Pharmacotherapy of GI Motility Disorders (Constipation & Diarrhea)

1. Pharmacotherapy of GI Motility Disorders (Constipation & Diarrhea) Nasir Ali Afsar MBBS, M.Phil, Ph.D Senior Lecturer of Pharmacology

2. Objectives of the lecture DRUG TREATMENT OF CONSTIPATION: Briefly review the causes of constipation & classify the laxatives/purgatives based on the mechanism of action. Discuss the mechanism of action, adverse effects & clinical uses of bulk, osmotic, lubricant & stimulant laxatives. Discuss the special role of lactulose in the treatment of hepatic encephalopathy. DRUG TREATMENT OF DIARRHEA: Classify the non-specific anti-diarrhoeal drugs. Discuss the mechanism of action and adverse effects of anti-motility & adsorbent drugs.

3. Some Physiological Facts Ingestion of Fluid (2 L) Fluid Secretion (7 L) Lumen of intestine Absorption (4-5 L in colon) Normal Motility (Cholinergic, Serotonergic, Peptidergic control) Normal stool (200-300 g/d) 60-80% water w/w

4. Constipation – definition • Infrequent or difficult passage of stools during defecation. • At least two of the following symptoms for at least three of the past six months: • Pass < 3 stools a week • Experience hard stools • Strain excessively during bowel movements • Experience a sense of incomplete evacuation • Need to use manual maneuvers for evacuation

5. Constipation – etiology • Dietary: • Inadequate fluid and/or fiber intake. • Lifestyle-related: • Ignoring the urge to evacuate or delaying until later. • Lack of physical activity (especially in older adults). • Changes in routine, including pregnancy, aging and travel. • Dehydration • Medications: diuretics, anticholinergics, laxative abuse.

6. Constipation – etiology • Disorders: • Irritable bowel syndrome • Chronic illness and specific diseases, such as stroke, diabetes, hypothyroidism and Parkinson's disease • Colorectal problems, such as intestinal obstruction, diverticulosis, anal fissures, hemorrhoids, spinal cord injuries, colorectal cancer • Hirschsprung's disease, a congenital absence of myenteric plexus in distal part of large intestine.

7. Constipation – treatment Treat the underlying cause Lifestyle/ habit change Laxatives – only as a last option

8. Laxatives – classification • Bulk-forming Agents: • Mode of action: promote peristalsis • Example: Psyllium, Bran • Lubricants/ Fecal Softeners: • Mode of action: make stools easier to pass • Example: Glycerin suppositories, liquid paraffin, docusate sodium

9. Laxatives – classification • Osmotic Laxatives: • Mode of action: draw water into stools to make them softer and easier to pass • Example: Lactulose • Stimulant Laxatives • Mode of action: Stimulate/ irritate the gut mucosa and induces reflexive peristalsis • Example: Bisacodyl, senna, docusate sodium

10. Lactulose – special features • Non-absorbable disaccharides, hence draw water through osmosis and act as laxatives • Given orally to control • Constipation • Hepatic encephalopathy

11. Lactulose – special features Hepatic Cirrhosis abnormal intrahepatic circulatory shunts  ammonia produced (normally) by coliform bacteria reaches systemic circulation unchecked  encephalopathy Lactulose lactic acid+acetic acid pH in colon  growth of coliforms. Antibiotics, such as neomycin and rifaximin could be used alone or with lactulose to eliminate coliforms.

12. Intestines: Normal vs Constipation Ingestion of Fluid Less Fluid Fluid Fluid Secretion Secretion Lumen of intestine Lumen of intestine Absorption More Absorption Decreased Motility Normal Motility Normal stool Constipation

13. Intestines: Intervention in Constipation Less Fluid Plenty of Fluid Fluid Fluid Secretion Secretion Lumen of intestine Lumen of intestine Osmotic agents More Absorption Less Absorption Motility enhancing drugs Decreased Motility Normal stool Constipation

14. Doctor, thanks for solving my problem…

15. Diarrhea – definition • An increased frequency or decreased consistency of bowel movements. • Medical Definition: stool weighs above 250 g/day, usually with fluid consistency. • Pseudodiarrhea: Diseases that cause hyperdefecation (only an increase in the number of bowel movements), or incontinence (involuntary loss of bowel contents) are not diarrhea. • Acute, if duration < 3 weeks.

16. Infectious Bacterial Viral Mycotic Parasitic Non-infectious Hypersensitivity Malabsorption Drugs IBS IBDs Neoplasia Endocrine Diarrhea – etiology

17. Diarrhea – treatment • Removal of causative agent, such as infectious agent, allergen etc. • Symptomatic • Replace volume • Reduce motility

18. Diarrhea – treatment ANTIMICROBIAL AGENTS – for infective diarrhea: • As per culture and sensitivity (C/S) • Till the stool report and bacterial C/S report is available, some antimicrobials could be used empirically against expected/suspected bacteria or parasites, as follows • Fluoroquinolones • Cotrimoxazole • Metronidazole

19. Diarrhea – treatment REHYDRATION: • Oral rehydration solution (ORS) or intravenous fluids could be used, as indicated. • The WHO has provided alternate recipes to prepare oral rehydration solution at home. All these recipes contain table salt (NaCl), sugar and water as the basic components.

20. Antidiarrheal agents • Antimotility Drugs • Opiates, anticholinergics • Surface Acting Agents • Psyllium, Kaolin, Pectin, Colloidal Bismuth • Miscellaneous • Bile salt binding resins (Cholestyramine) • Antisecretory: Octreotide • IBS: 5-HT3 Antagonists, 5-HT4 Agonists

21. Antidiarrheal agents • ANTI-MOTILITY AGENTS (useful for those with non-infective diarrhea) • Opioid agonists ( receptor stimulants) • Loperamide: does not cross BBB • Diphenoxylate: given with atropine (an antimuscarinic agent) to reduce abuse potential. • Codiene • Bismuth subsalicylate: unknown mode of action. • Drug-induced paralytic ileus: association with increased mortality in pediatric patients.

22. Antidiarrheal agents • PSYLLIUM absorbs fluid and solidifies stools. • KAOLIN and PECTIN adsorb on enterotoxins as well as absorb water to form bulk. • CHOLESTYRAMINE binds bile acids and is effective in treating bile salt induced diarrhea. • OCTREOTIDE (somatostatin analogue) decrease excessive secretion of GI fluids through inhibiting various local peptide hormones and are useful in secretory diarrhea. • CLONIDINE(2 agonist) also decreases excessive secretion of GI fluid and are useful in autonomic neuropathies.

23. Antidiarrheal agents Additional Drugs for Irritable Bowel Syndrome: 5-HT3 Blockers: Alosetron, reduce GI contractility, because serotonin plays an important role in regulating gut motility and reflexes through 5-HT3 receptors. 5-HT4Stimulants: Tegaserod. 5-HT4 receptors show predominantly inhibitory function.

24. Alternative treatment of diarrhea • BIOTHERAPY: Yogurt and oral supplementation of yeasts Lactobacillus acidophilus, L. bifidus, or Saccharomyces boulardiiare used especially in antibiotic-associated diarrhea. • Zinc supplementation, especially in children with chronic diarrhea. • The BRAT diet (bananas, rice, applesauce, and toast) provides soluble and insoluble fiber without irritation. If the toast is slightly burnt, the charcoal can help sequester toxins and pull them from the body.

25. Intestines: Normal vs Diarrhea Microbes/ Allergens/ Irritants Ingestion of Fluid Fluid Fluid Secretion More Secretion Lumen of intestine Lumen of intestine Absorption Less Absorption Increased Motility Normal Motility Normal stool Diarrhea

26. Intestines: Intervention in Diarrhea Microbes/ Allergens/ Irritants ORS  Antimicrobials Antisecretory Agents Fluid Fluid More Secretion Secretion Lumen of intestine adsorbant Lumen of intestine Less Absorption Absorption Antimotility Drugs Increased Motility Normal stool Diarrhea

27. THANK YOU • Disclaimer: This presentation is only an adjunct to the suggested Pharmacology textbooks. • REFERENCES • Pharmacology: by Range, Dale & Ritter. Ed. 7 • Katzung’s Basic and Clinical Pharmacology. Ed. 12 • Goodman & Gilman’s Pharmacological Basis of Therapeutics. Ed. 12