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UIC PCOL 425 - DRUGS THAT AFFECT GASTROINTESTINAL FUNCTION

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Page 1 of 9Thomas M. Guenthner, Ph.D.Department of PharmacologyE-418 MSA, m.c. [email protected] THAT AFFECT GASTROINTESTINAL FUNCTIONObjectives:1) Learn the mechanisms and uses of drugs that affect gastrointestinal motilitya) Pro-emetic agentsb) Antiemetic agentsc) Prokinetic agentsd) Antidiarrheal agentse) Laxatives and cathartics2) Learn the mechanisms and uses of drugs that affect gastric aciditya) Antacidsb) H2 histamine antagonistsc) Proton pump inhibitorsd) Prostaglandins3) Understand current therapeutic strategies for Peptic Ulcer Disease (PUD) andGastroesophageal 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. 1003-1037)__________________________________________Gastrointestinal maladies are a major source of patient complaints and result in major expenditures on both prescription and OTC pharmacological remedies2.5 million physician visits/ year in US related to constipationAnnual expenditures on laxatives in US > $1 x 10e9Page 2 of 9I. Drugs that affect GI motilityA) Pro- and antiemeticsEmesis is a complex reflex with multiple sensory and neuronal inputsProemetic drugs used primarily in cases of oral poisoningact primarily by direct effects on CTZ:Syrup of Ipecac - active principle: emetine (OTC)Apomorphine - more potent and rapid actingAntiemetic drugs used for motion sickness, postoperative nausea, nausea in response to chemotherapyand radiationhave multiple sites of actionH1 Antihistamine drugs:Page 3 of 9diphenhydramine (DRAMAMINE OTC) meclazine (BONINE OTC)act at vestibular afferents and brain stemminimally or ineffective vs. CT-induced nauseaAnticholinergic drug: Scopalamine (dermal patch) - slow releaseDrugs active vs CT- and radiation-induced nausea:D2 dopamine antagonists - act centrally at CTZMetoclopramidePromethazine5HT3 serotonin antagonistsOndansetronCannabinoidsDronabinol (delta 9 THC)Dexamethasone and benzodiazepines have secondary antiemetic effectsB) Prokinetic DrugsUsed to treat gastroparesis or lack of motility in upper GI tract.Postoperative paralysisDiabetic gastroparesisGastroesophageal reflux disease (GERD)Page 4 of 9Muscarinic agonists (bethanachol) and anticholinesterase drugs (neostigmine) - nolonger widely used due to nonspecificityMetoclopramide - primary effect, 5HT4 agonist; secondary effect, D2 antagonistalso antiemetic due to D2 antagonismCisapride - also 5HT4 agonist (cardiac toxicity limits its use)Domperidone - less effective, D2 antagonisim only, not available in USDirect effects on gastric smooth muscle:Octreotide - somatostatin analog - iv only used vs postoperative gastroparesisMacrolide antibiotics (erythromycin)used vs diabetic gastroparesisC) Antidiarrheal agentsDiarrhea occurs when capacity of gi epithelium to absorb water is exceeded by luminalcontents, either due to decreased absorption or increased secretion.Diarrhea is always inconvenient but often beneficial, and usually self limitingSymptomatic treatment can mask underlying pathologyImportant to replace fluids and electrolytesIntraluminal agents - increase stool viscosity and absorb waterNumerous OTC agents (KAOPECTATE, METAMUCIL)Bismuth salycilate + silicate clay (PEPTOBISMOL)also has antibacterial effects vs “traveller’s diarrhea”OpioidsLoperamide (IMODIUM)No significant CNS penetration, minimal abuse potential (available OTC)Diphenoxylate (LOMOTIL), Difenoxin (MOTOFEN)greater CNS effects, Rx onlyOther agentsOctreotide - paradoxical - antisecretory effects and decreases colonic toneiv only, used in severe AIDS- or CT-induced diarrheaPage 5 of 9alpha 2 agonistscholestyramine - binds bile saltsd) Laxatives and CatharticsConstipation occurs when excessive fluid reabsorbtion decreases stool volume. Thisleads to longer transit time and further water reabsorbtion. Objective is to break thiscycle by increasing stool volume or decreasing transit time.“Bulk” laxativesDietary fiberMethylcellulose (CITRUCEL)Psyllium seed husk (METAMUCIL)Retain water and support bacterial growthincreased bacterial fermentation produces short chain fatty acids, which stimulatemotility“Saline” Laxativesnon-absorbable inorganic salts, create hyperosmotic luminal environment whichincreases secretion and decreases reabsorbtiongiven orally or by enemaMgOH (milk of magnesia)MgSO4 (epsom salts)Mg CitrateNa phosphate (FLEET PHOSPHO SODA)can produce electrolyte and fluid imbalance. Avoid when renal insufficiency or cardiacdisease is present.Nondigestible sugars and alcoholsglycerin, sorbitol, lactulose, PEGStimulant Laxativesdirectly stimulate colonic motility, also enhance secretion of fluid and electrolytesDiphenylmethane derivativesPhenolphthalein (EXLAX) withdrawn due to possible cardiac toxicityBisacodylPage 6 of 9Natural Products - can induce vioilent catharsisCastor oil (ricin, ricinoleic acid)Anthroquinones (senna, cascara)Stool Softenerssurfactants (COLACE)mineral oilII. Drugs that Affect Gastric AcidityGastic hyperacidity (or hypersecretion) is an etiological factor in GERD and Peptic UlcerDisease (PUD). It results in tissue destruction (ulcers) both directly and by activation ofdigestive enzymes. Control of stomach acidity uses several approaches: neutralizationof existing acid, inhibition of acid secretion, enhancement of natural protectiveprocesses, and treatment of H. Pylorii infectionA) Antacidsweak inorganic bases that neutralize stomach acid and raise pH. Many OTC antacidsavailableBicarbonate (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 diseaseB) Inhibitors of acid secretionGastric acid is secreted by a proton pump located in the parietal cell. The activity of thispump is regulated by 1) neural stimulation via the vagus nerve; 2) endocrine stimulationvia gastrin relaesed from G cells; and 3) local relaese of histamine fromenterochromaffin-like (ECL) cells.Page 7 of 9H2 histamine antagonistsFirst selective inhibitors of proton pump activity, block stimulation of parietal cell activityby histamine.Distinct from H1 antagonists, which block proinflammatory effects of histamine. LackH1 antagonist effects like drowsiness.Are now available OTC. Have been mostly supplanted by direct proton pump inhibitors(see


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UIC PCOL 425 - DRUGS THAT AFFECT GASTROINTESTINAL FUNCTION

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