Pharmacology Mentor

Pharmacotherapy of Peptic Ulcer

Scope: Pathophysiology, Drug Classifications, Mechanisms of Action, Clinical Pharmacology, and Therapeutic Guidelines. I. Introduction and Pathophysiology Peptic ulcer disease (PUD) is a chronic, relapsing inflammatory disorder characterized by a breach in the mucosa of the stomach (gastric ulcer) or the proximal duodenum (duodenal ulcer) extending through the muscularis mucosae. The pathophysiology of PUD is best understood as a disruption of the delicate equilibrium between aggressive factors and defensive mechanisms. The Balance Hypothesis A peptic ulcer develops when the aggressive factors overwhelm the mucosal defenses. Pharmacotherapy aims to restore this balance by either reducing aggression or bolstering defense. Aggressive Factors Defensive Factors Gastric Acid (HCl): Direct corrosion. Mucus Layer: Physical barrier against acid/pepsin. Pepsin: Proteolytic enzyme. Bicarbonate (HCO3-): Neutralizes acid at the epithelial surface. Helicobacter pylori: Bacterial infection. Prostaglandins (PGE2, PGI2): Stimulate mucus/bicarbonate; maintain blood flow. NSAIDs: Inhibit protective prostaglandin synthesis. Mucosal Blood Flow: Removes acid; supplies oxygen/nutrients for repair. Regulation of Acid Secretion The central target of most anti-ulcer drugs is the parietal cell. The final common pathway for acid secretion is the Proton Pump (H+/K+-ATPase). The parietal cell is stimulated by three primary secretagogues acting on specific basolateral receptors: Histamine: Binds to H2 receptors (Gs-coupled) → increases cAMP → activates Protein Kinase A. Acetylcholine: Binds to M3 muscarinic receptors (Gq-coupled) → increases intracellular Ca2+. Gastrin: Binds to CCK2 receptors (Gq-coupled) → increases intracellular Ca2+. H+(intracellular) + K+(luminal) + ATP &xrarr; H+(luminal) + K+(intracellular) + ADP + Pi II. Agents Reducing Intragastric Acidity A. Proton Pump Inhibitors (PPIs) Agents: Omeprazole, Esomeprazole, Lansoprazole, Pantoprazole, Rabeprazole. 1. Mechanism of Action PPIs are prodrugs. They are weak bases that circulate in the blood in an inactive form. Ion Trapping: They diffuse into the highly acidic secretory canaliculi (pH < 1.0). Activation: In this environment, the PPI is protonated and forms a reactive sulfenamide cation. Irreversible Inhibition: This forms a covalent disulfide bond with cysteine residues (specifically Cys813) on the H+/K+-ATPase pump. Pharmacological Consequence Because the inhibition is covalent (irreversible), acid secretion is suppressed until the parietal cell synthesizes new pump proteins (approx. 18–24 hours). This explains the long duration of action despite a short plasma half-life. 2. Clinical Uses & Pharmacokinetics Uses: PUD, GERD, Zollinger-Ellison Syndrome, NSAID prophylaxis, H. pylori eradication. Metabolism: Hepatic via CYP2C19 and CYP3A4. Note: Genetic polymorphism in CYP2C19 (common in Asian populations) can affect efficacy. 3. Adverse Effects & Interactions Nutritional Deficiencies (B12, Iron, Calcium). Increased risk of bone fractures and C. difficile infection. Rebound hypersecretion upon stopping. Drug Interaction Alert Omeprazole inhibits CYP2C19. Clopidogrel (Plavix) is a prodrug requiring CYP2C19 for activation. Concurrent use may reduce the antiplatelet efficacy of clopidogrel. Pantoprazole or Rabeprazole are preferred in these patients. B. Potassium-Competitive Acid Blockers (P-CABs) Agent: Vonoprazan. This is a newer class of drugs. Unlike PPIs, P-CABs compete reversibly with K+ ions at the pump. They do not require acid activation. They offer a rapid onset (day 1) and are highly effective in H. pylori eradication. C. H2 Receptor Antagonists (H2RAs) Agents: Famotidine, Nizatidine, Cimetidine. Mechanism: Reversible block of H2 receptors. Highly effective for nocturnal acid secretion. Adverse Effects (Cimetidine): Cimetidine is a potent CYP inhibitor and has anti-androgenic effects (gynecomastia) in men. Tolerance: Rapid tolerance (tachyphylaxis) develops within 3 days, limiting long-term use. III. Agents Neutralizing Acid (Antacids) Antacids are weak bases that react with gastric hydrochloric acid to form a salt and water. Al(OH)3 + 3HCl → AlCl3 + 3H2O Type Agents Features Adverse Effects Systemic Sodium Bicarbonate Rapid onset; absorbed. Metabolic alkalosis; Fluid retention. Non-Systemic Magnesium Hydroxide Potent; poor absorption. Diarrhea (osmotic). Aluminum Hydroxide Slow acting. Constipation; Hypophosphatemia. Calcium Carbonate Potent; rapid. Rebound acid; Kidney stones. IV. Mucosal Protective Agents A. Sucralfate Forms a viscous, sticky polymer in acid (pH < 4) that adheres to the ulcer crater ("Band-Aid" effect). Note: Requires acid to work; do not give with PPIs. B. Misoprostol (Prostaglandin E1 Analogue) Stimulates mucus/bicarbonate secretion and inhibits acid. Specifically indicated for prevention of NSAID-induced ulcers. Contraindication Pregnancy Category X: Misoprostol stimulates uterine contractility and can induce abortion. C. Bismuth Compounds Coats the ulcer and possesses direct antimicrobial activity against H. pylori. Causes harmless blackening of stool/tongue. V. Pharmacotherapy of H. pylori (2024 Update) The goal is bacterial eradication. High intragastric pH is required to optimize antibiotic efficacy. 1. First-Line: Bismuth Quadruple Therapy (BQT) Preferred due to rising clarithromycin resistance. PPI (b.i.d.) Bismuth Subcitrate (q.i.d.) Tetracycline (500 mg q.i.d.) Metronidazole (q.i.d.) Duration: 10–14 days. 2. The "Modern" Approach: Vonoprazan-Based Therapy Superior acid suppression leads to higher eradication rates. Dual Therapy: Vonoprazan + Amoxicillin. Triple Therapy: Vonoprazan + Amoxicillin + Clarithromycin. 3. Clarithromycin Triple Therapy (Restricted) Only use if local resistance is known to be < 15%. (PPI + Clarithromycin + Amoxicillin). VI. Summary of Drug Classes Drug Class Prototype Mechanism Target Main Limitation PPIs Omeprazole Irreversible H+/K+ block Bone fracture risk; C. diff risk. P-CABs Vonoprazan Reversible K+ competition Newer agent; cost. H2 Blockers Famotidine Histamine H2 block Tachyphylaxis (tolerance). Prostaglandins Misoprostol EP3 agonist Diarrhea; Abortifacient. Coating Agents Sucralfate Physical barrier Drug binding interactions. VII. Conclusion The pharmacotherapy of peptic ulcer disease relies on restoring the balance between aggressive and defensive factors. While PPIs remain the standard for acid suppression, the management of H. pylori is shifting toward Bismuth Quadruple Therapy and Vonoprazan-based regimens to combat antibiotic resistance.