1. GASTRO INTESTINAL TRACT PHARMACOLOGY - 1 LECTURE 7

2. The Gastrointestinal Tract Gastroesophageal Reflux Disease (GERD) Peptic Ulcer Disease (PUD) Duodenal Ulcer Nausea Emesis IBS Diarrhea Constipation

3. Gastroesophageal Reflux Disease (GERD) GERD is when acid and pepsin from the stomach flows backward up into the esophagus often called heartburn; 1) Overproduction of acid/pepsin 2) Over relaxation of the Lower Esophageal Sphincter (LES); Complications; if not treated - severe chest pains, bleeding or a pre- malignant change in the lining of the esophagus called Barrett’s esophagus – can result in adenocarcinoma

5. General Considerations - Backflow of stomach acid into the esophagus - Esophagus is not equipped to handle stomach acid => scaring - Usual symptom is heartburn, an uncomfortable burning sensation behind the breastbone (MI often mistaken for GERD !) - More severe symptoms: difficulty swallowing, chest pain - Reflux into the throat can cause sore throat - Complications include esophageal erosions, esophageal ulcer and narrowing of the esophagus (esophageal stricture) - In some patients (~10%), the normal esophageal lining or epithelium may be replaced with abnormal (Barrett's) epithelium. This condition (Barrett's esophagus) has been linked to cancer of the esophagus. - Treatment : Generally antacids

6. PEPTIC ULCER – A benign lesion of gastric or duodenal mucosa occurring at a site where the mucosal epithelium is exposed to acid and pepsin; – 1) Excess acid production – 2) Intrinsic defect in the mucosal defense barrier – Average size ¼ and ½ inch in diameter Peptic Ulcer Disease Affects All Age Groups Men Have Twice The Risk as Women Do Genetic Factors Increase Acid Production and/or Decrease in Bicarbonate and PG Production

7. Pathophysiological Processes Involved in Duodenal and Gastric Ulcers HP NSAID Cancer (ZE) Other Duodenal Ulcer Gastric Ulcer

10. Strategies for Inhibiting Parietal Cell Acid Secretion Gastrin Antagonists H+H+ Histamine Antagonists Muscarinic Antagonists CCK2 H2H2 M3M3 ↓ Ca +2 ↓cAMP ↓ Ca +2 PP Gastric Lumen

11. Cyclooxygenase Pathway Arachidonic Acid COX-1 Prostaglandin H2 Prostaglandin G2 Prostacycline Synthase Prostacycline PG12 Prostacycline E2, F2 Prostacycline G2 Prostaglandin Synthase Thromboxane Synthase Thromboxane A2 Thromboxane B2 RESULT = DECREASED ACID SECRETION & INCREASED MUCUS PRODUCTION

12. PPI- Omeprazole Prototype H +, K + -ATPase inhibitor; A prodrug that needs a low pH to be active; Irreversible (forms a covalent bond with the proton pump) - long lasting inhibition of acid production; Profound reduction of gastric acid - elevates gastric pH significantly (20mg/day for 7days will decrease acid by 95%); Highly protein bound; Metabolized by CYP2C & CYP3A; plasma half life of 1 to2 hours but long duration of action; Should be taken just prior to a meal and should NOT be taken with other acid-suppressing agents. Others: esomeprazole, lansoprazole and pantoprazole

13. Histamine H 2 Antagonists Decrease Acid Output Histamine Protein Kinase ATP cAMP K+K+ H+H+ Histamine Antagonist Acid Output (mEq/hr) Time (hr) 1 2 3 4 5 H 2 antagonist administered orally at arrow 10 20 30 PP Cimetidine (Tagamet) Ranitidine (Zantac) Famotidine (Pepcid) Nizatidine (Axid)

14. Strategies for Inhibiting Parietal Cell Acid Secretion Gastrin Histamine Acetylcholine Ca 2+ Protein Kinase ATP cAMP Prostaglandin Agonists (-) K+K+ H+H+ PP H2H2 M3M3 CCK 2 EP 3 Ca 2+

15. Drugs for Acid-Peptic Disorders - Anticholinergics Blockade of acetylcholine at muscarinic (M 3 /M 1 ) receptors – Effectively blocks acid secretion (30 to 40%) – Limited by side-effects Side-effects are typical of anticholinergics such as atropine – Dry mouth – Tachycardia – Blurred vision – Bowel discomfort (constipation) – Difficulty in urination

16. Drugs for Acid-Peptic Disorders - Anticholinergics General muscarinic receptor antagonists (block all types of muscarinic receptors) – Atropine – Propantheline (Pro-Banthine) – Dicyclomine (Bentyl) Selective M 1 receptor antagonists – Pirenzepine – Telenzepine

17. Drugs for Acid-Peptic Disorders – Prostaglandins (PGE 2 & PGI 2 ) Inhibits: – Acid secretion – Gastrin release – Pepsin secretion Stimulates : – Mucus secretion – Bicarbonate secretion – Mucosal blood flow These compounds act by both inhibition of acid production and by increasing defense mechanisms Act at prostaglandin EP 3 receptors on parietal cells & on epithelial cells These compounds are also effective against direct damage produced by alcohol, aspirin and NSAIDs, and are therefore termed “cytoprotective”

18. Drugs for Acid-Peptic Disorders - Prostaglandins Misoprostol (Cytotec): Synthetic Analog of Prostaglandin E 1 Anti-acid secretory 0.1 to 0.2 mg results in 85% to 95% acid reduction Prevention of NSAID gastric ulcers Side Effects Diarrhea Abortion Exacerbate IBD and should not be given

19. Drugs for Acid-Peptic Disorders - Antacids Antacids are weak bases that neutralize HCl in the stomach; They do not decrease the secretion of acid, and in some cases increase secretion; They do not suppress nocturnal acid secretion 1. Neutralize acid 2. Decrease acid load to duodenum 3. Diminish pepsin activity

20. Drugs for Acid-Peptic Disorders - Antacids Magnesium hydroxide Magnesium trisilicate Magnesium-aluminum mixtures Calcium carbonate Sodium bicarbonate

21. Drugs for Acid-Peptic Disorders – Sucralfate (Carafate) Sucralfate is a basic aluminum salt of sucrose octasulfate; In the presence of acid (pH < 3-4) some of the aluminum ions dissociate and the resulting negatively charged molecule polymerizes to form a viscous paste-like substance; This substance adheres strongly to gastric and duodenum mucosa and adheres even more strongly to partially denatured proteins such as those found at the base of the ulcer.

22. H. pylori Eradication Rates with Either Dual, Triple or Quad Therapy (1999)

23. GENERIC NAME DOSING DURATION CURE RATE (%) Dual therapies omeprazole 500 mg TID 14 days 70-80 amoxycillin 1,000 mg TID 14 days ranitidine 400 mg BID 28 days 73-84 clarithromycin 500 mg TID 14 days lansoprazole 30 mg TID 14 days 66-77 amoxycillin 1,000 mg TID 14 days

24. H. pylori Eradication Rates with Either Dual, Triple or Quad Therapy (1999) Cont. GENERIC NAME DOSING DURATION CURE RATE (%) Triple therapies lansoprazole 30 mg BID 14 days 86-92 amoxycillin 1,000 mg BID 14 day clarithromycin 500 mg BID 14 days

25. H. pylori Eradication Rates with Either Dual, Triple or Quad Therapy (1999) Cont. GENERIC NAME DOSING DURATION CURE RATE (%) Quad therapies bismuth subsalicylate Two tablets 7 days 85-95 525 mg QID metronidazole 250 mg QID 7 days tetracycline 500 mg QID 7 days omeprazole 20 mg BID 7 days or lansoprazole 30 mg BID 7 days

26. NEXT LECTURE Nausea Emesis IBS Diarrhea Constipation

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