Proton pump inhibitors

Proton pump inhibitors (PPIs) are a group of drugs used primarily to inhibit gastric acid secretion. They have largely replaced H₂ blockers such as cimetidine in the management of conditions caused by excessive gastroesophageal acidity (e.g., dyspepsia, GERD, Barrett's esophagus, peptic ulcers). PPIs act by completely and irreversibly inhibiting the H+/K+ ATPase enzyme system (gastric proton pump) in the parietal cells of the stomach, resulting in decreased acid production and an increase in gastric pH. PPIs are available in oral and intravenous forms, of which the oral form is more commonly administered. Intravenous PPIs are reserved for management of severe disease, since they can cause irreversible visual disturbances in rare cases. Other side effects are predominantly gastrointestinal, including symptoms such as nausea and abdominal pain, and usually decrease during the course of treatment. Significant drug interactions occur especially with anticoagulants (warfarin, clopidogrel) and should be considered before prescribing PPIs.

• Commonly used PPIs
  • Omeprazole
  • Esomeprazole
  • Pantoprazole
  • Lansoprazole, dexlansoprazole
  • Rabeprazole
• Administration
  • 1 Tablet/day taken in the morning on an empty stomach (see “Effects” below)
  • Duration
    • 1–12 weeks depending on the underlying condition
    • Long-term administration for complicated disease, but should generally be avoided (see “Side effects” below)

The individual PPIs differ in their pKa, bioavailability, peak plasma levels, and route of excretion. However, because these differences have not yet proven to be clinically relevant, PPIs are often used interchangeably.
References:^[1][2][3]

• Irreversible inhibition of H⁺/K⁺ ATPase in parietal cells → increases stomach pH
• Complete suppression of gastric acid secretion

References:^[1]

• Gastrointestinal
  • Nausea, diarrhea, abdominal pain, flatulence
  • ↑ Risk of C. difficile infection
  • Reactive hypergastrinemia ^[4]
  • ↓ Absorption of iron and vitamin B12
  • ↓ Absorption of calcium and magnesium → ↑ risk of osteoporosis in long-term use→ ↑ risk of fractures in elderly individuals
• Neurological
  • Lightheadedness, headaches
  • Possibly increased risk of developing cognitive impairment/dementia ^[5]
• Others
  • Exanthema
  • Visual disturbances (rare)
  • ↑ Risk of pneumonia ^[6][7][8]
  • In rare cases, acute interstitial nephritis

References:^[1][5]

We list the most important adverse effects. The selection is not exhaustive.

• Peptic ulcer disease (gastric and duodenal ulcers)
• Prevention of stress ulcers
• Gastroesophageal reflux disease
• Gastritis
• Combination treatment in Helicobacter pylori eradication therapy
• Zollinger-Ellison syndrome (gastrinoma)
• Gastropathy caused by NSAIDs
• Special indication: MALT lymphoma (stages I and II)

References:^[1]

Although several drug interactions are suspected, those with omeprazole and esomeprazole have proven to be of clinical significance, mainly in CYP2C19-mediated interactions (primarily due to CYP2C19 inhibition):

• Clopidogrel: ↓ activation
• Warfarin; , phenprocoumon: ↓ clearance
• Phenytoin, carbamazepine: ↑ clearance
• Nifedipine: ↑ absorption, ↓ clearance
• Diazepam: ↓ clearance

References:^[9]