1) The document discusses medications used to treat gastrointestinal disorders by suppressing acid secretion or affecting gastrointestinal motility. It covers proton pump inhibitors, H2 receptor antagonists, antacids, and other drugs used for conditions like GERD, ulcers, constipation, and diarrhea. 2) Specific drugs are highlighted for treating acid reflux including PPIs like omeprazole, H2 blockers like ranitidine, and antacids. Treatment for H. pylori infection and complications of long-term acid suppression are also reviewed. 3) Laxatives for constipation are categorized and specific examples given for each type. Opioid derivatives and adsorbents are outlined

1. Gastrointestinal Pharmacotherapy Sarah Nelson, Pharm.D. March 3, 2009

2. Objectives Discuss the process of acid secretion in the gastrointestinal tract Differentiate medications used to suppress gastric acid secretion Explain the role of gastrointestinal motility in disease states Differentiate medications used to account for impaired gastrointestinal motility

3. Gastrointestinal tract http://www.nationmaster.com/encyclopedia/Gastrointestinal-tract

4. Disorders of the Esophagus and Stomach Gastroesophageal Reflux Disease (GERD) Dyspepsia/Non-erosive reflux disease (NERD) Esophagitis (erosive) Peptic ulceration H. pylori associated peptic ulcers Ali, T. Miner, P. New Developments in gastroesophageal reflux disease diagnosis and therapy. Curr Opin in Gastroenterology. 2008;24:502-508

5. Gastric Secretion http://www.nature.com/nrd/journal/v2/n2/images/nrd1010-f2.gif

6. Stomach Anatomy http://www.nlm.nih.gov/medlineplus/ency/images/ency/fullsize/19223.jpg

7. Defense Mechanisms Lower esophageal sphincter Secretion of gastric mucus Stimulated by prostaglandin E 2 and I 2 Secretion of bicarbonate ions Brunton, Laurence. Goodman & Gillman’s The Pharmacological Basis of Therapeutics . 11 th Edition. USA; McGraw-Hill Company, 2006.

8. GERD Definition: when the reflux of stomach contents causes troublesome symptoms or complications Diagnosis: Presence of symptoms Demonstration of reflux Identification of existing damage from reflux Ali, T. Miner, P. New Developments in gastroesophageal reflux disease diagnosis and therapy. Curr Opin in Gastroenterology. 2008;24:502-508

9. Epidemiology 44% of adults in the US experience heartburn ≥ 1 time/month Up to 15-18% of adults in the US experience heartburn weekly Heartburn or substernal burning is the most commonly recognized manifestation of GERD Shaheen, N., Ransohoff, D.F. Gastroesophageal Reflux, Barrett Esophagus, and Esophageal Cancer: Scientific Review. J AMA . 2002;287(15):1972-1981

10. Risk Factors for GERD Obesity Food (spicy, chocolate, peppermint) Age Smoking Caffeine Alcohol Pregnancy Dipiro, Joseph et al. Pharmacotherapy: A Pathophysiologic Approach . 6 th Edition. USA; McGraw-Hill Company, 2005.

11. Stages of GERD Brunton, Laurence. Goodman & Gillman’s The Pharmacological Basis of Therapeutics . 11 th Edition. USA; McGraw-Hill Company, 2006. PPI once or twice daily Chronic, unrelenting Immediate relapse off therapy Esophageal complications III PPI vs. H2RA Frequent symptoms +/- esophagitis II Lifestyle modification Antacids/H2 RA as needed sporadic 2-3 episodes/wk I (NERD) Medical Management Description Stage

12. Treatment of GERD Decrease acidity of stomach contents Antacids H2 receptor antagonists Proton pump inhibitors Protect gastric mucosa sucralfate Brunton, Laurence. Goodman & Gillman’s The Pharmacological Basis of Therapeutics . 11 th Edition. USA; McGraw-Hill Company, 2006.

13. Antacids Chemically neutralize stomach acid Base (OH) 3 or CO 3 + Al, Ca, or Mg CaCO 3 = calcium carbonate (Tums ®) Al (OH) 3 + Mg (OH) 2 = Maalox ® Some contain simethicone (a surfactant) Al (OH) 3 + Mg (OH) 2 + simethicone = Mylanta ® Site GI chapter

14. Antacids Mechanism of Action: Antacid + HCl salt + water Examples Al(OH) 3 + 3 HCl AlCl 3 + 3H 2 O CaCO 3 + 2 HCl CaCl 2 + 2H 2 0 + CO 2 Site GI chapter

15. Antacids Side Effects Constipation (Al containing products) Diarrhea (Mg containing products) Electrolyte imbalances Decreases absorption of other drugs Place in Therapy Minor, infrequent dyspepsia With other acid suppressants on an as needed basis Calcium supplementation Site GI chapter

16. H 2 -Receptor Antagonists Block histamine from binding to H 2 receptors on parietal cell Decrease rate of activation by histamine decreased acid secretion Blocks basal and bolus acid secretion Basal: continuous acid secretion Bolus: secretion in response to stimuli (food, etc) Brunton, Laurence. Goodman & Gillman’s The Pharmacological Basis of Therapeutics . 11 th Edition. USA; McGraw-Hill Company, 2006.

17. H 2 -Receptor Antagonists Cimetidine (Tagamet ® ) Not used often due to drug interactions Ranitidine (Zantac ® ) 150-300mg by mouth twice daily Famotidine (Pepcid ® ) 20-40mg by mouth twice daily Nizatidine (Axid ® ) 150-300mg by mouth twice daily Brunton, Laurence. Goodman & Gillman’s The Pharmacological Basis of Therapeutics . 11 th Edition. USA; McGraw-Hill Company, 2006.

18. H 2 -Receptor Antagonists Side Effects Well tolerated Many drug interactions, esp. with HIV medication Tolerance can develop with long term use Place in Therapy As needed for minor dyspepsia Daily to control frequent symptoms Low dose for symptoms w/o esophagitis High dose for symptoms w/ esophagitis Brunton, Laurence. Goodman & Gillman’s The Pharmacological Basis of Therapeutics . 11 th Edition. USA; McGraw-Hill Company, 2006.

19. Proton Pump Inhibitors Most potent inhibitors of acid secretion Decrease daily acid secretion 80-95% Require activation by acid in stomach Irreversibly binds and inactivates the H + /K + -ATPase H + /K + -ATPase is the pump molecule that secretes acid from the parietal cell into the lumen of the stomach Brunton, Laurence. Goodman & Gillman’s The Pharmacological Basis of Therapeutics . 11 th Edition. USA; McGraw-Hill Company, 2006.

20. Proton Pump Inhibitors Site GI chapter 20mg daily 20mg daily Rabeprazole (Aciphex ® ) 20-40mg daily 40mg daily Pantoprazole (Protonix ® ) 15 mg daily 15-30mg daily Lansoprazole (Prevacid ® ) 20mg daily 20-40mg daily Esomeprazole (Nexium ® ) 20mg daily 20-40mg daily Omeprazole (Prilosec ® ) Prevention Healing Drug

21. Proton Pump Inhibitors Side Effects Well tolerated Takes multiple doses to get full effect Place in Therapy Symptomatic GERD with esophagitis Promote healing of gastric ulcers Hypersecretory conditions Prevent NSAID-associated gastric ulcers Brunton, Laurence. Goodman & Gillman’s The Pharmacological Basis of Therapeutics . 11 th Edition. USA; McGraw-Hill Company, 2006.

22. Miscellaneous Other medications used for GERD Prostaglandin analogues (i.e. misoprostol) Bind a EP 3 receptor on parietal cells, decreasing cAMP (energy) available for H + /K + -ATPase Sucralfate Sucrose + Al(OH) 3 which forms a viscous layer on the gastric mucosa Prevents acid from contacting mucosa Metoclopramide Stimulates gastric motility increased clearance of stomach acid Site GI chapter

23. Complications of GERD Ulceration (w/ or w/o H. pylori) Asthma exacerbations Esophageal strictures Adenocarcinoma Barrett Esophagus Shaheen, N., Ransohoff, D.F. Gastroesophageal Reflux, Barret Esophagus, and Esophageal Cancer: Scientific Revies. J AMA . 2002;287(15):1972-1981 Dougherty, R., Fahy, J. Acute exacerbations of asthma: epidemiology, biology and the exacerbation-prone phenotype. Clinical and Experimental Allergy. 2009;39(2):193-202

24. H. Pylori Infection Gram-negative rod Not always associated with an active ulcer Associated with gastritis, leads to: Gastric/duodenal ulcers Gastric adenocarcinoma Gastric B-cell lymphoma Eradication is standard of care to promote healing of ulcer and to prevent recurrence Brunton, Laurence. Goodman & Gillman’s The Pharmacological Basis of Therapeutics . 11 th Edition. USA; McGraw-Hill Company, 2006.

25. H. Pylori Infection 3 Drug Combination Proton pump inhibitor (high dose) 2 antibiotics (clarithromycin + amoxicillin OR metronidazole 4 Drug Combination Proton pump inhibitor (high dose) 2 antibiotics (metronidazole + tetracycline OR amoxicillin OR clarithromycin) Bismuth subsalicylate All regimens 14 days in duration Patient compliance is difficult with intense regimens Brunton, Laurence. Goodman & Gillman’s The Pharmacological Basis of Therapeutics . 11 th Edition. USA; McGraw-Hill Company, 2006.

26. Acid-rebound Phenomenon Chronic suppression of acid secretion leads to hypergastrinemia Gastrin stimulates ECL cells to release histamine increased acid secretion from activation of histamine receptor on parietal cell Brunton, Laurence. Goodman & Gillman’s The Pharmacological Basis of Therapeutics . 11 th Edition. USA; McGraw-Hill Company, 2006.

27. Disorders of the Lower GI Tract Constipation Diarrhea

28. Gastrointestinal Motility The GI tract is in a continuous contractile, absorptive, & secretory state Muscle, CNS, ENS (enteric nerve system), and humoral pathways control GI movement 4 phases to movement in the GI tract Peristalsis is most important, moves contents through GI tract Brunton, Laurence. Goodman & Gillman’s The Pharmacological Basis of Therapeutics . 11 th Edition. USA; McGraw-Hill Company, 2006.

29. GI Motility http://img.tfd.com/vet/thumbs/gr294.jpg increased transit time - Increased water absorption constipation decreased transit time -Decreased water and nutrient absorption diarrhea

30. Constipation Affects up to 27% of Americans Accounts for 2.5 mil. physician visits/year $400 million spent on OTCs annually Definition Unsatisfactory defecation that results in infrequent stool, difficult stool passage, or both Cash, B. et al. Update on the Management of Adults with Chronic Idiopathic Constipation. The Journal of Family Practice. 2007;56(6):S13-20

31. Constipation http://www.helpfulhealthtips.com/Images/C/constipation1.jpg

32. Causes of Constipation GI disorders Irritable bowel syndrome, hernia, anal fissures Metabolic disorders Diabetes with neuropathy, hypothyriodism Pregnancy Psychogenic disorders Medications Analgesics, antacids, iron preparations Dipiro, Joseph et al. Pharmacotherapy: A Pathophysiologic Approach . 6 th Edition. USA; McGraw-Hill Company, 2005.

33. Treatment of Constipation Lifestyle modifications Fiber-rich diet Adequate fluid intake Appropriate bowel habits and training Exercise Medications Bulk-forming laxatives Stimulant laxatives Hyperosmotic laxatives Stool softeners Brunton, Laurence. Goodman & Gillman’s The Pharmacological Basis of Therapeutics . 11 th Edition. USA; McGraw-Hill Company, 2006.

34. Bulk-Forming Laxatives 3 kinds Psyllium (Metamucil ® ) Methylcelluose (Citrucel ® ) Calcium polycarbophil (Fibercon ® ) Increases colonic mass which triggers peristalsis Increases water content of stool via hydrophilic forces Brunton, Laurence. Goodman & Gillman’s The Pharmacological Basis of Therapeutics . 11 th Edition. USA; McGraw-Hill Company, 2006.

35. Stimulant Laxatives Induce low-grade inflammation in the small and large intestine Promotes accumulation of water and stimulates motility Provides soft or semifluid stool in 6-12 hours Bisacodyl (Dulcolax ® ) 5-15 mg by mouth daily; 10mg rectally daily (rectal administration effective within 1 hour) Castor Oil Senna (Senokot ® ) 8.6mg sennosides 1-2 times per day (1-2 tablets once or twice daily) Brunton, Laurence. Goodman & Gillman’s The Pharmacological Basis of Therapeutics . 11 th Edition. USA; McGraw-Hill Company, 2006. Dipiro, Joseph et al. Pharmacotherapy: A Pathophysiologic Approach . 6 th Edition. USA; McGraw-Hill Company, 2005.

36. Hyperosmotic Laxatives Osmotically mediated water retention (via cations-Al, Mg, etc) which stimulates peristalsis Provides watery fecal evacuation in 1-6 hours Magnesium hydroxide (Milk of Mag) 5-15mL by mouth four times daily Polyethylene glycol (Miralax ® ) Dose used depends on level of evacuation Sodium phosphate (Fleets Phosphosoda ® ) Brunton, Laurence. Goodman & Gillman’s The Pharmacological Basis of Therapeutics . 11 th Edition. USA; McGraw-Hill Company, 2006. Dipiro, Joseph et al. Pharmacotherapy: A Pathophysiologic Approach . 6 th Edition. USA; McGraw-Hill Company, 2005.

37. Stool Softeners/Lubricants Docusate (Colace ® ) Stool softener Mixes aqueous and fatty material in the intestinal tract, leading to increase stool water content Used to prevent constipation or straining 1-2 capsules by mouth once or twice daily Mineral Oil (Nujol ® ) Lubricant Coats stool and allows for easier passage 15-30mL orally as needed Causes softening and passage of stool in 1-3 days Brunton, Laurence. Goodman & Gillman’s The Pharmacological Basis of Therapeutics . 11 th Edition. USA; McGraw-Hill Company, 2006.

38. Diarrhea Prevalence of diarrhea varies in developed vs. non-developed countries 1.3 billion episodes/yr in developing countries 4 million deaths Can be associated with an infectious cause Shigella, Salmonella, E. Coli among most common Most diarrhea is self-limiting Defined as an increase in stool frequency or water content Dipiro, Joseph et al. Pharmacotherapy: A Pathophysiologic Approach . 6 th Edition. USA; McGraw-Hill Company, 2005.

39. Diarrhea http://www.ghi.com/WebMD/topics/diarrhea.jpg

40. Opioid Derivatives Bind the µ -receptor on enteric nerves, epithelium, and muscle Decrease GI motility Increase absorption of water from the bowel Diphenoxylate (Lomotil ® ) 5mg by mouth 4 times daily (max 20mg/day) Loperamide (Immodium ® ) 4mg by mouth first, then 2mg by mouth after each loose stool (max 16mg/day) Site GI chapter Dipiro, Joseph et al. Pharmacotherapy: A Pathophysiologic Approach . 6 th Edition. USA; McGraw-Hill Company, 2005.

41. Adsorbents Non-selectively absorbs intestinal fluid Regulates stool texture and viscosity Bind bacterial toxins and bile salts Attapulgite (Kaopectate ® ) 30-120mL after each loose stool Can bind other medications, must space out from others by 2 to 3 hours Brunton, Laurence. Goodman & Gillman’s The Pharmacological Basis of Therapeutics . 11 th Edition. USA; McGraw-Hill Company, 2006.

42. Bismuth Salicylate Anti-secretory, anti-inflammatory, antimicrobial effects Used for the prevention and treatment of traveler’s diarrhea PeptoBismol ® 30mL (2 tabs) every hour as needed (up to 8 times/day) Excessive use can lead to salicylate poisioning Brunton, Laurence. Goodman & Gillman’s The Pharmacological Basis of Therapeutics . 11 th Edition. USA; McGraw-Hill Company, 2006.

43. Probiotics Replaces normal colonic microflora Restores intestinal function and suppresses the growth of pathogenic bacteria Lactobacillus acidophilus (Lactinex ® ) 2 tabs or 1 packet of granules 3-4 times daily Dairy Products 200-400 grams of lactose Special ‘lactobacillus’ containing yogurts Dipiro, Joseph et al. Pharmacotherapy: A Pathophysiologic Approach . 6 th Edition. USA; McGraw-Hill Company, 2005.

44. Conclusion Approximately 1/3 of your patients will be taking a medication for GERD Approximately ¼ of your patients will be taking a medication for constipation GERD, constipation, and diarrhea affect a patient’s quality of life

45. Questions?