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Chapter 78

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Chapter 78

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  1. Chapter 78 Drugs for Peptic Ulcer Disease

  2. Peptic Ulcer Disease • Definition • Group of upper GI disorders • Degrees of erosion of the gut wall • Severe erosion can be complicated by hemorrhage and perforation • Cause • Imbalance between mucosal and aggressive factors

  3. Fig. 78–1. The relationship of mucosal defenses and aggressive factors to health and peptic ulcer disease. When aggressive factors outweigh mucosal defenses, gastritis and peptic ulcers result.

  4. Pathogenesis of Peptic Ulcers • Defensive factors • Mucus • Secreted cells of the GI mucosa • Forms a barrier to protect underlying cells from acid and pepsin • Bicarbonate • Secreted by epithelial cells of stomach and duodenum • Most remains trapped in the mucus layer to neutralize hydrogen ions that penetrate the mucus • Blood flow • Poor blood flow can lead to ischemia, cell injury, and vulnerability to attack • Prostaglandins • Stimulate the secretion of mucus and bicarbonate

  5. Pathogenesis of Peptic Ulcers • Aggressive factors • Helicobacter pylori, also known as H. pylori • Gram-negative bacillus that can colonize in the stomach and duodenum • Lives between epithelial cells and the mucus barrier • Escapes destruction by acid • Can remain in GI tract for decades • Half of the world infected, but most people do not develop symptomatic peptic ulcer disease (PUD)

  6. Pathogenesis of Peptic Ulcers • Aggressive factors • Helicobacter pylori, also known as H. pylori (cont’d) • 60%–70% of patients with PUD have H. pylori infection • H. pylori may also promote gastric cancer • Duodenal ulcers are much more common among people with H. pylori infection than among people who are not infected • Eradication of the bacterium promotes healing of the PUD and minimized recurrence of PUD

  7. Pathogenesis of Peptic Ulcers • Aggressive factors • Nonsteroidal anti-inflammatory drugs (NSAIDs) • Inhibit the biosynthesis of prostaglandins • Decrease blood flow, mucus, and bicarbonate • Gastric acid • Causes ulcers by directly injuring cells of the GI mucosa and indirectly by activating pepsin • Increased acid alone does not increase ulcers but is a definite factor in PUD • Pepsin • Proteolytic enzyme in gastric juice • Smoking • Delays ulcer healing and increases risk for recurrence

  8. Pathogenesis of Peptic Ulcers • Summary of ulcer development • Most common cause • Infection with H. pylori (HP) is the most common cause of gastric and duodenal ulcers • Additional factors must be involved: 50% harbor HP, but only 10% develop PUD • Second most common cause • NSAIDs

  9. Overview of Treatment • Goals of drug therapy • Alleviate symptoms • Promote healing • Prevent complications • Prevent recurrence • Drugs do not alter the disease process; they create conditions conducive to healing

  10. Classes of Antiulcer Drugs • Antibiotics • Antisecretory agents • Mucosal protectants • Antisecretory agents that enhance mucosal defenses • Antacids

  11. Three Ways Antiulcer Drugs Work

  12. Drug Selection: H. pylori–Associated Ulcers • Antibiotics • Should be given to all patients with gastric/duodenal ulcers and documented H. pylori • Antisecretory agents

  13. Drug Selection: NSAID-Induced Ulcers • Prophylaxis • Risk factors for ulcer development (older than 60 years, history of ulcers, high-dose NSAID therapy) • Treatment • Proton pump inhibitors (PPIs) (eg, omeprazole) are preferred • Misoprostol is also effective, but can cause diarrhea • Antacids, sucralfate, and histamine2 receptor blockers are not recommended • Discontinue NSAIDs, if possible

  14. Nondrug Therapy • Diet • Traditional “ulcer diet” does not accelerate healing • No convincing evidence indicates that caffeinated beverages promote ulcers or delay healing • Change eating pattern to 5–6 small meals a day (reduces pH fluctuations) • Avoid smoking, aspirin, other NSAIDs, and alcohol if a trigger

  15. Evaluation of Therapy • Monitor for relief of pain • Keep in mind: cessation of pain and disappearance of ulcer rarely coincide • Pain may subside before complete healing or may continue after healing • Radiologic or endoscopic examination of ulcer site • H. pylori tests

  16. H. pylori Tests • Noninvasive • Breath test • Serum test • Stool test • Invasive • Endoscopic specimen obtained and evaluated

  17. H. pylori Treatment • Minimum of two antibiotics (up to three) prescribed to decrease risk of developing resistance • Amoxicillin • Clarithromycin • Bismuth compounds • Tetracycline • Metronidazole • Tinidazole

  18. Antibiotic Regimen • 2007 ACG updated guidelines for managing H. pylori • Use minimum of two antibiotics, preferably three • Antisecretory agent (PPI, H2 antagonist) • Barriers to compliance • Can require up to 12 pills/day (14 days) • GI side effects • Expensive (about $200)

  19. Histamine2-Receptor Antagonists • Cimetidine (Tagamet) • Ranitidine (Zantac) • Famotidine (Pepcid) • Nizatidine (Axid)

  20. Histamine2-Receptor Antagonists • First-choice drugs for treating gastric and duodenal ulcers • Promote healing by suppressing secretion of gastric acid • All four equally effective • Serious side effects uncommon

  21. Fig. 78–2. A model of the regulation of gastric acid secretion showing the actions of antisecretory drugs and antacids.

  22. Cimetidine (Tagamet) • Pharmacokinetics • Absorption slowed if taken with meals • Crosses the blood-brain barrier with difficulty • May cause some CNS side effects

  23. Cimetidine (Tagamet) • Therapeutic uses • Gastric and duodenal ulcers • Gastroesophageal reflux disease (GERD) • Zollinger-Ellison syndrome • Aspiration pneumonitis • Heartburn, acid indigestion, and sour stomach

  24. Cimetidine (Tagamet) • Adverse effects • Antiandrogenic effects • CNS effects • Pneumonia • IV bolus: can experience hypotension and dysrhythmias

  25. Ranitidine (Zantac) • Shares many properties of cimetidine • More potent, fewer adverse effects, causes fewer drug interactions than cimetidine (and has less ability to cross CNS) • Adverse effects • Significant ones uncommon • Does not bind to androgen receptors

  26. Ranitidine (Zantac) • Therapeutic uses • Short-term treatment of gastric/duodenal ulcers • Prophylaxis of recurrent duodenal ulcers • Treatment of Zollinger-Ellison syndrome and hypersecretory states • Treatment of GERD

  27. Famotidine (Pepcid) • Actions similar to those of ranitidine • Therapeutic uses • Short-term treatment of gastric/duodenal ulcers • Prophylaxis of recurrent duodenal ulcers • Treatment of Zollinger-Ellison syndrome and hypersecretory states • Treatment of GERD • Over-the-counter (OTC): to treat heartburn, acid indigestion, sour stomach

  28. Famotidine (Pepcid) • Adverse effects • Does not bind to androgen receptors • Possible increased risk for pneumonia caused by elevation of pH

  29. Nizatidine (Axid) • Actions much like those of ranitidine and famotidine • Therapeutic uses • Duodenal/gastric ulcers • GERD, heartburn, acid indigestion, and sour stomach

  30. Proton Pump Inhibitors • Most effective drugs for suppressing secretion of gastric acid • Therapeutic uses: short term • Gastric/duodenal ulcers • GERD • Well tolerated • Selection of PPI based on cost and prescriber preference • Can increase the risk of serious adverse events, including fracture, pneumonia, acid rebound, and possibly intestinal infection with Clostridium difficile

  31. Omeprazole (Prilosec) • First available proton pump inhibitor • Actions and characteristics • Inhibits gastric secretion • Short half-life • Used for short-term therapy • Adverse effects • Usually inconsequential with short-term use • Headache • Gastrointestinal effects • Pneumonia • Rebound acid hypersecretion • C. difficile infection • Gastric cancer

  32. Other PPIs • Dexlansoprazole • Rabeprazole • Pantoprazole

  33. Other Antiulcer Drugs • Sucralfate (Carafate) • Misoprostol (Cytotec) • Antacids

  34. Sucralfate (Carafate) • Creates a protective barrier up to 6 hours • Therapeutic uses • Acute ulcers and maintenance therapy • Adverse effects • Constipation (in only 2% of patients) • Drug interactions • Minimal • Antacids may interfere with effects of sucralfate

  35. Misoprostol (Cytotec) • Therapeutic uses • Only approved GI indication is prevention of gastric ulcers caused by long-term NSAID therapy • Adverse effects • Most common: dose-related diarrhea (13%–40%) and abdominal pain (7%–20%) • Contraindicated during pregnancy: category X • Significant actions need to be taken to ensure that pregnancy does not occur after therapy starts, and that patient is not pregnant at therapy initiation

  36. Antacids • React with gastric acid to produce neutral salts or salts of low acidity • Decrease destruction of the gut wall by neutralizing acid • May also enhance mucosal protection by stimulating production of prostaglandins • Except for sodium bicarbonate, antacids do not alter systemic pH • Use with caution in patients with renal impairment