How do peptic ulcer drugs work on the acid pathway?
After a meal, gastrin stimulates enterochromaffin-like (ECL) cells to release histamine. Histamine binds H2 receptors on parietal cells, raising cAMP and activating protein kinase A, which moves H+/K+ ATPase pumps to the cell membrane and increases acid secretion. Every acid-suppressing drug acts at one point on this chain: H2 blockers at the receptor, PPIs at the final step, the proton pump itself.
| Class | Examples | Mechanism | One-line use |
|---|---|---|---|
| Proton pump inhibitors | Omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole | Block the parietal-cell H+/K+ ATPase (prodrugs activated by acid) | Most potent acid reduction; first line for ulcer healing |
| H2 blockers | Famotidine, cimetidine, nizatidine (ranitidine withdrawn) | Competitive reversible block of histamine H2 receptors | Nocturnal acid control; alternative when PPI unsuitable |
| Antacids | Aluminium, magnesium, calcium salts | Neutralise gastric acid; aluminium also inhibits pepsin | Quick symptom relief |
| Mucosal protectant | Sucralfate | Polyanion gel barrier over the ulcer | Duodenal ulcer healing |
| Prostaglandin analogue | Misoprostol (PGE1) | Reduces acid; increases mucus and bicarbonate | Prevention of NSAID ulcers |
| Bismuth | Bismuth subsalicylate | Blocks bacterial adhesion to gastric epithelium | Part of H. pylori quadruple therapy |
What should you know about proton pump inhibitors?
PPIs are benzimidazole derivatives and prodrugs. They are absorbed in the proximal small bowel, reach the parietal cells through the blood, and are activated only by acid-catalysed cleavage in the secretory canaliculi, then block the H+/K+ ATPase. Because pumps are recycled, a full effect takes a few days, and onset is slower than with H2 blockers. They are best taken before food when pumps are being activated: first thing in the morning once daily, with a second dose about 30 minutes before dinner if twice daily.
Hepatic CYP2C19 is the dominant metabolising enzyme, so genetic and ethnic variation changes exposure. People of Asian ethnicity tend to have higher bioavailability and should start at lower doses, while rapid metabolisers may respond better to esomeprazole or rabeprazole, which are less affected by CYP2C19 polymorphism. IV formulations exist for lansoprazole, pantoprazole and esomeprazole.
| Topic | Points |
|---|---|
| Indications | Oesophagitis, non-erosive reflux disease, peptic ulcer disease, NSAID-ulcer prevention, Zollinger–Ellison syndrome, part of H. pylori triple therapy |
| Hypomagnesaemia | Rare but serious; tetany, seizures, arrhythmias; may need PPI withdrawal |
| Infections | Associated with C. difficile and other enteric infections and possibly community-acquired pneumonia |
| Rebound acid secretion | Raised gastrin → ECL hyperplasia; acid hypersecretion on stopping after long use |
| Deficiencies | Vitamin B12 (clinically rare) and iron; slight calcium malabsorption |
| Other | Fundic gland polyps rise with long use, without a malignancy link; fracture and dementia associations are inconsistent |
What are the key facts about H2 blockers?
H2 blockers are reversible competitive antagonists at histamine H2 receptors on parietal cells and suppress both basal and stimulated acid secretion. Onset is about 60 minutes with a duration of 4 to 10 hours, and all agents have similar efficacy. Ranitidine has been withdrawn in the United States and suspended in Europe and Australia after contamination with the carcinogen NDMA. They are metabolised by the liver and cleared mainly by the kidney.
| Drug | Points to remember |
|---|---|
| Cimetidine | Inhibits CYP1A2, CYP2C9, CYP2D6: interactions with theophylline, SSRIs and warfarin; prolonged high doses cause gynaecomastia, reduced sperm count, impotence and galactorrhoea |
| Famotidine | Active duodenal ulcer 40 mg once daily or 20 mg twice daily; gastric ulcer 40 mg once daily; half-life 2.5–3.5 h; renal dose adjustment below creatinine clearance 50 mL/min; rare QT prolongation |
| Nizatidine | Higher oral bioavailability (over 70%); shorter half-life (1–2 h); adjust dose in renal impairment |
- Tachyphylaxis: tolerance can develop after 7–14 days of continued use, so as-needed dosing is preferred for symptom control.
- CNS effects: confusion, delirium and hallucinations in renal or hepatic impairment or in people over 50; cimetidine is most likely to cause them.
- Nocturnal symptoms: ACG guidance suggests adding a bedtime H2 blocker for persistent night-time symptoms despite a PPI.
- Zollinger–Ellison syndrome: famotidine up to 20 mg every 6 hours, with a stated maximum of 160 mg every 6 hours, though PPIs are first line.
- Safer for the gut flora: H2 blockers carry a lower infection risk than PPIs.
How do sucralfate, misoprostol, bismuth and antacids act?
| Drug | Mechanism | Dose / key adverse effects |
|---|---|---|
| Sucralfate | Aluminium–sucrose octasulfate complex forms a polyanion gel barrier; adsorbs pepsin, increases mucus and bicarbonate, binds growth factors. Not a buffer and does not change acid production | 1 g four times daily on an empty stomach for duodenal ulcer (4–8 weeks); about 5% absorbed; constipation commonest; aluminium accumulation in renal impairment; can reduce absorption of other drugs |
| Misoprostol | Synthetic PGE1 analogue; acts on parietal cell prostaglandin receptors to reduce acid and increases mucus and bicarbonate | 200 microgram four times daily; diarrhoea, abdominal pain; uterotonic and abortifacient; box warning in pregnancy (premature birth, abnormalities, abortion) |
| Bismuth subsalicylate | Hydrolyses to bismuth and salicylate; bismuth salts are bactericidal and block H. pylori adhesion to gastric epithelium | 300 mg four times daily in quadruple therapy for 10–14 days |
| Antacids | Neutralise gastric acid; aluminium hydroxide also inhibits pepsin | Used for symptom relief; calcium salts also raise lower oesophageal sphincter tone |
How is H. pylori eradicated in a peptic ulcer?
Helicobacter pylori is a gram-negative, spiral, microaerophilic bacterium that colonises the stomach. H. pylori and NSAIDs account for most peptic ulcers. Non-invasive tests are the urea breath test and stool antigen; antibody serology is not recommended because it cannot separate active from past infection. Invasive tests on biopsy include rapid urease testing, histology, culture and PCR. To avoid false-negative results, test at least 2 weeks after stopping a PPI and 4 weeks after antibiotics; the same two tests confirm eradication.
| Regimen | Components | Duration and place |
|---|---|---|
| Classic triple therapy | PPI + clarithromycin + amoxicillin (or metronidazole) | 7–14 days; now reserved for areas of low clarithromycin resistance and no prior macrolide exposure |
| Bismuth quadruple therapy | PPI + bismuth + tetracycline + nitroimidazole (metronidazole) | 10–14 days (14-day commonly recommended); first-line option, especially after macrolide exposure or penicillin allergy |
| Concomitant (non-bismuth) quadruple | PPI + amoxicillin + clarithromycin + metronidazole | First-line alternative where regional resistance allows |
| Salvage | Levofloxacin-based or rifabutin-based | After failure, guided by susceptibility testing |
| Vonoprazan regimens | Potassium-competitive acid blocker with amoxicillin ± clarithromycin | Dual therapy 14 days; helpful in clarithromycin-resistant strains |
What about NSAID ulcers, Zollinger–Ellison syndrome and refractory ulcers?
- Definitions: a mucosal lesion over 5 mm is an ulcer; under 5 mm it is an erosion.
- NSAID-induced ulcer: stop or reduce the NSAID; also stop corticosteroids, bisphosphonates or anticoagulants if possible; misoprostol prophylaxis is sometimes used.
- H. pylori ulcer: PPI-based eradication regimen above. Ulcer recurrence is common, exceeding 60% in most series.
- Zollinger–Ellison syndrome: gastrin-secreting tumour, usually pancreatic or duodenal; multiple ulcers in the duodenum and jejunum; diagnosed by serum gastrin; PPIs are first line.
- Bleeding ulcer: ACG advice is high-dose PPI continuously or intermittently for 3 days after successful endoscopic haemostasis.
- Refractory ulcer: over 5 mm and not healed after 8–12 weeks of PPI. Look for persistent H. pylori, continued NSAID use, gastrinoma or gastric cancer. Surgery (vagotomy or partial gastrectomy) is considered if unresponsive, non-compliant or high-risk; see post-gastrectomy syndromes.
- Complications: upper GI bleeding, gastric outlet obstruction, perforation, penetration and gastric cancer.
For other acid-related indications compare oesophageal cancer and Barrett oesophagus, and for nausea drugs often combined with acid suppression see anti-emetic drugs. Vitamin B12 absorption depends on gastric acid releasing B12 from food proteins, which links long-term PPI use to the picture in megaloblastic anaemia.