Phase 1 Block 1 PPT Pharmacology of the Large Intestine October 2023 PDF

Phase 1 Block 1 PPT Pharmacology of the Large Intestine Dr Dan Mitchell, PPT Theme Lead Warwick Medical School Email: [email protected]  Learning Outcomes List the classes of drugs used to treat disorders of GI motility; Describe the molecular and cellular mec...

Phase 1 Block 1 PPT Pharmacology of the Large Intestine Dr Dan Mitchell, PPT Theme Lead Warwick Medical School Email: [email protected]  Learning Outcomes List the classes of drugs used to treat disorders of GI motility; Describe the molecular and cellular mechanism of action of drug therapies for disorders of GI motility; Relate molecular and cellular mechanism of drug action to responses at the tissue and organ level in the treatment of common disorders of GI motility. From the Phase 1 Drugs List  Classes of drugs used to treat disorders of GI motility 1. Purgatives i. Bulk laxatives ii. Osmotic laxatives iii. Faecal softeners iv. Stimulant purgatives 2. Anti-diarrhoeal agents i. Anti-motility agents  1i. Bulk Laxatives Polysaccharide polymers that are not broken down by the normal process of digestion. Retain water in the GI lumen, softening and increasing faecal bulk and promote increased motility. E.g. methylcellulose plant gums such as bran, agar, guar or ispaghula husk methylcellulose Citrucel®, ispaghula husk Fybogel® Time of action: 1-3 days Usage: Good first choice in common constipation (but not recommended for opoid-associated constipation)  1ii. Osmotic Laxatives Poorly absorbed solutes: saline purgatives, macrogols and lactulose. Promote movement of fluid by osmosis across the wall into the GI tract lumen. This accelerates small intestine transit and results in an abnormally large volume of fluid entering colon. Distension leads to purgation.  Osmotic Laxatives Saline Purgatives Magnesium sulphate and magnesium hydroxide Potent, rapid action (1-2 hrs), watery evacuation. Usage: Bowel prep. prior to procedure Macrogols Inert polymers of ethylene glycol Sequester fluid in the bowel Usage: treatment of faecal impaction in children long-term management of chronic constipation  Osmotic Laxatives Lactulose Semi-synthetic disaccharide of fructose and galactose. Colonic bacteria convert it to its two component monosaccharides, which are NOT absorbed into the blood by the intestines. Fermentation yields lactic acid Act: within 1-3 days and acetic acid in the large Usage: intestine - these function as Chronic constipation osmotic laxatives. Opioid-associated constipation.  1iii. Faecal Softeners Docusate, arachis oil enema Anionic surfactants: lower surface tension at oil- water interface, allowing water or fats to enter the stool. Faecal matter is softened. Action time: slower, i.e. 3-5 days to keep stools soft. Usage: constipation & rectal fissures and/or haemorrhoids.  1iv. Stimulant Purgatives Stimulate colonic motility Bisacodyl Usually given as a suppository. Stimulates rectal mucosa, resulting in mass movements and defaecation in 15-30 minutes. Usage: only short courses should be used, commonly used in opioid- associated constipation. Senna Contains derivatives of anthracene combined with sugars to form glycosides. Passes unchanged into colon, where bacterial action releases free anthracene derivatives. Anthracene derivatives are absorbed by the intestinal mucosal and have a direct effect on myenteric plexus: Innervation of the GI Tract Berne & Levy, Principles of Physiology, Mosby  Effect of Senna on Colonic Motility Strain gauge recordings: Senna Proximal colon Mid colon 1 Mid colon 2 Mid colon 3 Distal colon  “Cathartic Colon” Anatomical and physiological changes in the colon that occurs with chronic use of stimulant laxatives (> 3 times per week for at least 1 year). laxative dependency tachyphylaxis (requires higher doses) Can lead to serious medical consequences such as fluid and electrolyte imbalance. Signs and symptoms include bloating, a feeling of fullness, abdominal pain, and incomplete faecal evacuation.  Prevention of Constipation Easier to prevent than to treat. The relief of constipation with osmotic laxatives should immediately be followed with prevention using increased fibre and a nightly decreasing dose of osmotic laxative. In various conditions (such as chronic use of opioids), combinations of osmotic, bulk-forming and stimulant agents may be necessary to prevent constipation.  Diarrhoea from the Greek “diarrhoia" meaning "a flowing through“. Frequent watery, loose bowel movements. Numerous causes including infectious agents, toxins, anxiety, drugs. Major cause of death in malnourished infants. Involves increased GI motility and secretion, decreased absorption. Fluid and electrolyte loss.  Types of Diarrhoea Secretory diarrhoea Increased active secretion, or an inhibition of absorption e.g. cholera. Osmotic diarrhoea Loss of water due to a heavy osmotic load, e.g. in maldigestion (e.g. Coeliac disease), where the nutrients remain in lumen. Motility-related diarrhoea Abnormally high GI motility, decreasing time available for absorption. Can occur in diabetic neuropathy. Inflammatory diarrhoea Damage to mucosal lining or brush border leads to passive loss of protein-rich fluids, and decreased ability to absorb fluids. Causes include bacteria, viral or parasitic infections or autoimmune problems e.g. inflammatory bowel disease.  Classes of drugs used to treat disorders of GI motility 1. Purgatives i. Bulk laxatives ii. Osmotic laxatives iii. Faecal softeners iv. Stimulant purgatives 2. Anti-diarrhoeal agents i. Anti-motility agents  2i. Anti-motility Agents Opioids: e.g. Loperamide, codeine. loperamide Imodium® Loperamide has a relatively selective action on GI tract. Act on m-opioid receptors in the myenteric plexus and intestinal smooth muscle: – increase activity of the circular smooth muscles. – decrease activity of the longitudinal muscles. Effect of Loperamide on Colonic Motility Strain gauge recordings Loperamide Proximal colon Distal colon  Anti-motility Agents Increase segmented (haustral) contractions of proximal colon, thus increasing mixing and water reabsorption. Diminish peristaltic activity of distal colon, thus diminishing propulsive mass movements. Contract pyloric, ileocaecal and anal sphincters. Result in firmer stool and decreased defaecation frequency. Usage: symptomatic treatment of acute uncomplicated diarrhoea in adults (adjunct to rehydration therapy) Side effects: Chronic use leads to constipation, abdominal cramps, dizziness. Paralytic ileus can also occur. Caution: Do not use in young children.  Resources Medical Pharmacology & Therapeutics 6th Edition – Waller & Sampson. Chapter 35. Available via ClinicalKey Student. Rang & Dale’s Pharmacology 9th Edition. Chapter 31. Available via ClinicalKey Student.