What is Proton Pump Inhibitor (PPI) therapy?

What is PPI Therapy?

PPI (Proton Pump Inhibitor) therapy is a treatment using medications that irreversibly block the gastric H+/K+ ATPase enzyme (the proton pump) in parietal cells, providing the most potent suppression of gastric acid secretion available in clinical practice. 1

Mechanism of Action

PPIs are prodrugs that require activation in the acidic environment of gastric parietal cells, where they irreversibly bind to and inhibit the H+/K+-ATPase enzyme, the final common pathway for acid secretion. 2, 3 This mechanism results in:

• Gastric acid suppression lasting up to 36 hours, far exceeding other acid-suppressing agents 4
• Acid production suppression by 37-68% over 24 hours with H2-receptor antagonists versus more profound and prolonged suppression with PPIs 4

Available PPI Medications

The commonly used PPIs include 1:

• Omeprazole
• Lansoprazole
• Pantoprazole
• Rabeprazole
• Esomeprazole
• Dexlansoprazole

Relative Potency Equivalents (compared to 20 mg omeprazole) 1:

• Lansoprazole 30 mg = 27 mg omeprazole
• Pantoprazole 40 mg = 9 mg omeprazole
• Rabeprazole 20 mg = 36 mg omeprazole
• Esomeprazole 20 mg = 32 mg omeprazole

Metabolism and Drug Interactions

All PPIs are metabolized by the hepatic cytochrome P-450 system, predominantly CYP2C19. 1 This creates important clinical considerations:

• Genetic polymorphisms in CYP2C19 significantly affect metabolism of omeprazole, lansoprazole, and pantoprazole, but have less effect on rabeprazole 1, 5
• Omeprazole has the highest risk for drug-drug interactions among PPIs, while rabeprazole and pantoprazole have the lowest risk 5
• Omeprazole should be avoided with clopidogrel, as it inhibits CYP2C19 and reduces clopidogrel's antiplatelet activity, even when dosed 12 hours apart 6, 4

Primary Clinical Indications

Gastrointestinal Protection

PPIs reduce upper GI bleeding risk by 50% in patients on antiplatelet therapy, with a relative risk of 0.19 (95% CI: 0.07-0.49) when combined with thienopyridines compared to thienopyridines alone. 4

Patients at high risk for upper GI bleeding who should receive PPI gastroprotection include those with 4:

• History of upper GI bleeding
• Taking multiple antithrombotics (anticoagulants plus antiplatelet agents)
• Taking aspirin or NSAIDs with additional risk factors (age >60 years, severe comorbidity, concurrent corticosteroids, or anticoagulants)
• On dual antiplatelet therapy

Acid-Peptic Disorders

Standard PPI doses (omeprazole 20 mg, lansoprazole 30 mg, pantoprazole 40 mg, or rabeprazole 20 mg daily for 2-4 weeks) are more effective than H2-receptor antagonists for healing duodenal and gastric ulcers. 2

For gastroesophageal reflux disease (GERD), PPIs are more effective than H2-receptor antagonists, with standard doses given for 4-8 weeks. 2

For eosinophilic esophagitis, omeprazole 20 mg twice daily for at least 8-12 weeks is recommended before assessing histological response. 4

H. pylori Eradication

When prescribing PPIs for H. pylori eradication, higher-potency PPIs (esomeprazole or rabeprazole) at doses of 20-40 mg twice daily are recommended as part of triple therapy. 1

Important Safety Considerations

Serious Adverse Effects

PPIs can cause acute tubulointerstitial nephritis at any point during therapy, presenting with decreased renal function, and should be discontinued if suspected. 6

Long-term PPI use (≥1 year) at high doses (multiple daily doses) is associated with increased risk of osteoporosis-related fractures of the hip, wrist, or spine. 6, 7

PPIs may trigger or exacerbate cutaneous and systemic lupus erythematosus, typically occurring within weeks to years of continuous therapy. 6

PPI therapy is associated with increased risk of Clostridium difficile-associated diarrhea, particularly in hospitalized patients. 6

Rebound Acid Hypersecretion

Patients discontinuing long-term PPI therapy may develop transient upper GI symptoms due to rebound acid hypersecretion (RAHS), a physiologic phenomenon resulting from hypergastrinemia-induced parietal cell proliferation during chronic PPI use. 4

Prescribing Principles

PPIs should only be used when there is reasonable expectation of benefit based on scientific evidence or prior treatment response, at the lowest effective dose and shortest duration appropriate to the condition being treated. 1, 6, 7

Regular review of ongoing indications for PPI use is recommended to avoid unnecessary long-term therapy. 1

Patients should be carefully assessed for upper GI bleeding risk factors before considering PPI de-prescribing, as hidden risk factors (such as over-the-counter aspirin use) are common. 4