Proton Pump Inhibitor

Indications

Contraindications

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

Mechanism

Benzimidazole Proton Pump Inhibitors
Binds proton pump of parietal cell
Inhibits >90% of total daily gastric acid production
PPIs irreversibly bind proton pump

Pharmacokinetics

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

Dosing
Adults (Take 30 minutes prior to a meal)

Omeprazole (Prilosec)
1. Duodenal Ulcer or erosive esophagitis: 20 mg orally daily
2. Gastric Ulcer: 40 mg po qd
3. Generic in 2002, OTC
Lansoprazole (Prevacid)
1. Duodenal Ulcer or erosive esophagitis: 15 mg orally daily
2. Gastric Ulcer: 30 mg po qd
3. Generic, OTC
Pantoprazole (Protonix)
1. Duodenal Ulcer or erosive esophagitis: 40 mg orally daily
2. Parenteral dosing available
Rabeprazole (Aciphex)
1. Erosive esophagitis: 20 mg orally daily
Dexlansoprazole (Dexilant)
1. Dose: 30 mg daily
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
Esomeprazole Strontium
1. Dose 49.3 mg orally daily is equivalent to Esomeprazole Magnesium (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 Esomeprazole Magnesium (Nexium)
5. (2014) Presc Lett 21(2): 8

Dosing
Children

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
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
References
1. Baird (2015) Am Fam Physician 92(8): 705-14 [PubMed]

Precautions
General

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)
Maximize non-pharmacologic measures (e.g. GERD precautions)
1. Avoid Alcohol, Tobacco, NSAIDs
2. Reduce the need for longterm Proton Pump Inhibitor
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
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

Precautions
Pregnancy and Lactation

Pregnancy Category C: Omeprazole
Pregnancy Category B: Other agents

Protocol
Discontinuation or Deprescribing

Indications
1. Recurrence of GERD or Gastritis symptoms on abruptly stopping Proton Pump Inhibitor
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
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

Lab
Monitoring for longterm Proton Pump Inhibitor

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

Efficacy

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
References
1. Vigneri (1995) N Engl J Med 333:1106-10 [PubMed]

Drug Interactions

Decreased Absorption (due to increased gastric pH)
1. Griseofulvin
2. Ketoconazole
3. Itraconazole
4. Iron Salts
5. Vitamin B12
6. Cefpodoxime
7. Enoxacin
Increased Absorption (due to increased gastric pH)
1. Nifedipine (Procardia)
2. Digoxin
Drug level increases specific to Prilosec (CYP 450)
1. Carbamazepine (Tegretol)
2. Diazepam (Valium)
3. Phenytoin (Dilantin)
4. Warfarin (Coumadin)
5. Methotrexate
Drug level decreases specific to Prevacid (CYP 450)
1. Theophylline
Drug lowered efficacy specific to Prilosec
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]

Efficacy
Relative Potency

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)
References

Adverse Effects
General and Short-term

Adverse Effects
Complications of prolonged use

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]
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]
Hypomagnesemia
1. Odds Ratio 3.79
2. Markovits (2014) J Clin Pharmacol 54(8): 889-95 [PubMed]
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]
Vitamin B12 Deficiency
1. Bradford (1999) Pharmacother 33:641-3 [PubMed]
2. Lam (2013) JAMA 310(22): 2435-42 [PubMed]
Iron Deficiency Anemia
1. Decreased iron absorption in the absence of adequate gastric acid
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]
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]
Cardiovascular Disease Risk Factor
1. Shah (2015) PLoS One 10(6):e0124653 +PMID:26061035 [PubMed]
Dementia
1. Association with longterm PPI and Dementia in observational studies
2. Gomm (2016) JAMA Neurol +PMID:26882076 [PubMed]
Renal Failure
1. Acute Kidney Injury increased risk
2. Chronic Kidney Disease increased risk of progression

References