Proton Pump Inhibitor

Aka: Proton Pump Inhibitor, PPI Therapy

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II. Indications

  1. Peptic Ulcer Disease
  2. Gastroesophageal Reflux
  3. Erosive Esophagitis
  4. Zollinger-Ellison Syndrome

III. Contraindications

  1. Hypersensitivity to Proton Pump Inhibitors
  2. Use with caution in severe liver disease

IV. Mechanism

  1. Benzimidazole Proton Pump Inhibitors bind the parietal cell's proton pump (H+/K+ ATPase)
  2. Inhibits >90% of total daily gastric acid production
  3. PPIs irreversibly bind proton pump

V. Pharmacokinetics

  1. All PPIs have short plasma half life of 1-2 hours
  2. Effect is delayed 5-7 days until proton pumps are fully blocked

VI. Dosing: Adults (Take 30 minutes prior to a meal)

  1. Omeprazole (Prilosec)
    1. Duodenal Ulcer or erosive Esophagitis: 20 mg orally daily
    2. Gastric Ulcer: 40 mg po qd
    3. Generic in 2002, OTC
  2. Lansoprazole (Prevacid)
    1. Duodenal Ulcer or erosive Esophagitis: 15 mg orally daily
    2. Gastric Ulcer: 30 mg po qd
    3. Generic, OTC
  3. Pantoprazole (Protonix)
    1. Duodenal Ulcer or erosive Esophagitis: 40 mg orally daily
    2. Parenteral dosing available
  4. Rabeprazole (Aciphex)
    1. Erosive Esophagitis: 20 mg orally daily
  5. Dexlansoprazole (Dexilant)
    1. Dose: 30 mg daily
  6. Esomeprazole Magnesium (Nexium)
    1. Erosive Esophagitis: 20 to 40 mg orally daily
    2. Generic 40 mg tab in May 2014, and 20 mg tab planned for OTC
  7. Esomeprazole Strontium
    1. Dose 49.3 mg orally daily is equivalent to EsomeprazoleMagnesium (Nexium) 40 mg
    2. Created as a patent extender in 2014 by changing the Esomeprazole salt from Magnesium to strontium
    3. Do not use in children due to possible bone adverse effects with Strontium
    4. Very expensive ($150/month in 2014) and no advantage over soon to be generic EsomeprazoleMagnesium (Nexium)
    5. (2014) Presc Lett 21(2): 8

VII. Dosing: Children

  1. Lansoprazole (Prevacid)
    1. Delivery
      1. May be compounded into liquid for dosing in infants
      2. May sprinkle opened capsule onto food or into juice
      3. Available in a disintegrating tablet
    2. Weight <10 kg (and age 3-12 months)
      1. Dose: 7.5 mg twice daily or 15 mg daily
      2. Dose: 1 mg/kg/day (0.5 to 1.6 mg/kg)
    3. Weight 10-30 kg
      1. Dose: 15 mg daily
    4. Weight >30 kg and adults
      1. Dose: 30 mg daily
  2. Omeprazole (Prilosec)
    1. Delivery
      1. May sprinkle opened capsule onto food
    2. Infants
      1. Dose: 0.7 mg/kg/day
    3. Weight 5-10 kg (and age >1 year old)
      1. Dose: 5 mg daily
    4. Weight 10-20 kg
      1. Dose: 10 mg daily
    5. Weight >20 kg
      1. Dose: 20 mg daily
  3. References
    1. Baird (2015) Am Fam Physician 92(8): 705-14 [PubMed]

VIII. Precautions: General

  1. Longterm Proton Pump Inhibitor use has significant risks (see adverse effects below)
    1. Avoid >8 weeks of use in elderly (unless serious Esophageal Reflux, Barrett's Esophagus)
  2. Maximize non-pharmacologic measures (e.g. GERD precautions)
    1. Avoid Alcohol, Tobacco, NSAIDs
    2. Reduce the need for longterm Proton Pump Inhibitor
  3. Balance adverse effects against the risks of discontinuing acid suppression
    1. Barrett's Esophagus requires longterm Proton Pump Inhibitor
      1. Acid suppression to prevent progression to Esophageal Cancer
    2. Hiatal Hernia will likely require longterm Proton Pump Inhibitors
  4. Use the lowest effective dose and for the shortest duration that controls symptoms
    1. Consider discontinuation protocol below
    2. Consider less complete acid suppression (e.g. H2 Blocker)
    3. Consider limited 4 week course of PPI for Duodenal Ulcer
    4. Consider limited 8 week course of PPI for Erosive Gastritis or Gastric Ulcer
      1. Then taper to other acid suppression (e.g. H2 Blocker)
    5. Consider brief intermittent use (e.g. 2-4 weeks) for exacerbations

IX. Protocol: Discontinuation or Deprescribing

  1. Indications
    1. Recurrence of GERD or Gastritis symptoms on abruptly stopping Proton Pump Inhibitor
  2. Use H2 Blocker (e.g. Ranitidine) when symptoms arise on days a Proton Pump Inhibitor is not taken
    1. May consider as needed dosing of Proton Pump Inhibitor if symptoms not relieved with H2 Blocker
  3. Taper over 4-6 weeks
    1. If taking twice daily, shift to once daily
    2. Next, take every other day
    3. Then, take every third day
    4. Then, continue to increase the interval between doses

X. Lab: Monitoring for longterm Proton Pump Inhibitor

  1. Serum Creatinine annually
  2. Serum Vitamin B12 level every 5 years
  3. Serum Magnesium if symptoms present
  4. Complete Blood Count every 2 years
  5. Alexander (2017) PPI Side Effects, Mayo Clinical Reviews, Rochester, MN

XI. Efficacy

  1. Gastroesophageal Reflux treatment with Omeprazole
    1. Patients with healed Esophagitis (n=175)
    2. Treated with 1 of 3 drugs to prevent recurrence
      1. Ranitidine: 49% Remission
      2. Ranitidine and Cisapride: 66% Remission
      3. Cisapride: 54% Remission
      4. Omeprazole 80% Remission
      5. Omeprazole and Cisapride: 89% Remission
  2. References
    1. Vigneri (1995) N Engl J Med 333:1106-10 [PubMed]

XII. Drug Interactions

  1. Decreased Absorption (due to increased gastric pH)
    1. Ampicillin
    2. Atazanavir
    3. Cefpodoxime
    4. Enoxacin
    5. Erlotinib
    6. Griseofulvin
    7. Itraconazole
    8. Iron Salts
    9. Ketoconazole
    10. Mycophenolate
    11. Nelfinavir
    12. Vitamin B12
  2. Increased Absorption (due to increased gastric pH)
    1. Nifedipine (Procardia)
    2. Digoxin
  3. Other Interactions
    1. Increases serum chromogranin A levels (False Positive risk in neuroendocrine tumor evaluation)
  4. Drug level decreases specific to Lansoprazole (CYP 450)
    1. Theophylline
  5. Drug level increases specific to Omeprazole (CYP 450)
    1. Carbamazepine (Tegretol)
    2. Diazepam (Valium)
    3. Phenytoin (Dilantin)
    4. Warfarin (Coumadin)
    5. Methotrexate
  6. Drug lowered efficacy specific to Omeprazole
    1. Clopidogrel (Plavix)
      1. Increased major coronary events occurred within one year of PTCA
        1. Attributed to Omeprazole's interaction with Clopidogrel
        2. Gaglia (2010) Am J Cardiol 105(6): 833-8 [PubMed]
      2. Pantoprazole (Protonix) does not lower Clopidogrel efficacy
        1. Juurlink (2009) CMAJ 180(7): 713-8 [PubMed]
      3. Avoid Omeprazole following PTCA and coronary stenting
        1. Consider H2 Blocker or Pantoprazole instead
      4. As of 2015, no consistent Drug Interaction between Proton Pump Inhibitors and Clopidogrel
        1. Melloni (2015) Circ Cardiovasc Qual Outcomes 8(1): 47-55 +PMID: 25587094 [PubMed]

XIII. Efficacy: Relative Potency

  1. General
    1. Potency and outcomes appear to be similar for all PPI
    2. Literature appears to offer conflicting results
    3. Most potent agents appear to be
      1. Rabeprazole (Aciphex)
      2. Esomeprazole (Nexium)
  2. References
    1. Dammann (1999) Eur J Gastroenterol Hepatol 11:1277-82 [PubMed]
    2. Williams (1999) Aliment Pharmacol Ther 13(suppl 3):3 [PubMed]
    3. Hartmann (1996) Aliment Pharmacol Ther 10(3):359-66 [PubMed]
    4. Bastaki (2000) J Physiol Paris 94(1):19-23 [PubMed]
    5. Florent (1997) Eur J Gastroenterol Hepatol 9(2):195 [PubMed]
    6. Spencer (2000) Drugs 60:321 [PubMed]

XIV. Adverse Effects: General and Short-term

  1. Headache
  2. Diarrhea
  3. Abdominal Pain
  4. Nausea

XV. Adverse Effects: Complications of prolonged use

  1. Clostridium difficile
    1. Number Needed to harm: 67 hospitalized patients on PPI for 2 weeks
    2. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm290838.htm
    3. Bavishi (2011) Aliment Pharmacol Ther 34(11):1269-81 [PubMed]
  2. Spontaneous Bacterial Peritonitis (SBP) in Cirrhotic patients
    1. Increased risk (with Odds Ratio 2-3) of SBP, and higher risk than with H2 Blockers
    2. Campbell (2008) Dig Dis Sci 53(2): 394-8 [PubMed]
    3. Deshpande (2015) J Gastroenterol Hepatol 28(2): 235-42 +PMID:23190338 [PubMed]
  3. Hypomagnesemia
    1. Odds Ratio 3.79
    2. Markovits (2014) J Clin Pharmacol 54(8): 889-95 [PubMed]
  4. Decreased Bone Mineral Density
    1. Hip Fracture, wrist Fracture and spine Fracture risk increase (Osteoporosis related Fracture sites)
      1. Number needed to harm (Hip Fracture): 1263 on PPI for >1 year
    2. Possibly associated with Vitamin D decreased serum levels
    3. Targownik (2012) Am J Gastroenterol 107:1361–9 [PubMed]
  5. Vitamin B12 Deficiency
    1. Bradford (1999) Pharmacother 33:641-3 [PubMed]
    2. Lam (2013) JAMA 310(22): 2435-42 [PubMed]
  6. Iron Deficiency Anemia
    1. Decreased iron absorption in the absence of adequate gastric acid
  7. Gastric Carcinoma
    1. Historically, on first release in 1988, bi-annual Gastrin levels were recommended (but soon dispensed with)
    2. Gastric Cancer risk is low (RR 1.191) with 10 years of continuous use
      1. Abrahami (2022) Gut 71(1): 16-24 [PubMed]
      2. Seo (2021) Gut 70(11): 2066-75 [PubMed]
  8. Community Acquired Pneumonia
    1. Risk increases with PPI dosage
    2. H2-Blockers also conferred risk, but less than PPI
    3. Laheij (2004) JAMA 292:1955-60 [PubMed]
  9. Cardiovascular Disease Risk Factor
    1. Shah (2015) PLoS One 10(6):e0124653 +PMID:26061035 [PubMed]
  10. Dementia
    1. Association with longterm PPI and Dementia in observational studies
    2. Gomm (2016) JAMA Neurol +PMID:26882076 [PubMed]
  11. Renal Failure
    1. Acute Kidney Injury increased risk
      1. Antoniou (2015) CMAJ 3(2): E166-71 +PMID:26389094 [PubMed]
      2. Blank (2014) Kidney Int 86(4): 837-44 +PMID:24646856 [PubMed]
      3. Simpson (2006) Nephrology 11(5): 381-5 +PMID:17014549 [PubMed]
      4. Moledina (2016) J Nephrol 29(5): 611-6 +PMID:27072818 [PubMed]
    2. Chronic Kidney Disease increased risk of progression
      1. Lazarus (2016) JAMA Intern Med 176(2): 238-46 +PMID:26752337 [PubMed]
      2. Xie (2016) J Am Soc Nephrol 27(10):3153-63 +PMID:27080976 [PubMed]
      3. Klatte (2017) Gastroenterol 153(3): 702-10 +PMID:28583827 [PubMed]
  12. Serious infections in children (esp. gastrointestinal and ENT infections)
    1. Lassalle (2023) JAMA Pediatr 177(10):1028-38 +PMID: 37578761 [PubMed]

XVI. Safety

  1. Pregnancy
    1. Pregnancy Category C: Omeprazole (category B for other agents)
    2. Initial reports of associated Asthma and allergy with acid suppression
      1. Subsequent study did not show significant associations
      2. Noh (2023) JAMA Pediatr 177(3):267-77 +PMID: 36622684 [PubMed]

XVII. References

  1. (2012) Prescr Lett 19(3): 14 [PubMed]
  2. (2013) Prescr Lett 20(5): 30 [PubMed]
  3. (2001) Med Lett Drugs Ther 43(1103):36-7 [PubMed]
  4. Ament (2012) Am Fam Physician 86(1): 66-70 [PubMed]
  5. Vanderhoff (2002) Am Fam Physician 66(2):273-80 [PubMed]

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