Proton Pump Inhibitors

Proton pump inhibitors are substituted benzimidazole prodrugs that irreversibly block the H+/K+ ATPase of gastric parietal cells. They give the strongest and longest acid suppression of any class and are the first-line drugs for reflux disease, peptic ulcer, Helicobacter pylori eradication and gastroprotection.

Mechanism. Weak bases that concentrate in the acid canaliculus, convert to the active sulphenamide and bind pump cysteine residues. Acid secretion returns only as new pumps are synthesised, so effect outlasts the plasma half life of 1 to 2 hours and reaches full strength after 3 to 5 days.

Pharmacokinetics. Acid labile, so given as enteric-coated or buffered forms, 30 to 60 minutes before the first meal. Hepatic clearance by CYP2C19 and CYP3A4; no adjustment for renal impairment. CYP2C19 variants change exposure, least for pantoprazole and rabeprazole.

• Omeprazole 20 to 40 mg once daily.
• Esomeprazole 20 to 40 mg once daily.
• Lansoprazole 15 to 30 mg once daily.
• Pantoprazole 40 mg once daily.
• Rabeprazole 10 to 20 mg once daily.

Differences. Efficacy is similar at equipotent doses. Omeprazole and esomeprazole inhibit CYP2C19 and blunt clopidogrel activation; pantoprazole has the least interaction burden. Only some members (esomeprazole, pantoprazole, omeprazole) have intravenous forms.

• Reflux disease: full dose once daily for 4 to 8 weeks, then the lowest effective dose or on-demand use. Erosive oesophagitis needs 8 weeks and usually long-term maintenance.
• Peptic ulcer: duodenal ulcer 4 weeks, gastric ulcer 8 weeks. Stop the NSAID where possible and test for H. pylori.
• H. pylori eradication: a proton pump inhibitor twice daily at the usual dose for 14 days with antibiotics. Bismuth quadruple therapy (bismuth, tetracycline 500 mg four times daily, metronidazole 400 to 500 mg three times daily) is preferred where clarithromycin resistance is common or unknown. Clarithromycin 500 mg twice daily with amoxicillin 1 g twice daily suits only areas with low resistance.
• Gastroprotection: once daily for patients on NSAIDs or aspirin who are over 65, have a past ulcer, or take anticoagulants, corticosteroids or dual antiplatelet therapy.
• Ulcer bleeding after endoscopic haemostasis: esomeprazole or pantoprazole 80 mg intravenous bolus, then 8 mg/h for 72 hours; 40 mg intravenously twice daily is a common alternative.
• Zollinger-Ellison syndrome: omeprazole 60 mg daily initially, titrated to acid output, often in divided doses.
• Stress ulcer prophylaxis: only for ventilated patients over 48 hours or with coagulopathy; 40 mg intravenously daily.

Selection. Review the indication at 8 weeks. Do not continue open-ended for undifferentiated dyspepsia.

Contraindications. Hypersensitivity to the class; rilpivirine co-prescription.

Adverse effects. Headache, diarrhoea, nausea. With prolonged use: hypomagnesaemia, vitamin B12 and iron deficiency, Clostridioides difficile and enteric infection, community-acquired pneumonia, modest fracture risk, acute or chronic interstitial nephritis, subacute cutaneous lupus, fundic gland polyps and rebound acid hypersecretion on withdrawal. Symptom relief can mask gastric cancer.

Interactions.

• Clopidogrel: avoid omeprazole and esomeprazole; use pantoprazole.
• Atazanavir and rilpivirine: absorption falls; avoid.
• Ketoconazole, itraconazole, iron and mycophenolate: reduced absorption.
• Methotrexate (high dose), digoxin, tacrolimus: levels rise.

Special groups.

• Severe liver impairment: omeprazole and esomeprazole not over 20 mg daily, pantoprazole not over 40 mg daily. In cirrhosis, unnecessary use raises the risk of spontaneous bacterial peritonitis and hepatic encephalopathy.
• Pregnancy: omeprazole, lansoprazole and pantoprazole are acceptable when indicated.
• Breastfeeding: low milk transfer; acceptable.
• Children: omeprazole about 1 mg/kg once daily, usually 10 mg under 20 kg and 20 mg from 20 kg.
• Older adults: deprescribe when no clear indication remains.

Monitoring. Magnesium and vitamin B12 in long-term users, particularly with diuretics or digoxin; creatinine if it rises without cause.

Referral and escalation. Dysphagia, weight loss, anaemia, gastrointestinal bleeding, persistent vomiting, a mass, or new dyspepsia over 55 need endoscopy. Symptoms persisting after 8 weeks at full dose, Barrett oesophagus and recurrent ulcer need specialist review.