Pharm 101: Pantoprazole

Class

Proton Pump Inhibitor (PPI)

Pharmacodynamics

• Inhibit both fasting and meal-stimulated secretion by irreversibly inhibiting H/K ATPase in parietal cell canaliculus:
  • Concentrated and activated near site of action
  • Prodrug is rapidly protonated within the parietal cell canaliculus and is concentrated more than 1000-fold by Henderson-Hasselbach trapping
  • Undergoes rapid molecular conversion to active form which forms covalent disulfide bond with H/K ATPase, irreversibly inactivating enzyme
• In fasting state, only 10% of proton pumps are actively secreting acid and susceptible to inhibition. PPIs should thus be administered one hour before a meal so that peak serum concentration coincides with maximal activity of proton-pump secretion
• Effects of acid inhibition last up to 24 hours because of time required (at least 18 hours) to synthesise new H/K ATPase pump molecules

Pharmacokinetics

• Administered as inactive prodrug
• Lipophilic weak base (pKa 4-5)
• Bioavailability 77% (decreased 50% by food)
• Rapid first-pass and systemic hepatic metabolism*
• Negligible renal clearance
• Serum half life 1-2 hours, but acid inhibition lasts up to 24 hours due to irreversible inactivation of proton pump
• 3-4 day onset and offset:
  • Not all proton pumps are inactivated with first dose, 3-4 days of daily medication are required before full acid-inhibiting potential is reached
  • Similiar after stopping drug, 3-4 days for full acid secretion to return

Clinical uses

• Gastro-oesophageal reflux disease (GORD)
• Peptic ulcer disease
• H Pylori-associated ulcers
• Eradication of H Pylori (clarithromycin, amoxicillin, pantoprazole)
• Upper gastrointestinal bleeding

Adverse effects

• Gastrointestinal:
  • Diarrhoea, headache, abdominal pain in 1-5%
  • Increased risk of C difficile infection
• Metabolic:
  • B12 deficiency
  • Low Mg with secondary Low Ca
  • Osteoporotic fractures with long-term PPI
• Renal:
  • Acute interstitial nephritis
  • Chronic kidney disease

Precautions/contraindications

• *Dose reduction in severe liver impairment
• Drug interactions:
  • Decreased gastric acidity alters absorption of drugs for which intra-gastric acidity affects drug bioavailability e.g. digoxin, ketoconazole
  • PPIs can reduce clopidogrel activation

Further Reading

• Nickson C. Gastrointestinal Haemorrhage
• Nickson C. Stress Ulcer Prophylaxis