Proton Pump Inhibitors

The proton pump inhibitors (PPIs) omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole:

• Cause a dose-dependent inhibition of gastric acid secretion by inhibiting the proton pump in actively secreting gastric parietal cells.
• They have a much greater efficacy and longer duration than H₂-receptor antagonists.
• There are differences in the effectiveness of the actions of individual PPIs (e.g. pantoprazole binds more firmly to receptors) but these differences are not considered significant in influencing the choice of a particular drug.

The NICE guidelines for dyspepsia recommend that all PPIs are well tolerated and have similar efficacy so the least expensive PPI should be used.¹

• Short-term treatments for gastric and duodenal ulcers. Treatment in peptic bleeding reduces further bleeding and surgical intervention rates in studies comparing treatment with placebo or H₂-antagonists, but there is no evidence of an effect on mortality.²
• In combination with antibacterials for the eradication of Helicobacter pylori.
• An initial short course of a proton pump inhibitor is the treatment of choice in gastro-oesophageal reflux disease (GORD) with severe symptoms. Proton pump inhibitors are superior to H₂-antagonists in empirical treatment of typical gastro-oesophageal reflux disease symptoms.³
• Patients with endoscopically confirmed erosive or ulcerative oesophagitis, or oesophagitis complicated by stricture, usually need to be maintained on a proton pump inhibitor.
• Proton pump inhibitors are also used in the prevention and treatment of NSAID-associated ulcers.
• Omeprazole and lansoprazole are effective in the treatment of the Zollinger-Ellison syndrome.
• The NICE guideline for the management of dyspepsia in adults in primary care advises the use of proton pump inhibitors for the following indications:¹
  • Uninvestigated dyspepsia:
    • Empirical treatment is often appropriate but PPIs may mask the symptoms of gastric cancer and so a thorough assessment, exclusion of any 'red flags' (e.g. bleeding, dysphagia, recurrent vomiting and weight loss) and caution is required. The duration of treatment should be only for between 2 and 4 weeks and the patient then reviewed if over 45 years old or if symptoms recur or persist.
    • Initial management is either empirical treatment with a proton pump inhibitor or testing for and treating H. pylori.
    • There is currently insufficient evidence to guide which should be offered first.
    • A 2-week washout period following proton pump inhibitor use is necessary before testing for H. pylori with a breath test or a stool antigen test.
  • Gastro-oesophageal reflux disease:
    • Treat with a full-dose proton pump inhibitor for 1 or 2 months.
    • If symptoms recur following initial treatment, then give a proton pump inhibitor at the lowest dose possible to control symptoms, with a limited number of repeat prescriptions.
    • However in cases of severe GORD, oesophageal haemorrhage or stricture of Barrett's oesophagus, then the full treatment dose of PPI should be continued.
  • Barrett's oesophagus:
    • Long-term PPI therapy is required. Twice daily PPI therapy may be recommended for patients who do not respond clinically to once daily therapy.
    • There is no evidence that acid suppression therapy with PPIs causes regression of Barrett's oesophagus or prevents progression to adenocarcinoma of the oesophagus.
  • Peptic ulcer disease:
    • Give H. pylori eradication therapy to H. pylori-positive patients who have peptic ulcer disease.
    • For patients using NSAIDs with diagnosed peptic ulcer, stop the use of NSAIDs where possible.
    • Offer full-dose proton pump inhibitor or H₂-receptor antagonist therapy for 2 months and, if H. pylori is present, subsequently offer eradication therapy.
    • NICE guidelines recommend that "for NSAID-associated ulceration in patients who need to continue NSAID treatment, once the ulcer has healed a lower dose of PPI may be used". However this is not normally reduced due to possible occurrence of asymptomatic ulcer deterioration.
  • Non-ulcer dyspepsia:
    • Initial treatment for H. pylori if present, followed by symptomatic management and periodic monitoring.
  • NICE also recommends the following when reviewing patient care:
    • Patients requiring long-term management of dyspepsia symptoms should be reviewed annually, including encouragement to try stepping down or stopping treatment.
    • Intermittent therapy (2-4 week course of treatment when symptoms recur) is often appropriate instead of continuing with low dose PPI. There is no evidence for the relative effectiveness of different regimes but there is still uncertainty regarding the long-term safety of PPIs (gastric atrophy and theoretical predisposition to gastric cancer).
    • Continuing with antacid and/or alginate therapy may be appropriate.

• Liver disease: dose should not be increased above the normal full dose, e.g. 20 mg daily in the case of omeprazole.
• Pregnancy: not known to be harmful.
• Breast-feeding: present in breast milk but not known to be harmful.
• Proton pump inhibitors may mask symptoms of gastric cancer; particular care is required in those whose symptoms change and in those over 45 years of age. Alarm features for possible malignancy include:⁶
  • Dyspepsia with one or more of the following:
    • Chronic gastrointestinal bleeding
    • Progressive unintentional weight loss
    • Progressive difficulty swallowing
    • Persistent vomiting
    • Iron deficiency anaemia
    • Epigastric mass
    • Suspicion of cancer after investigation with a barium meal
  • People over 55 years of age with persistent or unexplained dyspepsia

Referral for suspected upper gastrointestinal cancer⁷

Urgent referral for endoscopy/referral to specialist:

• Patients of any age with dyspepsia and any of the following:
  • Chronic gastrointestinal bleeding
  • Dysphagia
  • Progressive unintentional weight loss
  • Persistent vomiting
  • Iron deficiency anaemia
  • Epigastric mass
  • Suspicious barium meal result
  • Obstructive jaundice (depending on clinical state); consider urgent ultrasound if available
• Unexplained worsening of dyspepsia and:
  • Barrett's oesophagus
  • Known dysplasia, atrophic gastritis or intestinal metaplasia
  • Peptic ulcer surgery over 20 years ago
• Refer urgently for endoscopy any patient aged 55 years and older with unexplained and persistent recent-onset dyspepsia alone

• Antacids: antacids should preferably not be taken at the same time as other drugs since they may impair absorption.
• Lansoprazole and omeprazole inhibit cytochrome P450 and can prolong elimination of other drugs; this is a minor effect but wise to monitor phenytoin and warfarin therapy. Pantoprazole doesn't affect drug metabolism.
• Oestrogens and progestogens: manufacturer advises lansoprazole possibly accelerates metabolism of oral contraceptives.

• Generally well tolerated and only occasional adverse effects
• Gastro-intestinal: diarrhoea, nausea and vomiting, constipation, flatulence, abdominal pain
• Headache, depression, malaise, dizziness, blurred vision
• Hypersensitivity reactions include pruritus, rash, urticaria, angioedema, bronchospasm, photosensitivity
• Peripheral oedema
• Muscle and joint pain
• Dry mouth, taste disturbance
• Proton pump inhibitors decrease gastric acidity and may increase the risk of gastro-intestinal infections