Contents

1. Introduction
2. The Parietal Cell and Acid Secretion
3. Mucosal Defence and Disease
4. Drug Classes
   • Antacids
   • Alginates
   • H₂ Receptor Antagonists
   • Proton Pump Inhibitors
   • Mucosal Protective Agents
5. Helicobacter pylori Eradication
6. Pharmacological Management of Common Conditions
   • GORD
   • Peptic Ulcer Disease
   • Stress Ulcer Prevention
   • Zollinger-Ellison Syndrome
7. Long-Term PPI Use: Adverse Effects
8. Summary
9. Drug Summary Table
10. Quiz

Abstract

• The parietal cell secretes hydrogen ions via the H⁺/K⁺ ATPase ("proton pump"). Three stimulants: histamine (H₂), gastrin, and acetylcholine: converge on the proton pump as the final common pathway.
• Proton pump inhibitors (PPIs): omeprazole, lansoprazole, pantoprazole: are the most powerful acid suppressants and the standard treatment for GORD, peptic ulcer disease, NSAID-induced ulceration prophylaxis, and as part of H. pylori eradication.
• H₂ receptor antagonists (famotidine, replacing ranitidine after the 2019 nitrosamine recall) are weaker but still effective for milder symptoms.
• Helicobacter pylori is eradicated with a 7-day course of triple therapy: a PPI plus two antibiotics (typically amoxicillin and clarithromycin).

Core

Introduction

Drugs that suppress gastric acid are amongst the most commonly prescribed in the UK; PPIs alone account for around 60 million prescriptions a year. The pharmacology is comparatively simple, hinging on the parietal cell and three converging stimulatory pathways.

The relevant gastrointestinal physiology is covered in Anatomy and Physiology of the Foregut and the disease processes in Upper Gastrointestinal Pathology.

The Parietal Cell and Acid Secretion

Parietal cells in the body of the stomach secrete hydrochloric acid into the lumen via the H⁺/K⁺ ATPase ("proton pump") located on the apical (canalicular) membrane: the inner surface of deep invaginations of the parietal cell that open into the gastric lumen. The pump exchanges intracellular H⁺ for luminal K⁺ and is the final common pathway for acid secretion.

Three stimulants act on basolateral receptors and converge on the proton pump:

• Histamine: released from enterochromaffin-like (ECL) cells in the gastric mucosa; binds parietal-cell H₂ receptors (G_s-coupled) → raises cAMP → activates the proton pump. The dominant pathway in basal acid secretion, and accordingly the most useful single drug target.
• Gastrin: released from G cells in the gastric antrum in response to peptides in the lumen and vagal stimulation; acts on parietal-cell CCK₂ receptors and (more importantly) drives ECL cell histamine release.
• Acetylcholine: released from vagal post-ganglionic fibres; acts on M₃ muscarinic receptors on the parietal cell, on ECL cells (driving histamine release), and on G cells.

Two regulatory hormones oppose acid secretion:

• Somatostatin: from D cells; inhibits gastrin, histamine and parietal cells directly.
• Prostaglandins (PGE₂): inhibit acid secretion and stimulate the protective mucosal barrier (mucus and bicarbonate). This explains why NSAIDs, which inhibit prostaglandin synthesis, are a leading cause of peptic ulcer disease.

Diagram: The parietal cell. Three stimulatory pathways (histamine, gastrin, acetylcholine) converge on the H⁺/K⁺ ATPase. H₂ receptor antagonists block one pathway; PPIs block the final common pathway.

Mucosal Defence and Disease

The integrity of the gastric mucosa depends on a balance between defensive and aggressive factors:

• Defensive factors: intact epithelium, tight junctions, mucus and bicarbonate (driven by prostaglandins), good blood flow, prostaglandin-mediated cell turnover.
• Aggressive factors: gastric acid, pepsin, Helicobacter pylori, NSAIDs, alcohol, bile reflux, smoking, and stress.

Disease (gastritis, peptic ulcer, GORD) emerges when aggressive factors outweigh defensive ones. Most pharmacological therapy works by reducing aggressive factors (acid suppression) or replacing defensive ones (mucosal protectants).

Drug Classes

Antacids

Antacids are weak bases that neutralise gastric acid in the lumen. They provide rapid but short-lived symptom relief and are first-line for occasional dyspepsia. Common preparations:

• Magnesium salts: can cause diarrhoea.
• Aluminium salts: can cause constipation.
• Compound preparations (e.g. Maalox, Mucogel) combine the two so the side effects cancel out.
• Calcium carbonate: rapid but can cause acid rebound.

Antacids interfere with the absorption of many drugs (notably tetracyclines, quinolones, levothyroxine, iron, bisphosphonates), so should be separated by at least 2 hours.

Alginates

Gaviscon and similar preparations contain alginates that form a viscous gel "raft" floating on top of gastric contents. The raft prevents reflux into the oesophagus and is particularly useful in GORD, including symptom relief during pregnancy.

H₂ Receptor Antagonists

H₂ receptor antagonists ("H₂RAs") block the histamine pathway at the parietal cell, reducing acid secretion by around 60-70%. They are more useful for night-time symptoms (when basal histamine drive predominates) than for meal-related acid secretion.

• Famotidine: the standard H₂RA in current UK practice.
• Cimetidine: the original; now rarely used because it is a potent CYP enzyme inhibitor and causes gynaecomastia and erectile dysfunction (off-target anti-androgenic action).
• Ranitidine: was widely used until 2019, when an MHRA recall was issued because of nitrosamine contamination during manufacture.

H₂RAs are generally well tolerated; common side effects include diarrhoea, headache and dizziness.

Proton Pump Inhibitors

Proton pump inhibitors (PPIs): omeprazole, lansoprazole, pantoprazole, esomeprazole, rabeprazole: are pro-drugs activated in the acidic canaliculi of active parietal cells. They covalently inhibit the H⁺/K⁺ ATPase, irreversibly inactivating any pump that is currently active. New protein synthesis is needed for acid secretion to recover, which takes 24-48 hours.

Several pharmacological consequences follow from this mechanism:

• The drug must be taken 30 minutes before food to coincide with the activation of proton pumps by the meal.
• Once-daily dosing produces sustained acid suppression because new pumps are synthesised slowly.
• Stopping PPIs can cause rebound hyperacidity for a few days, mediated by gastrin upregulation during treatment.

Indications:

• GORD.
• Peptic ulcer disease.
• Component of H. pylori eradication.
• Prophylaxis against NSAID- and steroid-induced ulceration in high-risk patients.
• Stress ulcer prevention in critical care.
• Zollinger-Ellison syndrome.

Common side effects: headache, diarrhoea, abdominal pain, nausea. Long-term concerns are covered separately below.

Drug interactions: PPIs can reduce the activation of clopidogrel (which requires CYP2C19). The MHRA advises avoiding both omeprazole and esomeprazole in patients on clopidogrel; pantoprazole, lansoprazole or rabeprazole are preferred where a PPI is needed alongside clopidogrel.

Mucosal Protective Agents

Two drugs reinforce mucosal defences:

• Sucralfate: an aluminium-sucrose complex that polymerises in acidic conditions to form a sticky barrier over ulcers. Used in selected patients, including stress ulcer prevention in ICU.
• Misoprostol: a synthetic prostaglandin E₁ analogue. Replaces the prostaglandin signalling that NSAIDs inhibit, reducing the rate of NSAID-induced ulceration. Causes diarrhoea and uterine contractions (so contraindicated in pregnancy except where pregnancy termination is intended). Largely superseded by PPIs for NSAID gastroprotection.

Helicobacter pylori Eradication

Helicobacter pylori is a gram-negative spiral bacterium that colonises gastric mucosa, neutralising local acid using its urease enzyme. It is responsible for the majority of duodenal ulcers and a substantial fraction of gastric ulcers, and is a strong risk factor for gastric cancer and MALT lymphoma.

Diagnosis is by stool antigen test or urea breath test (avoiding endoscopy in most cases). PPIs and antibiotics must be stopped before testing as both produce false-negative results.

The standard NICE first-line eradication regimen is 7-day triple therapy:

PPI (e.g. lansoprazole or omeprazole) twice daily
+ amoxicillin 1 g twice daily
+ clarithromycin or metronidazole twice daily
, for 7 days

In penicillin allergy, replace amoxicillin with metronidazole (so the regimen becomes PPI + clarithromycin + metronidazole). Second-line regimens use a different antibiotic combination based on prior exposure.

Pharmacological Management of Common Conditions

GORD

NICE-recommended approach:

1. Lifestyle measures: weight loss, smoking cessation, smaller meals, avoiding late-evening meals, head-up sleeping.
2. Antacids and alginates for symptom-driven, occasional use.
3. PPI for 4-8 weeks as the first-line maintenance therapy.
4. Test and treat for H. pylori if uninvestigated.
5. If symptoms persist on PPI, consider doubling the dose, switching PPI, or referral for endoscopy.

Peptic Ulcer Disease

The two principal causes are H. pylori and NSAIDs. Management:

• Stop NSAIDs where possible; switch to a less ulcerogenic alternative (paracetamol +/− opioid).
• Treat H. pylori if present.
• Full-dose PPI for 4-8 weeks.
• Re-test for H. pylori eradication 4-8 weeks after treatment if appropriate.

Stress Ulcer Prevention

Critically ill patients (particularly those who are mechanically ventilated, coagulopathic, septic or burned) are at risk of stress-related mucosal disease. Standard ICU prophylaxis is a PPI, with H₂RAs and sucralfate as alternatives.

Zollinger-Ellison Syndrome

A rare gastrin-secreting tumour (gastrinoma), almost always pancreatic or duodenal, causing massive acid hypersecretion and resistant peptic ulceration. Treatment is high-dose PPI together with surgery for the tumour.

Long-Term PPI Use: Adverse Effects

PPIs are extremely safe in short-term use, but the sheer scale of long-term prescribing has prompted concern about a number of associations. Most are observational findings of uncertain causality; the BNF advises that they should be considered when reviewing whether continued PPI is necessary:

• Hypomagnesaemia.
• Vitamin B₁₂ deficiency (acid is needed to release dietary B₁₂).
• Iron deficiency for similar reasons.
• Increased risk of Clostridioides difficile infection: reduced acid barrier.
• Increased risk of community-acquired pneumonia: modest, more controversial.
• Osteoporosis and hip fracture: modest increase, possibly via altered calcium absorption.
• Acute interstitial nephritis: rare but well-documented.
• Rebound hyperacidity on stopping: can be reduced by gradual dose reduction or step-down to an H₂RA.

The pre-clinical takeaway is that any patient on a long-term PPI should have the indication periodically reviewed, and the dose stepped down or stopped where possible.

Summary

• The parietal cell H⁺/K⁺ ATPase is the final common pathway for acid secretion. Three stimulants converge on it: histamine (H₂), gastrin and acetylcholine.
• Antacids and alginates give rapid but short symptom relief. Useful in occasional dyspepsia and pregnancy.
• H₂RAs (famotidine) block one of three pathways: modest acid suppression. Cimetidine should be avoided because of CYP inhibition and anti-androgenic effects.
• PPIs (omeprazole, lansoprazole, pantoprazole) covalently inactivate the proton pump: the most powerful acid suppressants. Take 30 minutes before food. First-line for GORD, peptic ulcer disease and as gastroprotection.
• Helicobacter pylori is treated with 7-day triple therapy: PPI + amoxicillin + clarithromycin (or metronidazole if penicillin-allergic).
• Long-term PPI use is associated with hypomagnesaemia, B₁₂ deficiency, increased C. difficile infection, and other minor adverse effects: review the indication regularly.

Drug Summary Table

Class	Examples	Mechanism	Use	Key side effects / cautions
Antacids	Magnesium / aluminium salts (Maalox), calcium carbonate	Neutralise gastric acid	Occasional dyspepsia	Mg → diarrhoea; Al → constipation. Drug-absorption interactions (separate by 2 h)
Alginates	Gaviscon	Form viscous "raft" over gastric contents	GORD (incl. pregnancy)	Generally well tolerated
H2 receptor antagonists	Famotidine; cimetidine (avoid)	Block parietal-cell H2 receptor	GORD, peptic ulcer (mild)	Cimetidine: CYP inhibitor, gynaecomastia
PPIs	Omeprazole, lansoprazole, pantoprazole, esomeprazole, rabeprazole	Irreversible inhibition of H+/K+ ATPase	GORD, peptic ulcer, H. pylori eradication, gastroprotection	Headache, diarrhoea; long-term: hypomagnesaemia, B12 deficiency, ↑ C. diff, fractures, AIN. Avoid omeprazole/esomeprazole with clopidogrel
Mucosal protectants	Sucralfate; misoprostol	Sucralfate: physical barrier. Misoprostol: PGE1 analogue	NSAID gastroprotection (largely replaced by PPIs)	Misoprostol: diarrhoea, uterine contraction (CI in pregnancy)
H. pylori triple therapy	PPI + amoxicillin + clarithromycin (or metronidazole)	Suppress acid + 2 antibiotics	Eradication of H. pylori	7-day course; in penicillin allergy use clarithromycin + metronidazole

Reviewed by: Dr. Marcus Judge

Quiz

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