Peptic ulcer pharma
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"peptic ulcer"[MeSH Terms] AND "drug therapy"[MeSH Terms]
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Pharmacology of Peptic Ulcer Disease
Pathophysiological Basis of Treatment
Peptic ulcer disease (PUD) results from an imbalance between aggressive factors (gastric acid, pepsin, H. pylori, NSAIDs) and defensive factors (mucus, bicarbonate, mucosal blood flow, prostaglandins). Drug therapy targets one or more of these mechanisms.
1. Proton Pump Inhibitors (PPIs) - First-Line Agents
Drugs: Omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole
Mechanism: Irreversibly bind to the H⁺/K⁺-ATPase (proton pump) on the gastric parietal cell, blocking hydrogen ion secretion. Most effective when taken 30-60 minutes before a meal (activates parietal cells, allowing PPI uptake).
Key properties:
- Heal ulcers faster than H2 receptor antagonists
- Have some in vitro inhibitory activity against H. pylori
- Metabolized by cytochrome P450 (CYP2C19, CYP3A4) - may decrease metabolism of other CYP-dependent drugs (e.g., clopidogrel interaction with omeprazole)
- May inhibit absorption of drugs requiring gastric acidity (e.g., ketoconazole, iron, vitamin B12)
- All PPIs show similar efficacy regardless of route or brand
- Treatment of choice in patients who develop ulcers while on NSAIDs and must continue them
Adverse effects (long-term):
- Clostridioides difficile-associated diarrhea
- Increased fracture risk (reduced Ca²⁺ absorption)
- Hypomagnesemia
- Community-acquired pneumonia (aspiration of colonized stomach)
- Chronic kidney disease (rare)
- Rebound acid hypersecretion on abrupt discontinuation - taper over weeks, bridging with H2 blockers or antacids
Newer agent: Potassium-competitive acid blockers (P-CABs), e.g., vonoprazan - reversibly block K⁺ binding site on the proton pump; faster onset and acid suppression that is not meal-dependent. Used in some H. pylori regimens (dose: 20 mg twice daily).
2. H2 Receptor Antagonists (H2RAs)
Drugs: Cimetidine, famotidine, ranitidine (withdrawn in many countries due to NDMA contamination), nizatidine
Mechanism: Competitively inhibit histamine at H2 receptors on parietal cells, reducing cAMP-driven acid secretion. Note: They do NOT block acetylcholine- or gastrin-mediated stimulation directly, hence less complete acid suppression than PPIs.
Key properties:
- All four agents heal ulcers approximately equally
- Available OTC
- Renally excreted - dose reduction required in renal failure
- Long-term use leads to tolerance (tachyphylaxis)
- Abrupt discontinuation causes rebound acid hypersecretion
Adverse effects:
- Generally well tolerated
- Headache, confusion, lethargy, depression, hallucinations (especially in elderly or renal failure)
- Cimetidine has the most drug interactions (inhibits CYP450) - also causes gynecomastia, decreased libido, and impotence (anti-androgenic effect)
3. Antacids
Examples: Magnesium hydroxide, aluminum hydroxide, calcium carbonate, sodium bicarbonate (combinations)
Mechanism: Buffer (neutralize) gastric acid, raising intragastric pH. Also inactivate pepsin at pH >4.
Clinical use: Mainly for symptomatic relief (breakthrough pain) while definitive therapy takes effect. No longer used as primary treatment due to complexity of dosing.
Adverse effects:
- Mg²⁺-containing: diarrhea; avoid in renal failure (hypermagnesemia)
- Al³⁺-containing: constipation; in renal failure accumulates, causing osteomalacia and encephalopathy
- CaCO₃: milk-alkali syndrome; rebound acid hypersecretion
- Interfere with absorption of many drugs (tetracyclines, fluoroquinolones, iron)
4. Sucralfate
Mechanism: Aluminum hydroxide-sucrose complex that forms a sticky viscous gel in an acid environment, adhering to the ulcer crater and forming a physical barrier against acid and pepsin. Also stimulates prostaglandin synthesis and mucus secretion.
Clinical use: Duodenal ulcer healing. Less effective for pain relief than PPIs/H2RAs. Requires acidic environment - do NOT give within 30 minutes of antacids or PPIs.
Adverse effects:
- Constipation (main)
- Aluminum toxicity (avoid in renal failure)
- Inhibits absorption of many drugs - give other medications 2 hours before sucralfate
5. Misoprostol (Prostaglandin E1 Analogue)
Mechanism: Activates EP3 receptors on parietal cells - reduces cAMP, decreasing acid secretion. Also:
- Increases mucus and bicarbonate secretion
- Enhances mucosal blood flow (cytoprotective)
Clinical use: Prevention of NSAID-induced gastric and duodenal ulcers (not proven to heal established ulcers). Used when NSAIDs cannot be stopped.
Adverse effects:
- Diarrhea, abdominal cramps (dose-dependent)
- Absolutely contraindicated in pregnancy - causes uterine contractions and miscarriage (used medically as abortifacient)
6. Bismuth Compounds
Examples: Bismuth subcitrate (De-Nol), bismuth subsalicylate (Pepto-Bismol)
Mechanism:
- Forms a protective coat over the ulcer base
- Bactericidal against H. pylori (disrupts bacterial cell wall and metabolism)
- Stimulates prostaglandin synthesis and mucus secretion
- Inhibits pepsin activity
Clinical use: Component of quadruple therapy for H. pylori eradication. Never used as monotherapy.
Adverse effects:
- Black stools and darkening of the tongue (harmless - bismuth sulfide)
- Constipation
- High doses: bismuth encephalopathy (neurotoxicity)
7. H. pylori Eradication Regimens
H. pylori eradication is mandatory in all patients with documented PUD. Eradication dramatically decreases recurrence (from ~80% to <5% per year) and accelerates healing.
Key principle: No single drug works; combination therapy for 14 days is most effective.
Standard Triple Therapy (where clarithromycin resistance <15%)
| Drug | Dose |
|---|---|
| PPI (e.g., omeprazole) | 40 mg twice daily |
| Clarithromycin | 500 mg twice daily |
| Amoxicillin | 1 g twice daily |
OR replace amoxicillin with metronidazole 500 mg twice daily in penicillin allergy.
Prepackaged: Prevpac (lansoprazole + clarithromycin + amoxicillin) - taken twice daily x 14 days.
Bismuth-Based Quadruple Therapy (first-line if clarithromycin resistance >15%, or unknown)
| Drug | Dose |
|---|---|
| PPI | 20-40 mg twice daily |
| Bismuth compound | 2 tablets twice daily |
| Metronidazole | 500 mg three times daily |
| Tetracycline | 500 mg three times daily |
Non-Bismuth Quadruple Therapies (10-14 days)
- Concomitant: PPI + amoxicillin + clarithromycin + metronidazole (all together)
- Sequential: PPI + amoxicillin for 5 days → then PPI + clarithromycin + metronidazole for 5 days
- Hybrid: PPI + amoxicillin for 7 days → then PPI + amoxicillin + clarithromycin + metronidazole for 7 days
Salvage / Second-Line Therapies
When first-line fails, use antibiotics the patient hasn't been exposed to:
- Levofloxacin-based triple therapy (PPI + levofloxacin + amoxicillin)
- Bismuth quadruple therapy with rifabutin
- Quinolone-based quadruple therapy (bismuth + PPI + levofloxacin 500 mg daily + amoxicillin) for 10+ days
Test of cure: Urea breath test or stool antigen test, performed ≥4 weeks after completing therapy (and ≥2 weeks after stopping PPI/antibiotics/bismuth to avoid false negatives).
8. NSAID-Induced Ulcers
When NSAID use must continue:
- Stop NSAID whenever possible
- Add a PPI (preferred) or H2RA for healing
- Misoprostol for prevention if NSAIDs cannot be stopped
- Test and eradicate H. pylori (eradication alone does NOT eliminate NSAID ulcer risk - PPI must continue)
- Consider switching to a selective COX-2 inhibitor (lower GI risk, but not zero)
9. Treatment of Bleeding Peptic Ulcer
- Pre-endoscopy: IV PPI bolus followed by continuous infusion (reduces rebleeding risk after endoscopic hemostasis)
- Prokinetic: IV erythromycin 30 min before endoscopy improves gastric mucosal visualization
- Endoscopy within 24 hours: injection therapy (epinephrine), thermal therapy, or mechanical clipping
- Forrest classification guides endoscopic management (Ia = active spurting = highest risk; III = clean base = lowest risk)
- Post-endoscopy: Oral PPI twice daily; eradicate H. pylori if positive
Summary Table
| Drug Class | Mechanism | Primary Use | Key ADR |
|---|---|---|---|
| PPIs | Irreversible H⁺/K⁺-ATPase block | First-line healing + H. pylori regimens | Hypomagnesemia, fractures, C. diff |
| H2RAs | Competitive H2 receptor block | Healing, maintenance, renal pts | Tolerance, cimetidine drug interactions |
| Antacids | Acid neutralization | Symptomatic relief | Mg: diarrhea; Al: constipation |
| Sucralfate | Physical barrier + cytoprotection | Duodenal ulcer | Constipation, binds other drugs |
| Misoprostol | PGE1 analogue, antisecretory + cytoprotective | NSAID ulcer prevention | Diarrhea, teratogenic |
| Bismuth | Barrier + anti-H. pylori + pepsin inhibition | H. pylori quadruple therapy | Black stools, encephalopathy (overdose) |
| Antibiotics | H. pylori eradication | PUD with H. pylori | Resistance, GI side effects |
Sources: Tintinalli's Emergency Medicine (9e), Harrison's Principles of Internal Medicine (22e), Goldman-Cecil Medicine - textbooks accessed via medical library.
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