2. ACID-PEPTIC DISEASE AND TREATMENT Introduction - A. Acid peptic includes: 1.Peptic ulcers (stomach and duodenal) 2.Gastroesophageal reflux disorders (GERD) 3.Zollinger-Ellison syndrome B.Acid secretion is controlled by: 1.Histamine 2.Acetylcholine 3.Gastrin

3. Classes of acid-peptic diseases Stomach Duodenum

4. Common denominator for all three mechanisms

5. Peptic Ulcer Disease Imbalance between defenses and aggressive factors Defensive factors: – Defensive factors the stomach and duodenum from self-digestion – Mucus: continually secreted, protective effect – Bicarbonate: secreted from endothelial cells – Blood flow: proper blood flow maintains mucosal integrity – Prostaglandins: stimulate secretion of bicarbonate and mucus, promote blood flow, suppress secretion of gastric acid Aggressive factors: – Helicobacter pylori: gram negative bacteria, can live in stomach and duodenum.

6. The development of peptic ulcers may involve alterations in:

7. Goals of treatment in peptic ulcer disease: Pain relief Ulcer healing Prevention of complications and ulcer recurrence

8. Drugs available for the treatment of acid peptic diseases act by: Neutralizing gastric acid Reduce gastric acid secretion Enhance mucosal defenses “cytoprotectants” Antimicrobial activity against H. pylori

9. Antacids Simply work by neutralizing hydrochloric acid They are weak bases that react with hydrochloric acid to form salts and water By increasing the pH of the stomach, antacids also inactivate the action of pepsin; pepsin is know to contribute to ulcer formation by digesting proteins in the wall of the stomach At pH above 4, pepsin activity is significantly reduced

10. Common antacids contain Aluminum hydroxide Magnesium hydroxide Calcium carbonate Sodium bicarbonate

11. H 2 receptor antagonists Introduced in the 1970’s; became a very popular medication for the treatment of peptic acid diseases – Cimetidine (Tagamet) – Ranitidine (Zantac) – Famotidine (Pepcid) – Nizatidine (Axid) These drugs are competitive inhibitors of the H2 receptor in parietal cells H2 blockers also decrease (indirectly) gastrin- and acetylcholine-induced gastric acid secretion

12. Anticholinergic agents Dicyclomine (Bentyl) antagonizes the muscarinic Ach receptors on parietal cells thereby decreasing gastric acid secretion. They are seldom used in the treatment of ulcers because they are less effective than H2 blockers and proton pump inhibitors. Incidence of adverse effects, such as dry mouth, blurred vision, cardiac arrhythmias and urinary retention makes anticholinergic drugs less desirable for use in the treatment of peptic acid diseases.

13. Proton Pump Inhibitors The ultimate mediator of gastric acid secretion is the proton pump in parietal cells. A family of substituded benzimidazoles have been specifically developed to block the activity of this transport protein for proton (H + ) molecules. This pump is unique to the parietal cells. The pH of the stomach facilitates the mode of action of this class of drugs. Omeprazole is the prototype proton pump inhibitor.

14. Specific agents 1.Omeprazole (Prilosec) 2.Lanzopresole (Prevacid) 3.Rabeprazole (Aciphex) 4.Pantoprazole (Protonix) 5.Esomeprazole (Nexium) All PPIs have similar rates of absorption and oral bio- Availability. Rabeprazole and lansoprazole appear to have a significant faster onset of action than omeprazole and pantropazole. Comparisons of effectiveness suggest that esomeprazole inhibits acid secretion more effectively than other proton pump inhibitors at therapeutic doses.

15. PPIs Drugs are inactive at neutral pH, but since they are weak bases, they are activated in the acidic stomach milieu. PPIs need to pass intact through the stomach into the intestines where the drug is released from its enteric coating formulation for absorption into the blood. The pro-drug reaches the parietal cells via blood and then passes through the luminal side luminal side where the low pH activates the drug. Irreversibly inhibit the H + /K + ATPase in gastric parietal cells Because the drug irreversibly inhibits the proton pump, it produces a dose-dependent inhibition of gastric acid secretion that persists even after the drug disappears from plasma.

16. PPIs adverse effects PPIs are generally are well tolerated. A potential concern is that the large increase in gastrin production associated with PPI could have a trophic effect resulting in hyperplasia of parietal cells. In fact long-term treatment of rats with omeprazole (high doses) develop gastric carcinoid tumors. Concerns about infection of the stomach with opportunistic/nosocomial bacterial (e.g., Pneumonmia by C. difficile, enteric infections by Salmonella and E. coli). Drug-drug interactions by competition for CYP2C19 (e.g., clopidrogel).

17. Mucosal protective agents Mucosal erosion and ulceration is characteristic of peptic acid diseases resulting from pepsin-mediated hydrolysis of mucosal proteins. Mucosal protective agents create a barrier in stomach and intestinal mucosa that prevents the damaging effects of hydrochloric acid and pepsin. The also bind pepsin and bile salts. Bismuth is known to have bactericidal activity.

18. Mucosal protective agents Colloidal Bismuth compounds – Coating agent used in peptic ulcer disease – Bismuth salts combine with mucus glycoproteins to form a barrier that protects the ulcer from further damage by acid and pepsin. – Bismuth is also known to stimulate secretion of bicarbonate, PG and mucus – Colloidal bismuth has been shown to impede the growth of H. pylori. – Used in combination with antimicrobial agents and PPIs in patients that are H. pylori positive.

19. Mucosal protective agents Misoprostol – prostaglandin E1 analog (PG stimulate mucus and bicarbonate production) – used when treatment with NSAIDs inhibits endogenous PG synthesis Sucralfate – complex of aluminum hydroxide and sulfated sucrose – Undergoes polymerization and cross linking at low pH of stomach – Binds tightly to the necrotic/ulcerated tissue

20. Helicobacter pylori Introduction: – Gram-negative, spiral shaped bacterium. – Most common cause of non-NSAID-associated peptic ulcer diseases. – Can be found in the antrum of the stomach of a significant number of patients with duodenal and gastric ulcers. – Colonizes the epithelium of the gastric mucosa and lives in the acidic environment of the stomach. – H. pylori infection is know to be a causative agent for ulcers.

21. H. Pylori Epidemiology (cont.)

22. H. Pylori Epidemiology Prevalence of H. pylori infection correlates best with socio-economic status rather than race. In the United States, probability of being infected is greater for older persons (>50 years = >50%), minorities (African Americans 40-50%) and immigrants from developing countries (Latino > 60%, Eastern Europeans > 50%). The infection is less common in more affluent Caucasians ( < 40 years = 20%).

23. Helicobacter pylori (cont.) – H. pylori penetrate the mucus layer of host stomach and adhere the surface of gastric mucosal epithelial cells. – H. pylori is capable of living in the harsh acidic conditions of the stomach because it produces ammonia from urea by the enzyme urease. – The ammonia neutralizes the gastric acid and allows the bacteria to escape from elimination. – H. pylori then proliferates, migrates, and finally forms the infectious focus. – Ulcers developed by destruction of mucosa and immune- mediated inflammation and mucosal cell death.

25. Treatment options for H. Pylori Antibiotics Antisecretory agents Mucosal protectants Antisecretory agents that enhance mucosal defenses Antacids