Proton pump inhibitors (PPIs) are a class of gastric acid-suppressing agents that selectively and irreversibly inhibit the H⁺/K⁺ ATPase enzyme system (also known as the gastric proton pump) located on the parietal cells of the stomach. This inhibition leads to profound suppression of gastric acid secretion and provides relief from acid-related gastrointestinal (GI) disorders. PPIs are among the most widely prescribed medications globally and are considered more effective than H2-receptor antagonists in controlling gastric acidity.
1. Mechanism of Action
PPIs are prodrugs that require acidic conditions to become activated. They are absorbed in the small intestine, circulate systemically, and accumulate in the acidic secretory canaliculi of parietal cells in the stomach.
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After activation, PPIs bind irreversibly to sulfhydryl groups on the H⁺/K⁺-ATPase enzyme, which is the final step in gastric acid secretion.
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The inhibition remains until new proton pumps are synthesized, which typically takes 24–48 hours.
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They inhibit both basal and stimulated acid secretion, making them highly effective.
2. List of Common Proton Pump Inhibitors (Generic and Brand Names)
| Generic Name | Brand Names |
|---|---|
| Omeprazole | Prilosec, Losec |
| Esomeprazole | Nexium |
| Lansoprazole | Prevacid |
| Dexlansoprazole | Dexilant |
| Pantoprazole | Protonix |
| Rabeprazole | Aciphex |
| Ilaprazole | Noltec (approved in some countries) |
3. Therapeutic Indications
PPIs are primarily used for treating acid-related disorders, including:
A. Gastroesophageal Reflux Disease (GERD)
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For both erosive esophagitis and non-erosive reflux disease (NERD)
B. Peptic Ulcer Disease (PUD)
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Including gastric and duodenal ulcers
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NSAID-induced ulcer prevention and healing
C. Helicobacter pylori eradication
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As part of triple or quadruple therapy regimens
D. Zollinger–Ellison Syndrome (ZES)
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A rare condition involving gastrin-secreting tumors; requires high-dose PPI
E. Stress Ulcer Prophylaxis
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In critically ill or ICU patients
F. Upper Gastrointestinal Bleeding
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IV PPI to stabilize clots and reduce risk of rebleeding
G. Eosinophilic Esophagitis
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PPIs may reduce inflammation independent of acid suppression
4. Dosage and Administration
| Drug | Typical Dose (Adults) | Route | Frequency |
|---|---|---|---|
| Omeprazole | 20–40 mg | Oral | Once or twice daily |
| Esomeprazole | 20–40 mg | Oral/IV | Once daily |
| Lansoprazole | 15–30 mg | Oral | Once daily |
| Dexlansoprazole | 30–60 mg | Oral (dual delayed-release) | Once daily |
| Pantoprazole | 40 mg | Oral/IV | Once daily |
| Rabeprazole | 20 mg | Oral | Once daily |
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IV PPIs used in hospital settings for GI bleeding: e.g., pantoprazole 40 mg IV q12h or 80 mg bolus + infusion.
5. Pharmacokinetics
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Absorption: Rapid after oral administration
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Bioavailability: Increases on repeated dosing (except for rabeprazole)
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Metabolism: Extensively hepatic via CYP2C19 and CYP3A4
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Half-life: ~1–2 hours, but effect lasts 24–48 hours due to irreversible binding
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Excretion: Renal and fecal
6. Adverse Effects
A. Common Adverse Effects
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Headache
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Diarrhea or constipation
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Nausea
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Abdominal pain
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Flatulence
B. Long-Term Use Concerns
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Vitamin B12 deficiency: due to decreased gastric acid necessary for release from food
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Hypomagnesemia: can cause tetany, arrhythmia
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Iron and calcium malabsorption
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Osteoporosis-related fractures (hip, wrist, spine)
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Kidney disease: including acute interstitial nephritis and CKD
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Dementia: possible association, though evidence is inconclusive
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Clostridium difficile infection: increased risk due to reduced gastric acidity
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Pneumonia: increased risk of community- and hospital-acquired pneumonia
7. Contraindications and Precautions
| Contraindication | Explanation |
|---|---|
| Hypersensitivity to PPIs | Includes cross-reactivity across class |
| CYP2C19 poor metabolizers | Increased drug exposure |
| Pregnancy and breastfeeding | Some PPIs (e.g., omeprazole) are Category C |
| Severe liver disease | Requires dose adjustment or caution |
8. Drug Interactions
PPIs affect drug metabolism via CYP enzymes and gastric pH, influencing absorption or clearance of various agents.
A. Important Interactions
| Interacting Drug | Interaction Type | Clinical Relevance |
|---|---|---|
| Clopidogrel | Reduced activation via CYP2C19 | May reduce antiplatelet effect; avoid omeprazole/esomeprazole |
| Warfarin | Altered INR | Monitor INR when initiating/discontinuing PPI |
| Methotrexate | Delayed clearance | High-dose methotrexate toxicity risk |
| Ketoconazole, itraconazole | Reduced absorption | Acid-dependent absorption inhibited |
| Digoxin | Increased bioavailability | Risk of digoxin toxicity |
| Iron salts, calcium carbonate | Reduced solubility | Use citrate salt forms if needed |
| Mycophenolate mofetil | Reduced efficacy | Important in transplant recipients |
9. Comparison with Other Acid Suppressants
| Class | Examples | Onset | Duration | Potency | Notes |
|---|---|---|---|---|---|
| PPIs | Omeprazole, etc. | Delayed (~1 hr) | Long (24–48 hrs) | High | Irreversible H⁺/K⁺ ATPase inhibition |
| H2-receptor antagonists | Ranitidine (withdrawn), famotidine | Faster onset | Shorter | Moderate | Tolerance develops with chronic use |
| Antacids | Calcium carbonate, etc. | Immediate | Short | Low | Symptomatic relief only |
10. Clinical Use Guidelines
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GERD: Typically 4–8 weeks of PPI; consider step-down to H2-blocker if symptoms controlled
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Maintenance therapy: Use lowest effective dose for shortest duration; consider on-demand therapy
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H. pylori eradication: Triple or quadruple therapy includes PPI + 2 antibiotics ± bismuth
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Stress ulcer prophylaxis: Limit to ICU patients with risk factors
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Rebound acid hypersecretion: Taper PPIs rather than abruptly discontinuing
11. Special Considerations
A. Geriatric Patients
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Increased risk of fractures, kidney injury, and infections
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Avoid long-term use unless clear indication
B. CYP2C19 Polymorphisms
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Asians more likely to be poor metabolizers; may increase efficacy/toxicity
C. Deprescribing PPIs
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Recommended if no ongoing indication
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Gradual taper with transition to H2-blocker if needed
12. Novel and Dual-Release Formulations
Some formulations aim to improve delivery and compliance:
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Dexlansoprazole: Dual delayed-release mechanism; allows once-daily dosing with meal flexibility
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Enteric-coated granules: Protect drug from acid degradation
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IV formulations: Used in acute care, especially in GI bleeding
13. Current Research and Developments
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Potassium-competitive acid blockers (P-CABs): e.g., vonoprazan – faster onset, more stable acid suppression than PPIs
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Role in Barrett's esophagus, EoE, functional dyspepsia
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PPIs in COVID-19: Mixed evidence regarding risk modulation
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