salts laxatives Magnecium salts Magmil Sodium phosphate Solin oral 10-25 ml with 360 ml of water as needed Hyperosmolar laxatives Lactulose Duphalac 15-30 ml once or twice a day Sorbitol 15-30 ml once or twice a day Lactitol Ctri-lactitol Glycerin 3 g suppository once a day Polyethylene glycol (PEG) Colit, Colyte 8.5-34 g in 240 ml liquids Stimulant laxatives Anthraquinone Aloe Casanthranol Cascara 325 mg (or 5 ml) daily Senna Alaxyl (Senna + psyllium) 187 mg daily Polyphenol or diphenylmethane Phenophthalein Bisacodyl Dulcolax, Duolax 5-10 mg every night Surfactant laxatives Docusate 100 mg twice a day Castor oil 15-30 ml daily Dehydrocholic acid Bicogreen (Bisacodyl + aloe + cascara) Others Prokinetics 5-HT4 agonists Tegaserod 6 mg twice a day Prucalopride 2-4 mg once a day Cl-channel activator Lubiprostone 24 μg twice a day Guanylate cyclase C agonist Linaclotide 150-300 μg twice a day Peripheral opioid antagonists Alvimopan 0.5 mg twice a day Methylnaltrexone 0.15 mg/kg subcutaneous injection every other days - 513 -
- The Korean Journal of Medicine: Vol. 80, No. 5, 2011 - 우리나라의임상진료지침에서는 마그네슘제제는변비의치료에효과적이다. 라고제시하고있다 [9]. 고삼투성하제고삼투성하제에는락툴로우스 (lactulose), 락티톨 (lactitol), 솔비톨 (sorbitol), 글리세린 (glycerin), 폴리에틸렌글리콜 (polyethylene glycol, PEG) 등이있다. 이들하제는식이섬유나부피형성하제에반응이없거나이들을잘먹지못하는환자에게투여할수있다. PEG는고삼투성하제로서장에서흡수되지않고대장내에서높은삼투압을유지하여체내로의수분의흡수가일어나지않아액체상태로배변이된다. 우리나라에는 PEG 3350 ( 마이락스 ) 와 macrogel 4000 ( 폴락스, 둘코락스발란스 ) 등이사용되고있으며콜로라이트산 (colonlyte) 과코리트산은폴리에틸렌글리콜과전해질의복합성분으로되어있다. 500명이상의만성변비환자를대상으로한 9개의잘계획된연구에서몇가지중요한결과가도출되었다 [29-37]. 첫째, 매일 PEG를투여하면배변횟수를정상화시키고 (number needed to treat, NNT = 2.4), 대변굳기를개선시킨다 (NNT = 3.4). 둘째, 매일 PEG를투여하면다른하제를중단할수있고 (NNT = 3.1), 배변시힘주기를감소시킨다 (NNT = 3.2). 셋째, 6개월동안투여하여도부작용이없었다. 최근의한무작위대조군연구에서도변비환자에서 PEG를 6개월동안투여하여도심각한부작용은없었다 [38]. 37명의변비환자에서 PEG와락툴로우스의효과를비교한무작위대조군시험에서 PEG가락툴로우스에비하여배변횟수, 배변시힘주기, 부작용, 환자만족도등에서유의하게더나았다. 또한약제로인하여유발된변비의치료에도안전하고효과적이었다 [39]. 우리나라소아변비환자에서도 PEG를 6개월이상투여하였을때심각한부작용은관찰되지않았다 [40]. 우리나라의임상진료지침에서는 PEG (polyethylene glycol) 는변비의치료에효과적이다. 라고제시하고있다 [9]. 비흡수성다당류하제는고삼투성하제로서락툴로우스 (lactulose), 락티톨 (lactitol), 솔비톨 (sorbitol), 글리세린 (glycerine) 등이있다. 락툴로우스는갈락토스 (galactose) 와프록토스 (fructose) 의합성이당체로서소장에서흡수되지않고대장내세균에의해대사되어삼투효과를나타낸다. 락툴로우스는갈락토스 (galactose) 와프록토스 (fructose) 의합성이당제로혈중으로흡수되지않아전신순환이될위 험이없어서당뇨병환자에서도혈당을높이지않아서당뇨병환자의변비치료에도이용될수있다. 성인에서권장되는용량은시럽 15 ml씩 1일 2회투여하고필요에따라용량을조절한다. 대장에서가스를형성하기때문에복부팽만이나방귀를일으킬수도있고맛이너무달아서복용을어려워하는환자도있다. 만성변비환자 150명에대한두개의무작위대조군시험 [41,42] 과 opiate와연관되어발생한 57명의변비환자에대한무작위대조군시험 [43] 에서락툴로우스는배변횟수의정상화와대변굳기의호전을보였다. 124명의변비환자에서 psyllium과락툴로우스를 3주이상투여하면서효과와부작용을비교하였다. 변비치료의효과는두약제간에차이는없었으나락툴로우스가 psyllium에비하여더맛이좋아서순응도를높일수있다는장점이있다 [44]. 자극성하제자극성하제로는디하이드로콜린산 (dehydrocholic acid), 피마자기름 (castor oil) 과같은계면활성제 (surfactant laxative) 와센나 (senna) 나카스카라 (cascara) 와같은안트라퀴논 (anthraquinone) 제제, 페놀프탈레인 (phenolphthalein) 이나비사코딜 (bisacodyl) 과같은폴리페놀 (polyphenol) 등이있다. 자극성하제의작용기전은정확하게알려져있지않지만대장내에서수분및전해질의흡수를억제하고대장의근육신경총을자극하여축적하여장운동을촉진하는것으로알려져있다. 일반적인하제에반응이없는변비환자에게단기간동안간헐적으로자극성하제를투여해볼수있다 [45]. 대체적으로자극성하제는위약에비하여더효과적이다 [46]. 하제에대한무작위대조군시험은없으며이전의규모가작고환자군을대상으로한증례중심의연구들이있다 [47-58]. 증거는명확하지않지만전해질불균형, 복통, 오심, 팽만감등의부작용이발생할수있다. 비사코딜은만성변비환자에서장정결 (bowel preparation) 시일시적으로사용한다는보고 [59,60] 이외에변비치료에대한몇몇보고가있다. 비사코딜은위약에비해급성변비치료에있어서배변횟수와변굳기에서호전을보이며부작용은유사한정도로보고되었고 [61], 주로상행결장의장운동을촉진시켜효과를나타내는것으로보고하고있다 [62]. Sodium picosulfate 또한 triarylmethane 계열로비사코딜과유사하게작용한다. 액상형태로복용하면대장세균총에의 - 514 -
- Moo In Park. Treatment of constipation - 해가수분해되어복용 4-6시간후에작용을나타낸다. 만성변비환자에서 4주간투약한경우, 위약에비해배변횟수와삶의질을향상시켰다 [63]. 변비환자를대상으로비사코딜과 sodium picosulfate 를 4주간투약하면서효과를비교한연구에서두약제는동등한효과를나타냈다 [64]. 우리나라에는변비환자를대상으로한자극성하제의효과에관한연구는없지만, 일부변비환자에서사용되고있는실정이다. 우리나라에서사용되는하제는대부분복합성분이어서단기간사용되어야함에도불구하고약국등에서쉽게구입하여장기간사용하고있어서문제가될수있다. 우리나라의임상진료지침에서는 자극성하제는일부변비환자의치료에도움을준다. 라고제시하고있다 [9]. 대변연화제대변연화제에는 docusate, 디하이드로콜린산 (dehydrocholic acid) 피마자기름 (caster oil) 등이있다. Docusate는표면장력을줄여서대변을부드럽게하고소장과대장에서수분흡수를증가시켜장내액체에의해대변종괴를이동시킨다. 15명의노인성변비환자에서 docusate는위약에비하여대변의양을더증가시켰다 [65]. 그렇지만변비환자와정상인을대상으로한다른연구에서는그런효과는없었다 [66-68]. 또한 docusate는 psyllium과의비교연구에서변비를개선시키는유의한효과가있었지만 psyllium보다효과가적었다 [69]. 변비환자를대상으로한대변연화제의효과에관한연구는우리나라에는아직없지만, 임상적으로널리사용되고있는실정이다. 우리나라의임상진료지침에서는 대변연화제 (docusate) 는변비의치료에도움을준다. 라고제시하고있다 [9]. 기타하제최근에개발되어임상에도입되고있는약제들을소개하고자한다. 세로토닌 4형수용체작동체, 선택적 type-2 chloride channel (CIC-2) 자극제, guanylate cyclase C 작용제와말초성아편유사물질대항제등이있으며아직우리나라에도입되지않은약제가대부분이다. 세로토닌 4형수용체작동제세로토닌 (serotonin, 5-hydroxytryptamine, 5-HT) 은장관에서세로토닌 4형수용체 (5-HT 4 receptor) 를통하여장관의연동운동을중계하고장관에서분비를자극한다. 5-HT 4 수용체 에작용하는여러약제들이개발되었으며, 대표적인약제들로는 tegaserod, prucalopride, renzapride 등이있다. Tegaserod Tegaserod 는 5-HT 4 수용체에선택적으로작용하는부분작용제로소장에서통과시간을단축시키고장관분비를증가시키며내장구심신경의반응을억제시킨다 [70]. 이약제는변비형과민성장증후군을보이는여자환자와만성변비환자의치료에효과적이다 [71,72]. 최근우리나라에서도변비형과민성장증후군을보이는 81명의여자환자를대상으로 4주간 tegaserod를 6 mg 하루 2회복용하게한후복용전후환자의증상과삶의질의변화를비교하였는데복부불편감, 대변굳기, 배변시힘주기, 불완전배출감, 복부팽만감등의증상점수의전반적인호전을가져왔고, 삶의질또한향상되었다 [73]. 842명의만성변비환자를대상으로 13 개월동안 tegaserod 복용을관찰한연구에서약물로인한부작용은복통, 설사와두통이었으며, 심각한부작용은보고되지않아장기간투여해도안전한약물이라고보고되었으나 [74], 11,614명의복용환자중 13명에서허혈성심장혈관질환의발생이보고되면서 2007년 3월이후사용이중단되어우리나라에서변비치료제로상용화되고있지않다. 최근미국에서보고된 6개월관찰연구는 52,229명의 tegaserod 복용군과 52,229명의대조군사이에허혈성심장질환과허혈성뇌질환발생위험에차이가없었다고보고하였다 [75]. Prucalopride Prucalopride는선택적으로강력하게 5-HT 4 수용체에작용하는작용제로장운동을증가시켜만성변비에치료효과를보인다. 620 명의심한만성변비환자에게 12주동안 prucalopride 2 mg, 4 mg을각각투여한군과대조군을비교하였는데약제투여군에서대조군에비해주당 1회이상의완전자발적장운동의빈도가유의하게증가하였다 [76]. 다른연구에서도, 713명의만성변비환자에게 prucalopride 2 mg과 4 mg을복용한경우, 주당 3회이상의완전자발적장운동을보인빈도, 완전배변감, 질병의심각성및삶의질이호전되었다 [77]. Quigley 등 [78] 도 prucalopride를투여한경우대조군에비해환자의만족도, 변비의중증도및삶의질이호전되고배변횟수의증가를보여만성변비치료에효과적이라고보고하였다. 가장흔하게보고되고있는부작용은두통과복통이며, 심혈관계부작용은보고되지않았다. 또한, Camilleri - 515 -
- 대한내과학회지 : 제 80 권제 5 호통권제 609 호 2011 - 등 [79] 은고령환자를대상으로 4주간 prucalopride 2 mg을투여한경우에도활력징후, QT 기간을포함한심전도의변화가없어고령환자의변비치료에안전한약제라고보고하고있다. 이러한연구결과들은만성변비환자의치료에 prucalopride를안전하고효과적으로사용할수있음을제시해주고있다. 현재국내에서사용할수없지만조만간도입되길기대한다. 기타 enterokinetic 제제들최근 5-HT 4 수용체에매우선택적으로작용하여심장부작용을최소화하려는여러약제가연구단계에있으며, ATI-7505 [80] 와 Velusetrag (TD-5108) [81] 등이대표적이다. ATI-7505은 cisapride 와유사하게 5-HT 4 수용체에작용하지만, 심장부작용이없고, cytochrome p 450에의해대사되지않는다. 건강자원자를대상으로 9일동안 ATI-7505를각각 3, 10, 20 mg을 1일 3회로복용한연구에서투약군에서대조군에비해장통과시간이단축되었고, 특히 10 mg 복용군에서상행결장에서의이동이향상되었으며, 10 mg 복용군과 20 mg 복용군에서대변의굳기가호전되었다 [80]. 최근연구에서건강지원자와만성변비환자에서 Velusetrag 1회투여후장통과시간이빨라지는결과를보여대장운동촉진제로서의가능성이제시되었다 [81]. 우리나라에서는변비환자에서 cisapride 가효과적이라는보고가있었으나 [82], 현재우리나라변비환자에서 5-HT 4 수용체작용제로사용할수있는약제는없는실정이다. 부작용이적은안전한새로운약제들이개발되어임상에도입되고있어서향후우리나라변비환자에서도널리사용될것으로예상된다. 우리나라의임상진료지침에서는 세로토닌 4형수용체작동제는변비의치료에도움을준다. 라고제시하고있다 [9]. 선택적 type-2 chloride channel (CIC-2) 자극제 Lubiprostone Lubiprostone은만성변비환자의치료에있어서가장최근에 FDA 승인을받은약제로장상피세포의선택적 type 2 chloride channel (CIC-2) 자극제로작용하여장관분비를증가시켜변비증상을호전시킨다 [83]. 129명의만성변비환자를대상으로 3주간 lubiprostone을각각하루에 24, 48, 72 μg씩복용하는군과위약을복용하는대조군으로나누어비 교한결과, 대조군에비해 lubiprostone을복용한모든군에서자발적장운동횟수가의미있게증가하였으며, 복용량이증가함에따라점차적으로증가하는결과를보였다 [83]. Lubiprostone의가장흔한부작용은오심 (31.7%) 이었으며, 약 5% 의환자에서는오심으로인하여약물복용을중단하였다. 다른연구들에서도 lubiprostone 24 μg을 1일 2회복용한군에서대조군에비해 24시간내에자발적장운동을보인빈도가증가하였고, 복용 1주일째자발적장운동횟수가증가하였으며, 효과는 4주까지지속되었다 [84,85]. Lubiprostone의가장흔한부작용은오심 (31.7%) 이었으며, 약 5% 의환자에서는오심으로인하여약물복용을중단하였다 [84]. Lubiprostone 은복용첫날부터장운동을증가시키고, 전반적인변비증상을호전시키며, 복용중지속적인효과가유지되어만성변비치료에효과적인약제로보고되고있다. 향후우리나라에도도입되어난치성변비환자의치료에도움을줄것으로기대한다. Guanylate cyclase C 작용제 Linaclotide Linaclotide (MD-1100) 는 guanylate cyclase C 작용제로장상피세포의 guanylate cyclase-c 수용체와결합하여 cyclic guanosine monophosphate를증가시키고, 장관내로 chloride 와 bicarbonate 분비를증가시킨다. Linaclotide 는만성변비환자에서 4주간투여하였을때용량의존적으로장운동과임상증상의호전을보였다 [86,87]. 최근 310명의만성변비환자를대상으로 4주동안 linaclotide 75, 150, 300, 600 μg을 1일 1회복용한군과위약을복용한대조군으로구분하여용량에따른효과및안정성을보고하였다 [87]. Linaclotide 를복용한모든군에서대조군에비해주당자발적장운동횟수가의미있게증가하였으며복용 24시간이내에 75 μg을복용한경우를제외한모든 linaclotide 복용군에서대조군에비해자발적장운동을보이는빈도가유의하게더많았다. 또한, linaclotide 복용군에서완전자발적장운동의증가와대변굳기, 과도한힘주기, 복부불편감, 더부룩함과삶의질의호전을가져왔다. 가장흔한부작용은설사였으나, 빈도가낮았고고용량을투여한경우에주로나타났다. 아직우리나라에도입되지않았지만변비환자에서안전하고효과적으로투여할수있는약제이다. - 516 -
- 박무인. 변비의치료 - 말초성아편유사물질대항제아편유사제 (opioids) 는위배출을지연시키고, 장의연동운동을감소시켜장운동을느리게하므로만성적으로아편유사제를복용하는경우흔히변비를호소하게된다. 수술후에흔히볼수있는장마비의경우도수술전후여러복합적인요인과더불어통증조절을위해사용하는아편유사제에의해발생하거나악화될수있다. 이러한이유로아편유사제를복용하는환자에게발생한변비를치료하기위해아편유사물질대항제를이용한연구가이루어졌다. 이상적인약제는장에국소적으로작용하여변비와관련된증상을호전시키면서혈액- 뇌장벽을통과하지않아아편유사제의진통효과를유지할수있어야한다. Alvimopan과 methylnaltrexone 는말초 μ-아편유사물질수용체 (peripheral μ-opioid receptor) 에선택적으로작용하는대항제로서이러한선택적효과가입증되어 2008년 FDA 공인을받았으며, 현재활발히연구되고있다. Alvimopan Alvimopan는말초- 아편유사물질수용체에선택적으로작용함으로써아편유사제로유발된더부룩함, 복부불편감과배변횟수의감소등의부작용을호전시키면서진통효과에는영향을주지않는약제로, 아편유사제와관련된변비와급성수술후장마비의치료에효과적이다 [88-93]. 아편유사제로인한장기능이상 (opioid-induced bowel dysfunction, OBD) 을보이는 168명의환자에게 21일동안 alvimopan 1 mg, 0.5 mg 혹은위약을투여하여효과를비교하였는데약물투여 8 시간이내에장운동을보이는빈도는각각 54.3%, 43% 로, 대조군 29% 에비해유의하게더많았다. 첫장운동까지소요된평균시간은 alvimopan 1 mg 투여군에서 3시간으로대조군 21시간에비해유의하게짧았고환자의전반적인만족도도높았다 [88]. Webster 등 [89] 은 OBD환자 522명을대상으로치료용량에대한연구를보고하였으며, 각각 alvimopan 0.5 mg 1일 2회, 1 mg 1일 1회, 1 mg 1일 2회투여군과위약을투여한대조군으로나누어 6주간복용한결과, alvimopan 0.5 mg 1일 2회로복용한군이대조군과유사한정도의부작용을보이면서자발적장운동을증가시키고, 과도한힘주기, 대변굳기, 불완전배변감과복부불편감등전반적인증상의호전을보여, OBD 치료에가장적절한용량이라고제시하였다. Alvimopan는복부수술후발생할수있는수술후 마비치료에도효과적으로작용하며 [90,91], 특히환자조절정맥내진통장치 (intravenous patient-controlled analgesia, PCA) 를사용하는경우에효과적이다 [92]. Alvimopan의가장흔한부작용은오심, 구토및변비등인데그빈도가대조군과유사하게나타나서아편유사제로인한장기능이상및수술후마비환자의위장관기능회복에효과적인약제로보고되고있다 [89,93]. Methylnaltrexone Methylnaltrexone은 naltrexone으로부터유래된약물로장근육세포에국소적으로작용하여아편유사물질수용체를막아장의기능을정상화시키면서도아편유사제의진통효과를유지한다. 하제복용에도호전되지않는 133명의 OBD 환자를대상으로 2주동안 methylnaltexone을 0.15 mg/kg로 2일에 1회피하주사하였더니위약대조군에비해첫용량투여후 4시간이내에배변을보인빈도가유의하게더많았고, 첫용량투여후배변까지소요된시간도대조군에서 48시간이상소요된것에비해평균 6.3시간으로빠른효과를보여주었다 [94]. Portenoy 등 [95] 의연구에의하면, OBD 환자의변비치료에는 2일에 1회최소 methylnaltrexone 5 mg 이상을피하주사하는것이효과적이며, 이용량은진통효과의감소를초래하거나아편유사제의금단증상을유발하지않았다. 최근다른연구들에서도 methylnaltrexone 0.15 mg/kg로 2 일 1회피하주사하는것이아편유사제로인한변비치료에효과적이었다 [96,97]. Neutrotrophins Neutrotrophin-3는신경세포의생존과분화를조절하여신경조직체계를관리한다. 제2상, 무작위, 이중맹검, 위약-대조군연구에서 neutrotrophin-3를피하주사치료받은기능성변비환자에서배변횟수, 완전자발적장운동및대변굳기가호전되었다 [98]. 그러나약 30% 환자에서주사부위에통증이유발되었다. 행동요법바이오피드백은전기혹은기계적장치를이용하여생체내반응을인식하게하는교육전략이다 [99]. 만성변비환자에서바이오피드백치료는배변시골반저횡문근을이완하 - 517 -
- The Korean Journal of Medicine: Vol. 80, No. 5, 2011 - 게훈련하고소량의대변에의한직장팽창을인식할수있게하며복압을효과적으로상승할수있도록환자를교육하는것이다. 체계적인분석에의하면골반저기능부전환자에서바이오피드백의치료효과는 70% 정도된다 [100-104]. 바이오피드백은변비증상완화, 삶의질향상, 장통과시간의단축과하제의사용량감소등을가져온다 [99,103,104]. 장기간추적연구에서바이오피드백의효과는치료후 2년까지지속되었다 [102,103,105]. 그렇지만서행성변비에대한바이오피드백효과는아직확립되어있지않다. 최근의한연구에의하면출구폐쇄형변비환자가서행성변비환자에비하여더효과적인반응을보였다 [106]. 우리나라에서바이오피드백치료는변비환자에서사용되고있으며, 여러연구에서도골반저기능부전을동반한변비환자의 70-80% 에서바이오피드백치료에효과를보였고 [107-110], 치료에반응을보였던환자에서효과는 1년이상지속되었다 [110]. 우리나라의임상진료지침에서는 바이오피드백치료는골반저기능부전에의한변비환자의치료에효과적이다. 라고제시하고있다 [9]. 외과적치료천수신경자극 (sacral nerve stimulation, SNS) 1980년대초에신경인성변비환자에서척수 [111] 와천수신경근 [112] 에대한전기자극이처음시도되었다. 방광기능이상이나변실금환자에서영구적으로척수신경자극을주었을때배변횟수의증가와변비증상의완화를관찰하여천수신경자극을변비치료의한방법으로시도하게되었다 [113]. 일반적인치료에반응하지않는변비환자에서척수신경자극치료에대한소규모의여러연구들이시행되었으나치료성적은아주다양하였다 [112,114-121]. 아직까지작용기전이명확하게밝혀진것은아니지만일반적인치료에불응인난치성변비환자에서새로운비침습적치료법으로시도해볼만하다. 우리나라에서도변비환자를대상으로천수신경자극치료를시도해왔으며직장감각능저하를동반한변비환자와서행성변비환자에서치료효과가비교적양호하였다 [108,122]. 우리나라의임상진료지침에서는 천수신경자극 (sacral nerve stimulation, SNS) 은일부변비환자의치료에도움을 줄수있다. 라고제시하고있다 [9]. 아직우리나라에정식으로도입되지않았지만향후일반적인치료에반응하지않는난치성변비환자의치료에활용될것으로기대한다. 대장절제수술부분혹은전대장절제술은변비치료로서 19세기초반부터대장절제술후회장직장문합술로시행되어졌다. 수술후환자만족도는 39-100% 로다양하다 [123]. 서행성변비환자에서수술은내과적치료에반응이없는증상이심한난치성변비에국한되어야하며술전에위장관의생리학적검사가반드시선행되어야한다 [124]. 우리나라에서도난치성서행성변비환자에서수술적치료를시도해오고있다. 후향적연구에서수술후환자의만족도는양호하였다 [125-127]. 우리나라의임상진료지침에서는 난치성서행성변비환자의일부에서대장절제수술이치료에도움을준다. 라고제시하고있다 [9]. 난치성서행성변비환자에서수술적치료를고려해볼수있으나대상환자선별에신중을기해야한다. 결론변비는비교적흔한질환이며특히노인과여성에서더흔하다. 변비를일으키는뚜렷한원인이있는이차성변비는그원인에대한치료를시행하게되지만원인이불분명한경우는변비증상의완화를위하여여러가지방법으로치료하게된다. 우선생활습관의변화나고섬유소식이및운동등의보존적요법을먼저시도해보고이에반응이없는경우에약물치료를시도하게된다. 변비에사용되는하제는여러가지종류가있으며작용기전도서로중첩되어있기도하다. 약제투여에대한명확한지침은아직없는실정이며임상의들은경험적으로단일혹은병용처방을하게된다. 비약물적치료와약물치료에반응이없는변비에대해서는대장및항문직장의기능검사를시행하여아형으로분류하여적절하게치료한다. 골반저기능부전이동반된변비환자에서는바이오피드백요법이도움이된다. 이러한치료에반응이없는난치성변비에대하여외과적치료를고려한다. 변비치료로서새로운약제와외과적치료방법들이다각도로연구가활발히이루어지고있으며일선임상에서더욱더효과적으로변비치료에이용될수있기를기대한다. - 518 -
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