Drugs Affecting Acid Secretion

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

• The parietal cell secretes hydrogen ions via the H⁺/K⁺ ATPase ("proton pump"). Three stimulants, histamine (H₂), gastrin (a stomach hormone that stimulates acid release) and acetylcholine, converge on the proton pump, the final common pathway.
• Proton pump inhibitors (PPIs) (omeprazole, lansoprazole, pantoprazole) are the most powerful acid suppressants. They are the standard treatment for gastro-oesophageal reflux disease (GORD, acid washing up from the stomach into the oesophagus) and peptic ulcer disease. They also prevent ulcers caused by non-steroidal anti-inflammatory drugs (NSAIDs, such as ibuprofen) and form part of H. pylori eradication.
• H₂ receptor antagonists (famotidine, which replaced ranitidine after the 2019 recall for contamination with a nitrosamine, a chemical impurity linked to cancer) 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).

Introduction

Drugs that suppress gastric acid are amongst the most commonly prescribed in the UK. Proton pump inhibitors (PPIs) alone account for around 79 million prescription items (individual drugs on a prescription) a year in England. 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 membrane (the side facing the stomach lumen), also called the canalicular membrane. This membrane lines deep folds (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 (receptors on the side of the cell facing the blood supply) and converge on the proton pump:

• Histamine: released from enterochromaffin-like (ECL) cells (histamine-secreting cells) in the gastric mucosa. It binds parietal-cell H₂ receptors (G_s-coupled, meaning linked to a G protein) → raises cyclic AMP (cAMP, an intracellular messenger) → activates the proton pump. An important pathway in basal (resting, between-meal) acid secretion. H₂ receptor blockers therefore act mainly on basal and night-time acid, whereas PPIs, which block the final common pathway, suppress acid more powerfully.
• Gastrin: a hormone released from G cells in the antrum (the lower part of the stomach) in response to peptides in the lumen and vagal stimulation. It acts on parietal-cell CCK₂ (cholecystokinin-2) receptors and, more importantly, drives histamine release from ECL cells.
• Acetylcholine: released from vagal post-ganglionic fibres; acts on M₃ receptors (a muscarinic type of acetylcholine receptor) on the parietal cell, on ECL cells (driving histamine release), and on G cells.

Two regulatory signals oppose acid secretion:

• Somatostatin: a hormone from D cells (cells in the stomach lining) that inhibits gastrin, histamine and parietal cells directly.
• Prostaglandins (PGE₂): local signalling lipids that inhibit acid secretion and stimulate the protective mucosal barrier (mucus and bicarbonate). This explains why non-steroidal anti-inflammatory drugs (NSAIDs, such as ibuprofen), 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 (seals between neighbouring cells), mucus and bicarbonate (driven by prostaglandins), good blood flow, prostaglandin-mediated cell turnover.
• Aggressive factors: gastric acid, pepsin (a protein-digesting enzyme), Helicobacter pylori, NSAIDs, alcohol, bile reflux, smoking, and stress.

Disease (gastritis, meaning inflammation of the stomach lining; peptic ulcer; or gastro-oesophageal reflux disease, 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 (indigestion). Common preparations:

• Magnesium salts: can cause diarrhoea.
• Aluminium salts: can cause constipation.
• Compound preparations (e.g. Maalox, Mucogel) combine magnesium and aluminium salts so that their side effects cancel out.
• Calcium carbonate: rapid. Rebound hyperacidity (extra acid production once the antacid wears off) has been described in laboratory studies, but its clinical importance is uncertain.

Antacids interfere with the absorption of many drugs, notably tetracyclines and quinolones (types of antibiotic), levothyroxine (thyroid hormone replacement), iron and bisphosphonates (bone-protecting drugs). The NHS advises leaving 2 to 4 hours between an antacid and other medicines. The British National Formulary (BNF) gives drug-specific gaps. For example, leave at least 4 hours from levothyroxine, 2 hours before or 4 hours after an antacid for ciprofloxacin (a quinolone), and 2 to 3 hours from doxycycline (a tetracycline).

Alginates

Gaviscon and similar preparations contain alginates that form a viscous gel "raft" floating on top of gastric contents. The raft reduces 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. Basal acid secretion (the resting secretion between meals) is largely driven by histamine, so H₂RAs work best on it, particularly at night, where they inhibit it by about 70% (the exact figure depends on the drug and dose). Meal-stimulated secretion also involves gastrin and acetylcholine, so blocking histamine alone only partly suppresses acid output after meals (generally by 50% or less). H₂RAs are therefore more useful for night-time symptoms than for meal-related acid secretion.

• Famotidine: the standard H₂RA in current UK practice.
• Cimetidine: the original; now rarely used. It is a potent inhibitor of cytochrome P450 (CYP) enzymes (liver enzymes that break down many drugs). It also causes gynaecomastia (breast enlargement in men) and erectile dysfunction, through an off-target anti-androgenic action (it blocks the effects of male sex hormones).
• Ranitidine: was widely used until 2019. The Medicines and Healthcare products Regulatory Agency (MHRA) then recalled it as a precaution, because of possible contamination with a nitrosamine impurity called N-nitrosodimethylamine (NDMA). NDMA has the potential to damage DNA and cause cancer.

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

Proton Pump Inhibitors

Proton pump inhibitors (PPIs) (omeprazole, lansoprazole, pantoprazole, esomeprazole and rabeprazole) are pro-drugs (inactive until the body converts them to their active form). They are activated by acid in the canaliculi (acid-secreting channels) of active parietal cells. They covalently inhibit the H⁺/K⁺ ATPase (they form a strong chemical bond with it), inactivating any pump that is currently active. The effect is long-lasting rather than strictly irreversible. Recovery of acid secretion depends on new pumps being made (for PPIs other than pantoprazole, it may also depend on the bond to the pump slowly breaking down). In humans, the effect on acid secretion has a half-life of about 28 hours for omeprazole and about 46 hours for pantoprazole.

Several pharmacological consequences follow from this mechanism:

• Timing with food depends on the PPI. The NHS advises taking lansoprazole at least 30 minutes before a meal and pantoprazole an hour before, while omeprazole and esomeprazole can be taken with or without food. The aim of dosing before a meal is to have the drug in the blood when the meal activates the proton pumps.
• Once-daily dosing produces sustained acid suppression because new pumps are synthesised slowly.
• Stopping PPIs can cause rebound hyperacidity (higher-than-normal acid production after stopping). The rebound can last for weeks rather than days. In trials in healthy volunteers, acid-related symptoms were more common than with placebo (a dummy treatment) for about 2 weeks after a 4-week course, and were still more common 4 weeks after an 8-week course. It is driven by the raised gastrin levels (gastrin is the hormone that stimulates acid release) that develop during treatment.

Indications:

• GORD.
• Peptic ulcer disease.
• Component of H. pylori eradication.
• Prophylaxis (prevention) of ulcers caused by NSAIDs and steroids 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: Some PPIs can reduce the activation of clopidogrel (an antiplatelet drug that has to be activated by CYP2C19, a liver enzyme). The MHRA advises that use of either omeprazole or esomeprazole with clopidogrel should be discouraged (the BNF says to avoid the combination). The MHRA states that the current evidence does not support extending this advice to other PPIs, such as pantoprazole, lansoprazole or rabeprazole.

Mucosal Protective Agents

Two drugs reinforce mucosal defences:

• Sucralfate: an aluminium-sucrose complex (a compound of aluminium and sucrose) that polymerises (links up into a larger, sticky molecule) in acidic conditions to form a barrier over ulcers. Used for benign gastric and duodenal ulcers. It is also given for stress ulcer prevention in the intensive care unit (ICU), although the tablets are not licensed for that use.
• 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. Because it induces uterine contractions and is associated with miscarriage and birth defects, it must not be used in pregnancy (it is contraindicated) except where termination of pregnancy is intended. It has largely been replaced by PPIs for protecting the stomach from NSAIDs.

Helicobacter pylori Eradication

Helicobacter pylori is a gram-negative spiral bacterium (one that does not retain the Gram stain). It colonises the gastric mucosa. It neutralises local acid using its urease enzyme (which splits urea to release ammonia, an alkali). It is associated with most peptic ulcers: the BNF gives about 95% of duodenal ulcers and 70 to 80% of gastric ulcers. It is also a strong risk factor for gastric cancer and for mucosa-associated lymphoid tissue (MALT) lymphoma.

Diagnosis is by stool antigen test or urea breath test (avoiding endoscopy in most cases). Wait at least 2 weeks after stopping a PPI, and at least 4 weeks after finishing antibiotics, before testing. Both can cause false-negative results (the test misses an infection that is present).

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 500 mg twice daily
or metronidazole 400 mg twice daily
for 7 days

NICE advises choosing the cheapest regimen (the one with the lowest cost to buy), taking into account previous exposure to clarithromycin or metronidazole (each additional course of either increases the risk of antibiotic resistance). In penicillin allergy, amoxicillin is left out and the regimen becomes PPI + clarithromycin + metronidazole. If the patient has also had clarithromycin before, NICE advises a four-drug regimen: a PPI plus bismuth (a medicine that protects the stomach lining), metronidazole and tetracycline (an antibiotic). For people who still have symptoms after first-line treatment, second-line treatment is the same PPI and amoxicillin with whichever of clarithromycin or metronidazole was not used first. If both have been used, NICE advises a PPI, amoxicillin and tetracycline, or levofloxacin (a quinolone antibiotic) if a tetracycline cannot be used.

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