Adult and Children Constipation The role of laxative therapy Chudahman Manan

Adult and Children Constipation The role of laxative therapy Chudahman Manan Indonesian Society of Gastroenterology

Introduction (1) : Chronic constipation and irritable bowel syndrome (IBS), the most prevalent functional bowel disorders in North America (20-70%) Symptoms related to these motility disorders are chronic, sometimes severe, and can profoundly and negatively affect patients QOL Chronic constipation and IBS often leading to polypharmacy and a significant burden on healthcare resources.

Introduction (2) : odata from RSCM-Jakarta during 1998-2005, 2.397 colonoscopy exam, 216 (9%) indication for constipation o Gender comparative women and men (4 : 1)

LIFE Genetics Environment Social Context Drossman, DA; Gastro 2006

Epidemiology Constipation : Irritable bowel syndrome: a global perspective, WGO Global Guideline 2009. Data in Indonesia, of the 304 cases of digestive disorders is incorporated in Asian studies Functional Gastrointestinal Disorders Study (AFGID) in 2013, reported incidence of 5.3% functional constipation and constipation type IBS incidence of 10.5%.

Prevalence of Constipation (%) Prevalence of Constipation (%) Constipation Increases With Age and Is More Common in Women 12 10 Study 1 N = 42,375 Harari, et al Population: NHIS 1989 Criteria: self-report 25 20 Men Women 8 15 6 4 2 0 10 5 0 Study 2 Study 3 Study 4 N = 5,430 Drossman N = 1,149 Pare N = 10,018 Stewart Age Group (years) Sex NHIS = National Health Interview Survey Higgins PDR, et al. Am J Gastroenterol. 2004;99:750-759.

How Do We Define Constipation? o The American College of Gastroenterology (ACG) definition of constipation: o Unsatisfactory defecation characterized by infrequent stools, difficult stool passage, or both. Difficult stool passage includes straining, a sense of difficulty passing stool, incomplete evacuation, hard/lumpy stools, prolonged time to pass stool, or need for manual maneuvers to pass stool o The ACG Chronic Constipation Task Force also clarified what is meant by chronic: o Chronic constipation is defined as the presence of these symptoms for at least 3 months American College of Gastroenterology Chronic Constipation Task Force. Am J Gastroenterol. 2005;100(S1):1-4.

Myths and Misconceptions About Chronic Constipation Misconception Diseases arise from autointoxication by retained stools Fluctuations in hormones contribute to constipation A diet poor in fiber causes constipation Increasing fluid intake is a successful treatment for constipation Reality No evidence to support this theory Fluctuations in sex hormones during the menstrual cycle have minimal impact on constipation, but are associated with changes in other GI symptoms Changes in hormones during pregnancy may play a role in slowing gut transit A low fiber diet may be a contributory factor in a subgroup of patients with constipation Some patients may be helped by an increase in dietary fiber, others with more severe constipation may get worse symptoms with increased dietary fiber intake No evidence that constipation can be treated successfully by increasing fluid intake unless there is evidence of dehydration Muller-Lissner S, et al. Am J Gastroenterol. 2005;100:232-242. Heitkemper M, et al. Am J Gastroenterol. 2003;98(2):420-430.

More Misconceptions About Chronic Constipation Misconception Stimulant laxatives damage the enteric nervous system and increase the risk of cancer Laxatives cause electrolyte disturbances Laxatives induce tolerance Laxatives are addictive Reality Unlikely that stimulant laxatives at recommended doses are harmful to the colon No data support the idea that stimulant laxatives are an independent risk factor for colorectal cancer Laxatives can cause electrolyte disturbances, but appropriate drug and dose selection can minimize such effects Tolerance is uncommon in most laxative users, however tolerance to stimulant laxatives can occur in patients with severe constipation and slow colonic transit No potential for addiction to laxatives, but laxatives may be misused Muller-Lissner S, et al. Am J Gastroenterol. 2005;100:232-242.

Abdominal Pain: Salient Feature Absent in Chronic Constipation (-) Abdominal Pain Chronic constipation (+) Abdominal Pain IBS with constipation Presence or absence of abdominal pain is the major differentiating feature Brandt LJ, et al. Am J Gastroenterol. 2005;100(suppl 1):S5-S21.

Primary Constipation Slow-transit Constipation Characterized by prolonged intestinal transit time Altered regulation of enteric nervous system Decreased nitric oxide production Impaired gastrocolic reflex Alteration of neuropeptides (VIP, substance P) Decreased number of interstitial cells of Cajal in the colon Irritable Bowel Syndrome (IBS) with Constipation Alterations in brain-gut axis Stress-related condition Visceral hypersensitivity Abnormal brain activation Altered gastrointestinal motility Role for neurotransmitters, hormones Presence of non-gi sympt Headache, back pain, fatigue, myalgia, dyspareunia, urinary symptoms, dizziness

ROME III CLASSIFICATION Symptom onset at least 6 months before diagnosis Recurrent abdominal pain or discomfort at least 3 days a month in the past 3 months, associated with two or more of the following Improvement with defecation Onset associated with a change in frequency of stool Onset associated with a change in form (appearance) of stool

Clinical CC & IBS-C : Functional Gastrointestinal diseases (FGID) Patomechanism motility disorders The same clinical symptoms but IBS-C with abdominal pain CC slow & weak motility but IBS-C segmental spasm IBS-C strongly related to QOL Psychological factors influence of IBS-C

Ask the Right Questions o o o o o o o o o o o Define the meaning of constipation How long have you experienced these symptoms? Frequency of bowel movements? Abdominal pain? Other symptoms? What is most distressing symptom? Manual maneuvers to assist with defecation? Any limitation of daily activities? Are you taking any medications? What treatment have you tried? What investigations have been done? Locke GR III, et al. Gastroenterology. 2000;119:1761-1778.

Any Alarm Symptoms? Are Diagnostic Tests Needed? o o o o o o o o Hematochezia Family history of colon cancer Family history of inflammatory bowel disease Anemia Positive fecal occult blood test Unexplained weight loss 10 pounds Severe, persistent constipation that is unresponsive to treatment New-onset constipation in an elderly patient Locke GR III, et al. Gastroenterology. 2000;119:1761-1778. Brandt LJ, et al. Am J Gastroenterol. 2005;100(suppl 1):S5-S21.

Diagnosis : Diagnosis of IBS-C based on Rome criteria Diagnosis of CC depend on longstanding constipation without typical clinical symptom

Consider Secondary Causes Lifestyle Inadequate fiber/fluid Inactivity Psychological Depression Eating disorders Surgical Abdominal/pelvic surgery Colonic/anorectal surgery Constipation Drugs Opiates Antidepressants Anticholinergics Antipsychotics Antacids (Al, Ca) Ca channel blockers Iron supplements Metabolic/ Endocrine Hypercalcemia Hyperparathyroidism Diabetes mellitus Hypothyroidism Hypokalemia Uremia Addison s Porphyria Neurological Parkinson s Multiple sclerosis Autonomic neuropathy Aganglionosis (Hirschsprung s, Chagas) Spinal lesions Cerebrovascular disease Systemic Amyloidosis Scleroderma Polymyositis Pregnancy Gastrointestinal Colorectal: neoplasm, ischemia, volvulus, megacolon, diverticular disease Anorectal: prolapse, rectocele, stenosis, megarectum Candelli M, et al. Hepatogastroenterology. 2001;48:1050-1057. Locke GR, et al. Gastroenterology. 2000;119:1761-1766.

Treatment CC & IBS-C : According to pathophysiology Clinical diagnosis very important to choose the treatment Wrong choice of treatment will be worse clinical symptoms Treatment of CC with prokinetic or stimulant laxative Treatment of IBS-C with anti spasmodic

Definition PK : Pharmacokinetics is currently defined as the study of the time course of drug absorption, distribution, metabolism, and excretion. Clinical pharmacokinetics is the application of pharmacokinetic principles to the safe and effective therapeutic management of drugs in an individual patient.

Definition PD : Pharmacodynamics refers to the relationship between drug concentration at the site of action and the resulting effect, including the time course and intensity of therapeutic and adverse effects The effect of a drug present at the site of action is determined by that drug s binding with a receptor.

Relationship of pharmacokinetics and pharmacodynamics and factors that affect each.

Mode of action different laxatives Lissner, AGH 2012; 3:(1)

Classification of laxatives :

Bisacodyl pharmacodynamics Bisacodyl, a stimulant laxative, is hydrolyzed by intestinal brush border enzymes and colonic bacteria to form an active metabolite [bis-(p-hydroxyphenyl) pyridyl-2 methane; (BHPM)] that acts directly on the colonic mucosa to produce colonic peristalsis.

Bisacodyl pharmacokinetics : The osmotic activity of HalfLytely solution results in no net absorption or excretion of ions or water

Treating Constipation With Laxatives Laxative Bulking Agents Osmotic Laxatives Stimulant Laxatives Lubricants Stool Softeners Combinations Description Absorbs liquids in the intestines and swells to form a soft, bulky stool; the increase in fecal bulk is associated with accelerated luminal propulsion Draws water into the bowel from surrounding body tissues providing a soft stool mass and improved propulsion [saline, poorly absorbed mono- and disaccharides, polyethylene glycol] Cause rhythmic muscle contractions in the intestines, increase intestinal motility and secretions Coats the bowel and the stool mass with a waterproof film; stool remains soft and its passage is made easier Helps liquids mix into the stool and prevent dry, hard stool masses; has been said not to cause a bowel movement but instead allows the patient to have a bowel movement without straining Combinations containing more than 1 type of laxative; for example, a product may contain both a stool softener and a stimulant laxative Gallagher P, et al. Drugs Aging. 2008;25:807-821.

Laxatives Laxative Type Generic Name Brand Name(s) Bulk-forming Methylcellulose Citrucel Polycarbophil FiberCon, Fiber-Lax Psyllium Metamucil, Konsyl Lubricating Stool Softeners Saline Glycerin Mineral oil Magnesium hydroxide (milk of magnesia) and mineral oil Docusate sodium Magnesium hydroxide (milk of magnesia) Bisacodyl Glycerin suppository (generic) Mineral oil (generic) Phillips M-O Colace, Dulcolax Stool Softener, Phillips Liqui-Gels Ex-Lax Milk of Magnesia Laxative/Antacid Phillips Chewable Tablets Phillips Milk of Magnesia Ex-Lax Ultra, Dulcolax Bowel Prep Kit Stimulant Osmotic Sodium bicarbonate and potassium bitartrate Ceo-Two Evacuant Sennosides Ex-Lax Laxative Pills Castor oil Purge Senna Senokot Polyethylene glycol 3350 GlycoLax, MiraLAX Lactulose Kristalose

Aim of bisacodyl study: oto observe Complete Spontaneous Bowel Movements (CSBM) every week during 4 weeks treatment otwo condition related to bowel movement : Spontaneous Bowel Movement (SBM): spontaneous defecation Complete Spontaneous Bowel Movement (CSBM): spontanneous defecation with good sensation

Study result: Complete Spontaneous bowel movement at first day & 4 weeks after treatment : Placebo Bisacodyl Total patients 117 239 First step evaluation 1.1 1.1 4 weeks evaluation 2.0 5.2 Different result between bisacodyl & placebo 3.3 95% Confidence interval (2.6, 4.0) p-value <0.0001 Significant difference the end result from 2 groups, bisacodyl more superior than placebo

Percentage of patients Patients self assesment for quality of life (QOL) 60 50 40 30 20 PBO BIS 10 0 Good Satisfactory Not satisfactory Bad Bisacodyl increase QOL from patients with constipation recovery bowel habit every day. 80% patients have satisfied with Bisacodyl.

Suggested Management Algorithm for Chronic Constipation Bleeding, anemia, weight loss, sudden change in stool caliber, abdominal pain Alarm Symptoms Directed testing Refer to a specialist as needed No Alarm Symptoms Lifestyle, OTC, stimulant laxative + Response Continue regimen No response OTC = over-the-counter therapies (probiotics, herbal medications, stool softeners [docusate sodium], psyllium, methylcellulose, calcium polycarbophil, bisacodyl, senna)

Conclusions (1) : Chronic Constipation is a functional GI disorder consists of 2 types CIC and IBS-C Differences in clinical symptoms of IBS-C and CC are abdominal pain in IBS-C Pathophysiology is a motility disorder, CC with hipomotility and IBS-C with segmental spasm Diagnosis is based on history of illness refer to Rome criteria

Conclusions (2) : Treatment for CC with prokinetic or stimulant laxative & IBS-C with antispasmodic as primary drug Reassured he patient that the disease is not harmful & need longstanding treatment to improve QOL Development of new treatments not medically further research is still needed

Paediatric constipation

Journal of Pediatrics 2005;146:359-63 Constipation Prevalence

Classification of Pediatric constipation

Delayed passage of meconium Intestinal Obstruction / Anatomical Malformation Hirschsprung s Disease Meconium Ileus Functional Ileus Small left colon Maternal Drugs Hypothyroidism

Normal Frequency of Bowel Movements Evaluation and Treatment of Constipation in Infants and Children: Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Journal of Pediatric Gastroenterology & Nutrition. 43(3):e1-e13, September 2006.

Functional vs. Organic -- Functional Over 95% of Constipated children has functional constipation Functional: persistent, difficult, infrequent, or seemingly incomplete defecation without evidence of underlying structural or metabolic defect Most commonly due to with-holding after a painful bowel movement Presents most commonly at three age periods» At introduction of cereals and solid foods» At toilet training» At the start of school

Functional Constipation Classic History Child has a painful bowel movement When urge to have a bowel movement happens, the child consciously withholds stool by contracting their external anal sphincter and gluteal muscles The child might rise on their toes, rock back and forth, stiffen their buttocks and legs, assume unusual postures, and often will hide in a corner Eventually, the rectum habituates to the stimulus of the enlarging fecal mass, the urge to defecate subsides, and the retentive behavior becomes almost second nature or subconscious» Can develop soiling (encopresis)

Evaluation of Constipation Evaluation and Treatment of Constipation in Infants and Children: Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Journal of Pediatric Gastroenterology & Nutrition. 43(3):e1-e13, September 2006.

Overall approach to management Determine whether fecal impaction present Treat impaction if present Initiate treatment with oral medications Provide parental education Close follow up Adjust medications as necessary

% pasien SPS untuk Konstipasi Kronis Pada Anak* 90 80 70 60 50 40 30 20 10 0 Efikasi SPS Pada Konstipasi Anak Sangat efektif Efektif Tidak efektif Keterangan: Sangat efektif : Defekasi terjadi dalam sehari Efektif: Defekasi terjadi dalam 2 hari Tidak efektif: Tidak terjadi defekasi setelah 3 hari atau lebih Sodium picosulfate (SPS) efektif mengatasi konstipasi pada anak pada lebih dari 83% pasien. Dengan bentuk tetes, tidak berwarna, tidak berbau, dan tidak berasa, sodium picosulfate lebih mudah untuk diberikan pada pasien anak-anak. *sodium picosulfate cocok untuk anak di atas 4 tahun Kozaki T. Journal of New Remedies and Clinics. 1976;25(6): 1009-1012.

Toilet Hygiene Dynamics of the Anorectal Angle Anorectal Angle in Action Twice a day for 10-15 minutes after breakfast and dinner Gastrocolic reflex Sit up straight Thighs parallel to ground Good foot support Valsalva maneuver to increase abd pressure Blow up balloon No distractions Reasonable reward system

Enema Fleets Phosphosoda enema < 2 YO not recommended 2 4 YO = 33.75 ml (1/2 of a Pediatric Fleets enema <Pedia Lax>) 5-11 YO = 67.5 ml (full Pediatric Fleets enema <Pedia-Lax>) 12 YO and up 118 ml (adult Fleet enema) Retention of enema Hyperphosphatemia Hypocalcemia Never give more than one enema per day If enema not evacuated, do not give a second enema

Lactulose Second line in infants < 6 mo not responding to juice Limited role in those over 6 mo secondary to success of PEG 3350 Comes 10 g / 15 ml Dose = 1-3 ml/kg/day in single or divided doses Usually start ½ to 1 teaspoon a day and increase as needed Side effects Cramps, flatulence, colicky behavior

PEG 3350 Safe for use down to 6 months of age Comes 17 grams in a cap Roughly 4 teaspoons is in one cap (1 teaspoon = roughly 4 to 5 grams of PEG 3350 Easier to dose by teaspoon in infants Typical dose for maintenance is roughly 0.7 g/kg/day In older children typically start at max of 17 grams twice a day but can increase if needed Technically no max dose If not responding to 34 grams a day in older child or roughly 1 g/kg/day in younger child, consider adding a stimulant laxative, re-education, or referral

Sample Treatment regimen for older child (non infant) Start Miralax at discussed doses Increase or decrease dose by small amounts until desired effect is reached Follow up within 1 month Aggressive Approach After 8 weeks of soft daily bowel movements, begin to taper by small amounts every couple of weeks (1/4 of dose at a time is a good guide) until BM achieved without laxative If stools become hard again during taper, increase to the last effective dose and maintain for another 8 weeks Conservative approach Continue laxatives for 6 months of soft daily bowel movements, then wean slowly

Long Term Outcome of Constipation Gastroenterology 2003;125:357-363

Stimulants Senna Comes 8.8 mg/5ml or 8.8 mg tabs 2-6 YO 2.5 to 7.5 ml a day 6-12 YO 5-15 ml a day Try to limit to periodic dosing With regular use drug can lose effectiveness» Anecdotal evidence Bisacodyl 0.2 mg/kg/dose, max 10 mg per dose Comes in 5 and 10 mg tabs Use intermittently or for short periods Has very high side effect profile Cramping, diarrhea, abdominal pain, nausea

Summary Functional constipation mostly found in children Kind of laxative use depend on age of child Training must be done beside laxative drugs Laxative therapy is the initial step further toilet training should be conducted on an ongoing basis

Thank you very much for your kind attention