Key Facts

PPIs are the most potent class of acid-suppressing drugs, reducing gastric acid secretion by up to 99%. They are among the most commonly prescribed medications worldwide.

Epidemiology

Approximately 15% of the UK adult population is prescribed a PPI at any given time. PPI prescriptions cost the NHS over £100 million annually. There is growing concern about overprescription — up to 50% of long-term PPI use may lack a clear indication.

Aetiology

PPIs target the final common pathway of acid secretion:

• Bind covalently to cysteine residues on the alpha-subunit of H+/K+ ATPase
• Irreversible inhibition — acid secretion only recovers as new proton pumps are synthesised (half-life of pump turnover approximately 18 hours)
• All PPIs are benzimidazole derivatives and pro-drugs activated at pH <4

Pathophysiology

Gastric acid secretion is regulated by three stimulatory pathways:

• Histamine (H2 receptors) — from ECL cells
• Acetylcholine (M3 receptors) — vagal nerve
• Gastrin (CCK-B receptors) — from G cells

All three converge on the H+/K+ ATPase. PPI blockade of this final step provides superior acid suppression compared to H2 receptor antagonists. Prolonged suppression leads to compensatory hypergastrinaemia.

Indications

• GORD: Heartburn, acid regurgitation, dysphagia
• Peptic ulcer disease: Epigastric pain, relationship to meals
• H. pylori eradication: As part of triple therapy
• NSAID gastroprotection: Co-prescription with long-term NSAIDs in at-risk patients
• Zollinger-Ellison syndrome: Refractory acid hypersecretion
• Barrett's oesophagus: Long-term acid suppression

Side Effects

• Common: Headache, diarrhoea, nausea, abdominal pain
• Long-term risks: Hypomagnesaemia, vitamin B12 deficiency, iron deficiency, increased C. difficile risk, community-acquired pneumonia, hip fractures
• Rebound acid hypersecretion: On abrupt discontinuation after prolonged use

Red Flags (Refer for Endoscopy)

• Dysphagia
• Persistent vomiting
• Unintentional weight loss
• GI bleeding (haematemesis, melaena)
• Iron deficiency anaemia
• Epigastric mass
• Age >55 with new-onset dyspepsia and red flag features

Bedside

• H. pylori testing: Urea breath test (first-line non-invasive) or stool antigen test — stop PPI for 2 weeks before testing
• Symptom assessment: GORD questionnaire

Bloods

• FBC: Iron deficiency anaemia (red flag)
• Magnesium: If on long-term PPI (especially with diuretics or digoxin)
• Vitamin B12 and folate: In long-term use
• Gastrin levels: If Zollinger-Ellison suspected

Imaging

• OGD: Gold standard for upper GI pathology — indicated for red flags or treatment failure
• Barium swallow: If OGD not possible or to assess motility

Special Tests

• 24-hour pH monitoring: Gold standard for acid reflux quantification
• Oesophageal manometry: If motility disorder suspected
• CLO test: Rapid urease test on biopsy at OGD for H. pylori

Non-pharmacological

• Weight loss if overweight
• Elevate head of bed
• Avoid eating within 3 hours of bedtime
• Reduce alcohol, caffeine, fatty/spicy foods
• Smoking cessation

Pharmacological

GORD (NICE NG12/CG184):

• Step 1: Full-dose PPI for 4-8 weeks (e.g., omeprazole 20mg OD or lansoprazole 30mg OD)
• Step 2: Step down to lowest effective dose or use PRN
• Consider H2RA (ranitidine alternative: famotidine 20mg BD) if PPI not tolerated

H. pylori eradication (NICE CG184):

• First-line: PPI + amoxicillin 1g BD + clarithromycin 500mg BD or metronidazole 400mg BD for 7 days
• Second-line: PPI + amoxicillin 1g BD + metronidazole 400mg BD for 7 days (or vice versa)
• Confirm eradication with urea breath test at least 4 weeks after completing treatment

NSAID gastroprotection:

• Co-prescribe PPI with NSAIDs in patients aged >65, history of peptic ulcer, on anticoagulants/antiplatelets

Referral Criteria

• Red flag symptoms → urgent 2-week-wait referral
• Treatment failure after 8 weeks of PPI therapy
• Recurrent symptoms requiring long-term PPI
• Suspected Barrett's oesophagus

• GORD: 80-90% symptom improvement with PPI therapy
• Peptic ulcers: >95% healing rates with PPI + H. pylori eradication
• Barrett's oesophagus: Annual risk of progression to oesophageal adenocarcinoma approximately 0.5%
• Long-term PPI use: Absolute risk increase for hip fracture approximately 1 per 1000 patient-years
• C. difficile risk increased approximately 1.5-2.7 fold with PPI use

PPI Comparison Table

Drug Interactions