Thomas M Guenthner Ph D Department of Pharmacology E 418 MSA m c 868 996 2558 tmg uic edu DRUGS THAT AFFECT GASTROINTESTINAL FUNCTION Objectives 1 Learn the mechanisms and uses of drugs that affect gastrointestinal motility a Pro emetic agents b Antiemetic agents c Prokinetic agents d Antidiarrheal agents e Laxatives and cathartics 2 Learn the mechanisms and uses of drugs that affect gastric acidity a Antacids b H2 histamine antagonists c Proton pump inhibitors d Prostaglandins 3 Understand current therapeutic strategies for Peptic Ulcer Disease PUD and Gastroesophageal Reflux Disease GERD 4 Understand therapeutic strategies for Inflammatory Bowel Disease IBD Required Reading Katzung Basic and Clinical Pharmacology 8th edition Chapter 63 pp 1064 1076 Recommended Reading Goodman and Gilman 10th edition Chapters 37 39 pp 10031037 Gastrointestinal maladies are a major source of patient complaints and result in major expenditures on both prescription and OTC pharmacological remedies 2 5 million physician visits year in US related to constipation Annual expenditures on laxatives in US 1 x 10e9 Page 1 of 9 I Drugs that affect GI motility A Pro and antiemetics Emesis is a complex reflex with multiple sensory and neuronal inputs Proemetic drugs used primarily in cases of oral poisoning act primarily by direct effects on CTZ Syrup of Ipecac active principle emetine OTC Apomorphine more potent and rapid acting Antiemetic drugs used for motion sickness postoperative nausea nausea in response to chemotherapy and radiation have multiple sites of action H1 Antihistamine drugs Page 2 of 9 diphenhydramine DRAMAMINE OTC meclazine BONINE OTC act at vestibular afferents and brain stem minimally or ineffective vs CT induced nausea Anticholinergic drug Scopalamine dermal patch slow release Drugs active vs CT and radiation induced nausea D2 dopamine antagonists act centrally at CTZ Metoclopramide Promethazine 5HT3 serotonin antagonists Ondansetron Cannabinoids Dronabinol delta 9 THC Dexamethasone and benzodiazepines have secondary antiemetic effects B Prokinetic Drugs Used to treat gastroparesis or lack of motility in upper GI tract Postoperative paralysis Diabetic gastroparesis Gastroesophageal reflux disease GERD Page 3 of 9 Muscarinic agonists bethanachol and anticholinesterase drugs neostigmine no longer widely used due to nonspecificity Metoclopramide primary effect 5HT4 agonist secondary effect D2 antagonist also antiemetic due to D2 antagonism Cisapride also 5HT4 agonist cardiac toxicity limits its use Domperidone less effective D2 antagonisim only not available in US Direct effects on gastric smooth muscle Octreotide somatostatin analog iv only used vs postoperative gastroparesis Macrolide antibiotics erythromycin used vs diabetic gastroparesis C Antidiarrheal agents Diarrhea occurs when capacity of gi epithelium to absorb water is exceeded by luminal contents either due to decreased absorption or increased secretion Diarrhea is always inconvenient but often beneficial and usually self limiting Symptomatic treatment can mask underlying pathology Important to replace fluids and electrolytes Intraluminal agents increase stool viscosity and absorb water Numerous OTC agents KAOPECTATE METAMUCIL Bismuth salycilate silicate clay PEPTOBISMOL also has antibacterial effects vs traveller s diarrhea Opioids Loperamide IMODIUM No significant CNS penetration minimal abuse potential available OTC Diphenoxylate LOMOTIL Difenoxin MOTOFEN greater CNS effects Rx only Other agents Octreotide paradoxical antisecretory effects and decreases colonic tone iv only used in severe AIDS or CT induced diarrhea Page 4 of 9 alpha 2 agonists cholestyramine binds bile salts d Laxatives and Cathartics Constipation occurs when excessive fluid reabsorbtion decreases stool volume This leads to longer transit time and further water reabsorbtion Objective is to break this cycle by increasing stool volume or decreasing transit time Bulk laxatives Dietary fiber Methylcellulose CITRUCEL Psyllium seed husk METAMUCIL Retain water and support bacterial growth increased bacterial fermentation produces short chain fatty acids which stimulate motility Saline Laxatives non absorbable inorganic salts create hyperosmotic luminal environment which increases secretion and decreases reabsorbtion given orally or by enema MgOH milk of magnesia MgSO4 epsom salts Mg Citrate Na phosphate FLEET PHOSPHO SODA can produce electrolyte and fluid imbalance Avoid when renal insufficiency or cardiac disease is present Nondigestible sugars and alcohols glycerin sorbitol lactulose PEG Stimulant Laxatives directly stimulate colonic motility also enhance secretion of fluid and electrolytes Diphenylmethane derivatives Phenolphthalein EXLAX withdrawn due to possible cardiac toxicity Bisacodyl Page 5 of 9 Natural Products can induce vioilent catharsis Castor oil ricin ricinoleic acid Anthroquinones senna cascara Stool Softeners surfactants COLACE mineral oil II Drugs that Affect Gastric Acidity Gastic hyperacidity or hypersecretion is an etiological factor in GERD and Peptic Ulcer Disease PUD It results in tissue destruction ulcers both directly and by activation of digestive enzymes Control of stomach acidity uses several approaches neutralization of existing acid inhibition of acid secretion enhancement of natural protective processes and treatment of H Pylorii infection A Antacids weak inorganic bases that neutralize stomach acid and raise pH Many OTC antacids available Bicarbonate Baking Soda ALKA SELTZER Ca Carbonate TUMS Mg or Al hydroxide Milk of Magnesia MAALOX MYLANTA good for episodic treatment of indigestion but not effective vs chronic disease B Inhibitors of acid secretion Gastric acid is secreted by a proton pump located in the parietal cell The activity of this pump is regulated by 1 neural stimulation via the vagus nerve 2 endocrine stimulation via gastrin relaesed from G cells and 3 local relaese of histamine from enterochromaffin like ECL cells Page 6 of 9 H2 histamine antagonists First selective inhibitors of proton pump activity block stimulation of parietal cell activity by histamine Distinct from H1 antagonists which block proinflammatory effects of histamine Lack H1 antagonist effects like drowsiness Are now available OTC Have been mostly supplanted by direct proton pump inhibitors see below Mostly given to lower basal secretion of acid at night Cimetidine TAGAMET potent inhibitor of CYP3A4 Ranitidine ZANTAC does not inhibit CYP Famotidine
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