이창균 경희대학교 의학전문대학원 경희대학교 병원 소화기내과 만성변비의 진단과 내과적 치료 이창균 경희대학교 의학전문대학원 경희대학교 병원 소화기내과

Egyptian papyrus “The body is poisoned by material released from decomposing waste in the intestines…” Constipation as the “the disease of diseases” “Autointoxication” “Autointoxication theory” the 16th century BC

1920s: advertisement for a “candy cathartic”

An abdominal massage machine

Rectal dilators for constipation, 1938

Total colectomy for as a cure of “autointoxication” Constipation related to “civilization”

x Misconceptions 1 Daily bowel movements are important for overall health. Chronic constipation may result in poor general health because of failure to empty toxins from the colon in a timely fashion.

Dietary fiber hypothesis and “Western diseases” Don’t forget fiber in your diet ! - Dr. Denis Burkitt

Geographic prevalence of constipation

Let’s start to talk about current management of constipation. Jump forward to 2011 High prevalence 15% in adults (9% in children) High health care burden 6.3 million patient visits to medical centres total costs of $1.7 billion (in US) Let’s start to talk about current management of constipation.

What causes constipation?

Rome Criteria * ≥25% of defecations Symptoms ≥3 mo; onset ≥6 mo prior to diagnosis * ≥25% of defecations

Dynamics of defecation

3 types of functional constipation Normal transit constipation Slow transit constipation Pelvic floor dysfunctions

Diagnostic algorithm

Radioopaque marker (KolomarkTM) Colonic transit time Initial screening test: Normal- or slow transit constipation vs Pelvic floor dysfunction 7th day Rt Lt Radioopaque marker (KolomarkTM) RS

Diagnosis of pelvic floor dysfunctions Balloon expulsion test Anorectal manometry Defecography

Balloon Expulsion Test Balloon expulsion test is a simple, office-based screening test for defecatory disorders. After insertion of the latex balloon into the rectum, 50 ml of water or air is instilled into the balloon, and the patient is asked to expel the balloon into a toilet. Inability to expel the balloon within 2 or 3 minutes suggests a defecatory disorder. Lembo A et al. NEJM 2003;349:1360-8

Anorectal manometry

Normal Defecogram 102˚ 129˚

Anismus

What are the medical therapy for constipation? Basic advice Laxative agents Prokinetic agents Biofeedback treatment Normal or Slow transit C Pelvic floor dysfunctions

Basic advice Correct position for defecation Increasing dietary fiber intake Increasing water intake Adequate exercise Bulk-forming laxatives

Correct position for defecation “semi-squatting” position << natural squatting position ?

Basic advice

x Misconceptions 2 Constipation is the result of a diet poor in fiber, low fluid intake, and/or lack of exercise. Evidence가 없다고 하여 evidence가 아닌 것은 아니다.

Bulk-forming laxatives Stepwise approach Basic advice Dietary fiber Water ingestion Bulk-forming laxatives Psyllium Bran Methylcellulose Calcium polypcarbophil Osmotic laxatives Magnesium salts Sorbitol Lactulose Polyethylene glycol Stimulant laxatives Senna Bisacodyl 뮤타실 (일양) 아기오 (부광) 웰콘 (건일) 산화 마그네슘 (삼천당) 락티톨 두팔락(중외) 아락실 (부광) 둘코락스 (베링거)

Bulk-forming laxatives Usual Adult Dose Onset of Action Psyllium Up to 1 tsp TID 12-72 h Methylcellulose Calcium polycarbophil 2-4 tablets/day 24-48 h 부피형성하제는 소장에서 흡수되지 않고 대장 세균에 의해서도 분해되지 않아 수분을 함유할 수 있다. 수분 유지에 의해 장관내 대변부피가 증가하면 대변량이 증가 하고 대변이 부드러워져서 쉽게 배출된다. 하제의 일부는 장 내세균에 의해 대사되어 이산화탄소나 수소와 같은 가스를 형 성한다. 이로 인해 복부 팽만감이나 다량의 방귀를 유발한다. 충분한 양의 물과 함께 복용하는 것이 중요하며 장 협착이나 장 폐쇄 환자에서는 증상을 악화시킬 수 있으므로 사용해서는 안된다. 요약하면, 부피형성하제는 장기간 투약하면서 관찰한 연구 는 없지만 변비의 치료에 효과적이라고 말할 수 있다.

Osmolar agents Laxative Usual Adult Dose Onset of Action Polyethylene glycol 8.5-34 g in 240 mL liquids 2-4 days Lactulose 15-30 mL QD or BID 24–48 h Sorbitol 120 mL of 25% solution QD 24-48 h Glycerine 3 g suppository QD 15-60 min Magnesium sulfate 15 g QD 0.5-3 h Magnesium citrate 200 mL QD 마그네슘 제제는 삼투성 완하제로서 수산화 마그네슘, 구 연산 마그네슘, 황산 마그네슘 등이 있다. 마그네슘 이온은 장에서 거의 흡수되지 않아서 수분의 저류효과로 장관내압이 증가하여 하제로 작용한다. 과량 복용 시 고마그네슘 혈증을 일으킬 수 있어 신기능 부전 환자와 소아에서는 주의하여 투 여해야 한다. PEG는 고삼투성 하제로서 장에서 흡수되지 않고 대장 내 에서 높은 삼투압을 유지하여 체내로의 수분의 흡수가 일어나 지 않아 액체 상태로 배변이 된다. 우리나라 소아 변비 환자에서도 PEG를 6개월 이상 투여하 였을 때 심각한 부작용은 관찰되지 않았다.64 우리나라의 임상 의들은 대체적으로 PEG 투여가 변비의 치료에 효과적이라는 데 동의하였다. 요약하면, PEG는 변비 환자에서 안전하게 장기간 투약할 수 있는 효과적인 약제이다. 비흡수성다당류하제는 고삼투성 하제로서 락툴로우스 (lactulose), 락티톨(lactitol), 솔비톨(sorbitol), 글리세린 (glycerine) 등이 있다. 락툴로우스는 갈락토스(galactose)와 프록토스(fructose)의 합성 이당체로서 소장에서 흡수되지 않 고 대장내 세균에 의해 대사되어 삼투효과를 나타낸다.

Stimulant laxatives Laxative Usual Adult Dose Onset of Action Bisacodyl 10-20 mg PO QHS 6-10 h 10 mg suppository QD 15-60 min Senna 2-4 tablets QHS 6-12 h 자극성하제의 작용 기전은 정확하게 알려져 있지 않지 만 대장 내에서 수분 및 전해질의 흡수를 억제하고 장내에 축적하여 장운동을 촉진하는 것으로 알려져 있다. 일반적인 하제에 반응이 없는 변비 환자에게 단기간 동안 자극성하제를 투여해 볼 수 있다.

x Misconceptions 3 Chronic use of currently available stimulant laxatives is unsafe because they may damage the colon when used chronically. The basis for the concept that stimulant laxatives can damage the enteric nervous system and or colonic smooth muscle is largely derived from uncontrolled observations of humans and poorly designed studies in animals. In contrast, studies that do not report such damage are well done and numerous. The preponderance of evidence suggests that chronic use of available stimulant laxatives is not harmful to the colon, even if they are abused.

Bisacodyl Category I drug by the US-FDA Category I “Safe and effective”

x Misconceptions 4 Stimulant laxatives induce habituation and tolerance or physical dependence and addiction. There is some evidence that tolerance to stimulant laxatives occurs in those relatively few patients with severe slow transit constipation in whom most other laxatives are ineffective and whose colons are often characterized by loss of enteric neuronal elements. Although tolerance to laxatives has not been studied extensively in humans, it seems to be uncommon in the majority of laxative users. Because most laxatives are not absorbed and none cross the blood-brain barrier, there is no pharmacologic basis for addiction.

Better strategy for use of laxatives Non-stimulant laxatives on a daily basis + Stimulant laxatives twice or thrice weekly When patients fail to respond adequately to bulk or osmotic laxatives, a reasonable regimen is to attempt stimulant laxatives such as bisacodyl or senna when no spontaneous bowel movement occurs after 48 hours (thrice weekly) or 72 hours (twice weekly).

Probiotics in constipation ?

Monitoring response to treatment Spontaneous bowel movement (SBM) Complete SBM Bristol stool chart

Enterokinetic agents Historical agents Cisapride: withdrawal Metoclopramide: no effect Erythromycin: no effect

New prokinetic agents Tegaserod Prucalopride Lubiprostone non-selective serotonin (5-HT4) receptor agonist Prucalopride selective, high-affinity 5-HT4 receptor agonist Lubiprostone chloride channel activator Lubiprostone: bicyclic fatty acid  activates chloride channels of the apical membrane of the intestinal epithelial cells  moving water into the gut lumen.

Role of Serotonin

Serotonin and EC Cells in Constipation Serotonin stimulates small intestine and colonic motility and accelerates transit1 A study in 10 patients with chronic laxative use demonstrated a reduced number of serotonin immunoreactive cells, P<.052 Reduced number of serotonin cells in slow transit constipation contributes to reduced motility of the colon with consequent constipation2 1Talley , Aliment Pharm Ther 1992; 6: 273 2El-Salhy et al, Scand J Gastroenterol 1990; 10: 1007

Serotonin and Motor Activity Proximal Distal Interneurons in the Myenteric Plexus Movement of gut content Orad motor neurons (contraction) ACh / SP Caudad motor neurons (relaxation) VIP / NO CGRP Submucosal IPAN 5-HT4 receptor 5-HT1p receptor . . . . . . . . . 5-HT (serotonin) Enterochromaffin cells in GI tract release 5-HT Adapted from Grider et al, Gastroenterology 1998; 115: 370 Adapted from Gershon, Rev Gastroenterol Dis 2003; 3: S25

How prucalopride works? 5-HT4 수용체에 작용하는 작용제로 장운동을 증가시켜 만성 변비 치료에 효과를 보인다.

A placebo-controlled trial of prucalopride for severe chronic constipation N Engl J Med 2008;358(22):2344–54.

Misconceptions 5 ? Are enterokinetic agents a major advance in treating constipation? Are enterokinetic agents cost-effective in most constipated patients in the primary care setting?

Treatment of choice for pelvic floor dysfunction Biofeedback Pelvic floor rehabilitation Sensory and muscular training Treatment of choice for pelvic floor dysfunction 바이오피드백은 전기 혹은 기계적 장치를 이용하여 생체내 반응을 인식하게 하는 교육 전략이다.만성 변비 환자에서 바이오피드백 치료는 배변시 골반저 횡문근을 이완하게 훈련 하고 소량의 대변에 의한 직장 팽창을 인식할 수 있게 하며 복압을 효과적으로 상승할 수 있도록 환자를 교육하는 것이 다. 체계적인 분석에 의하면 골반저기능부전 환자에서 바이오 피드백의 치료 효과는 70%정도 된다.106-110 치료의 장점으로 는 변비 증상 완화, 삶의 질 향상, 장통과시간의 단축과 하제 의 사용량 감소 등을 가져온다.105,109,110 장기간 추적 연구에서 바이오피드백의 효과는 치료 후 2년까지 지속되었다.

Protocol for biofeedback therapy

Evidence-based summary for the treatment of constipation

Surgical treatment Severe refractory slow-transit constipation Colonic inertia Subtotal colectomy with ileorectal anastomosis

When to refer for specialist care Alarm symptoms Psychological treatment for irritable bowel syndrome Painful anorectal conditions anal fissure, haemorrhoids, abscess, or fistula Obstructed defecation Paradoxical puborectalis contraction Solitary rectal ulcer syndrome Rectocoele Rectal intussusception and rectal prolapse

on chronic constipation Acute on chronic constipation

SEMS in Acute colonic malignant obstruction

Stercoral ulcers

Take home messages Basic understanding of pathophysiology Stepwise approach of laxatives Biofeedback treatment for pelvic floor dysfunction Specialist referral for refractory cases

Educational web resources 대한소화기학회 (www.gastrokorea.org) 변비 치료에 관한 임상진료지침 (2011) Rome Foundation (www.romecriteria.org) British Society of Gastroenterology (www.bsg.org.uk) Core (www.corecharity.org.uk)

Enjoy your summer vacation!