Proton Pump Inhibitors

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PPIs: Intro & MOA - Pump Stoppers!

  • Most potent suppressors of gastric acid secretion.
  • Commonly used: Omeprazole, Lansoprazole, Pantoprazole, Esomeprazole, Rabeprazole.
  • Mechanism of Action (MOA):
    • Prodrugs: Administered in inactive form.
    • Accumulate in acidic parietal cell canaliculi (pH < 4).
    • Convert to active sulfenamide metabolite via H+ catalyzed process.
    • Irreversibly bind to cysteine residues of the H+/K+ ATPase (proton pump).
    • Inhibits final step in gastric acid ($H^+$) secretion pathway.
    • Effect lasts 24-48 hours until new pumps are synthesized.

⭐ PPIs cause irreversible inhibition of the H+/K+ ATPase (proton pump) in parietal cells.

Parietal cell acid secretion and PPI mechanism

PPIs: Pharmacokinetics - Body's Journey

  • Absorption (Oral):
    • Prodrugs: Enteric-coated, delayed-release (bypass stomach acid).
    • Site: Duodenum.
    • Food ↓ absorption; take 30-60 min pre-meal.
    • Bioavailability: Variable (omeprazole ~30-40% initially), ↑ with repeated doses.
  • Distribution & Activation:
    • Highly protein-bound (>95%).
    • Concentrate in parietal cell canaliculi.

    ⭐ PPIs are prodrugs; require activation by acid in parietal cell canaliculi to active form.

  • Metabolism:
    • Hepatic: CYP2C19 (major, genetic polymorphism) & CYP3A4 (minor).
  • Excretion:
    • Renal (inactive metabolites).
    • Short plasma $t_{1/2}$ (~1-2h); long action (irreversible H+/K+ ATPase binding).

PPIs: The Line-Up - Meet the Crew

Key Proton Pump Inhibitors (PPIs) used clinically, with typical adult daily doses and distinguishing characteristics:

PPIStandard Dose (mg)Key Features
Omeprazole20-40Prototype; first marketed; significant CYP2C19 inhibitor
Esomeprazole20-40S-isomer of omeprazole; higher bioavailability; CYP2C19 inhibitor
Lansoprazole15-30Available as ODT; also granules for suspension
Pantoprazole40Lower potential for drug interactions (less CYP2C19); IV form
Rabeprazole20Fastest onset of action (claimed); less CYP2C19 dependent metab.
Dexlansoprazole30-60R-enantiomer of lansoprazole; dual delayed-release formulation

PPIs: Clinical Uses - Healing Power

  • Gastroesophageal Reflux Disease (GERD): First-line, superior for healing esophagitis and symptom relief.
  • Peptic Ulcer Disease (PUD):
    • Healing gastric and duodenal ulcers.
    • Part of H. pylori eradication regimens.
  • Zollinger-Ellison Syndrome: Drug of choice for hypersecretory states.
  • Stress Ulcer Prophylaxis: In high-risk ICU patients.
  • NSAID-associated Ulcers: Prevention and treatment.
  • Eosinophilic Esophagitis: Effective for symptomatic and histologic improvement.
  • Functional Dyspepsia: For persistent symptoms.

⭐ PPIs are the most effective drugs for treating GERD and healing peptic ulcers.

PPIs: Adverse Effects & Interactions - Caution Zones

  • Common: Headache, diarrhea, nausea.
  • Long-term Risks:
    • Nutrient deficiencies: ↓Vit B12, ↓Mg (hypomagnesemia), ↓Ca (↑fracture risk).
    • Infections: ↑Clostridium difficile, ↑pneumonia.
    • Kidney: Acute Interstitial Nephritis (AIN).
    • Gastric: Fundic gland polyps; atrophic gastritis.

⭐ Long-term PPI use is associated with increased risk of osteoporotic fractures, Clostridium difficile infection, and hypomagnesemia.

  • Key Drug Interactions:
    • Omeprazole/Esomeprazole (CYP2C19 inhibitors): ↓clopidogrel efficacy. ⚠️
    • Altered pH: ↓absorption of ketoconazole, iron, some ARVs.
    • ↑Methotrexate toxicity.
  • Caution: Elderly; prolonged use (>1 year).

High‑Yield Points - ⚡ Biggest Takeaways

  • Most potent inhibitors of gastric acid secretion; irreversibly block H+/K+ ATPase.
  • Prodrugs, activated in parietal cell canaliculus; take 30-60 min before meals.
  • Uses: GERD, PUD, Zollinger-Ellison syndrome, H. pylori eradication regimens.
  • Long-term: ↑ risk of fractures, hypomagnesemia, C. difficile infection, pneumonia, Vit B12 deficiency.
  • Omeprazole inhibits CYP2C19, notably reducing clopidogrel efficacy.
  • Examples: Omeprazole, Pantoprazole, Lansoprazole, Esomeprazole.

Practice Questions: Proton Pump Inhibitors

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All of the following adverse effects can be caused by loop diuretics except :

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Flashcards: Proton Pump Inhibitors

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Gastroesophageal Refund _____ receptor antagonists (e.g. cimetidine) may be used to treat GERD and peptic ulcers, although PPIs are the first line treatment

TAP TO REVEAL ANSWER

Gastroesophageal Refund _____ receptor antagonists (e.g. cimetidine) may be used to treat GERD and peptic ulcers, although PPIs are the first line treatment

H2

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