Pharmacotherapy of Peptic Ulce

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.

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:

1. Histamine: Binds to H₂ receptors (Gs-coupled) → increases cAMP → activates Protein Kinase A.
2. Acetylcholine: Binds to M₃ muscarinic receptors (Gq-coupled) → increases intracellular Ca²⁺.
3. Gastrin: Binds to CCK₂ receptors (Gq-coupled) → increases intracellular Ca²⁺.

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.

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.

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.

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.

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

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.