Drugs for Peptic Ulcer Disease Chapter 78 Drugs for Peptic Ulcer Disease 1

Peptic Ulcer Disease Definition Cause 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 2

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. 3

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 4

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) 5

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 6

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 7

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 8

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 9

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

Three Ways Antiulcer Drugs Work Eradicate H. pylori (antibiotics) Reduce gastric acidity (antisecretory agents, misoprostol) Enhance mucosal defenses (sucralfate, misoprostol) 11

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

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 13

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 14

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 15

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

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

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) 18

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

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 20

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

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

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

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

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 25

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 26

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 27

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

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

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 30

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 31

Other PPIs Dexlansoprazole Rabeprazole Pantoprazole

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

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 34

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 35

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 36