Drugs Used in Peptic Ulcer Disease - Classification & Pharmacology

Pathophysiological Basis

Sites of action of anti-ulcer drugs on the parietal cell, ECL cell, and mucosal epithelium - Goodman & Gilman Fig 53-1

Classification of Anti-Ulcer Drugs

Group I - Drugs That Reduce Acid (Antisecretory Agents)

A. Proton Pump Inhibitors (PPIs) - Drug of Choice

• Given before the first meal (H⁺/K⁺-ATPase increases after fasting; meal activates pumps)
• Plasma t½ ~0.5-3 h, but acid suppression lasts 24-48 hours (new pump synthesis needed to restore secretion)
• Enteric-coated / delayed-release formulations protect drug from premature acid degradation
• Rebound acid hypersecretion occurs on stopping long-term PPI therapy
• Omeprazole inhibits CYP2C19 - relevant drug interaction with clopidogrel
• IV forms available: esomeprazole sodium, omeprazole sodium, pantoprazole

B. H₂ Receptor Antagonists (H₂RAs)

• Oral bioavailability good; peak levels in 1-3 h
• Duration: famotidine 10-12 h > ranitidine 6-8 h > cimetidine 4-5 h
• Tolerance develops within 3 days (secondary hypergastrinemia stimulates ECL histamine release)
• Cimetidine - inhibits CYP1A2, CYP2C9, CYP2D6; causes gynecomastia and impotence (anti-androgenic); crosses placenta
• Dose reduction needed in renal failure (renally excreted)
• Less potent than PPIs but useful in pregnancy and mild GERD

C. Potassium-Competitive Acid Blockers (P-CABs) - Newer Class

• Vonoprazan, Revaprazan, Tegoprazan
• Mechanism: Weak bases that accumulate in parietal cell canaliculi and competitively, reversibly block the K⁺-binding site of H⁺/K⁺-ATPase (unlike PPIs which are irreversible). Can bind both active and inactive pump forms.
• Advantages over PPIs: faster onset (effect on day 1), longer duration, no requirement for acid activation, food-independent dosing, less CYP2C19 variability
• Currently licensed mainly in Asia; vonoprazan trials ongoing in USA/Europe

D. Anticholinergics (Muscarinic Antagonists)

• Pirenzepine (selective M₁ antagonist) - blocks ACh stimulation of parietal cells and ECL cells
• Reduces acid secretion but less effective than PPIs or H₂RAs
• Side effects: dry mouth, blurred vision, urinary retention (typical anticholinergic)
• Largely replaced by PPIs; still used occasionally as add-on therapy

Group II - Drugs That Neutralize Acid (Antacids)

• Provide rapid symptom relief; used as needed
• Reduce absorption of many drugs (tetracyclines, fluoroquinolones, iron) - give 2 hours apart
• Systemic antacids (NaHCO₃) avoided in renal failure and hypertension
• Mg/Al combinations balance diarrhea vs. constipation

Group III - Cytoprotective Agents

A. Sucralfate

• Mechanism: In acidic pH, polymerizes to form a sticky gel that coats and adheres to ulcer base (especially proteins/fibrin in the ulcer crater), creating a physical barrier against acid and pepsin. Also stimulates mucus and bicarbonate secretion; enhances prostaglandin synthesis.
• Minimal systemic absorption - very safe
• Requires acidic pH to work - do NOT give with PPIs/antacids simultaneously
• Constipation is main side effect; reduces absorption of fluoroquinolones, digoxin, phenytoin
• Given 30 min before meals and at bedtime

B. Misoprostol (Prostaglandin E₁ analogue)

• Mechanism: Binds EP₃ prostanoid receptors on parietal cells → decreases cAMP → reduces acid secretion. Also binds EP₃ on superficial epithelial cells → increases mucus and bicarbonate secretion (cytoprotection).
• Main use: Prevention of NSAID-induced ulcers (replaces PGE₂ that NSAIDs deplete)
• Side effects: diarrhea (dose-limiting), abdominal cramps, uterine contractions
• Contraindicated in pregnancy (abortifacient - used in medical abortion protocols)

C. Bismuth Compounds

• Colloidal bismuth subcitrate (CBS), bismuth subsalicylate
• Mechanism: Coat ulcer base (like sucralfate); also have direct anti-H. pylori activity (inhibit bacterial enzymes, disrupt cell wall)
• Stimulate mucus and bicarbonate secretion
• Blacken stools and tongue (warn patients)
• Included in H. pylori eradication regimens (bismuth quadruple therapy)
• Risk of bismuth encephalopathy with prolonged high-dose use

D. Carbenoxolone

• Derivative of liquorice; enhances mucus secretion, increases mucosal cell turnover
• Side effects: sodium retention, hypokalemia, hypertension (mineralocorticoid-like)
• Largely obsolete; replaced by more effective agents

Group IV - Anti-H. pylori Regimens

Standard Triple Therapy (7-14 days)

• PPI (standard dose BD) + Clarithromycin 500 mg BD + Amoxicillin 1 g BD
• First-line in low clarithromycin-resistance areas

Bismuth Quadruple Therapy (14 days)

• PPI + Bismuth + Metronidazole + Tetracycline
• Used where clarithromycin resistance is high, or as rescue therapy

Sequential Therapy

• PPI + Amoxicillin for 5 days, then PPI + Clarithromycin + Metronidazole for 5 days

Levofloxacin-based Triple Therapy

• PPI + Levofloxacin + Amoxicillin (rescue regimen)

• Clarithromycin - macrolide, inhibits 50S ribosome
• Amoxicillin - β-lactam, inhibits cell wall synthesis
• Metronidazole - activated in anaerobic bacteria, damages DNA
• Tetracycline - inhibits 30S ribosome
• Bismuth - direct bactericidal (inhibits urease, disrupts cell wall)

Summary Table

• Goodman & Gilman's Pharmacological Basis of Therapeutics, Chapter 53 (Acid-Peptic Diseases)
• Katzung's Basic and Clinical Pharmacology, 16th Edition, Chapter 63
• Lippincott Illustrated Reviews: Pharmacology
• Goodman & Gilman, H₂ receptor antagonists, p. 1076-1098