What are the side effects of proton pump inhibitors (PPIs)?

Side Effects of Proton Pump Inhibitors

Proton pump inhibitors (PPIs) are associated with several significant side effects including increased risk of Clostridium difficile infection, bone fractures, acute and chronic kidney disease, vitamin B12 deficiency, and hypomagnesemia, which should be carefully considered when prescribing these medications. 1, 2

Common Side Effects

• Gastrointestinal effects:
  • Diarrhea
  • Nausea
  • Abdominal pain
  • Headache
  • Dizziness
  • Rash and pruritus 1, 3

Serious Adverse Effects

Gastrointestinal Infections

• Clostridium difficile-associated diarrhea (CDAD):
  • PPIs may increase risk of C. difficile infections 1
  • Presents as watery stool, stomach pain, and persistent fever
  • Particularly concerning in hospitalized patients 4
  • The only pertinent randomized controlled trial showed chronic pantoprazole use was associated with greater risk of enteric infections compared to placebo 2

Renal Effects

• Acute tubulointerstitial nephritis (TIN):
  • Can occur at any point during PPI therapy
  • May present with varying symptoms from hypersensitivity reactions to non-specific decreased renal function
  • Signs include decreased urination or blood in urine 1
• Chronic kidney disease:
  • Long-term use associated with increased risk 2, 5

Bone Health

• Increased fracture risk:
  • Multiple observational studies suggest increased risk of osteoporosis-related fractures (hip, wrist, spine)
  • Risk is higher with high-dose and long-term therapy (a year or longer)
  • Patients should use lowest effective dose for shortest duration needed 1, 2

Nutritional Deficiencies

• Vitamin B12 deficiency:
  • Long-term acid suppression (>3 years) may lead to malabsorption of cyanocobalamin
  • Caused by hypo- or achlorhydria 1, 5
• Hypomagnesemia:
  • Consistently reported in observational studies
  • Monitor magnesium levels in patients on long-term therapy 2, 6

Autoimmune Effects

• Lupus erythematosus:
  • Both cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) reported
  • Can occur as new onset or exacerbation of existing disease
  • Most common form is subacute CLE (SCLE)
  • Presents with rash, arthralgia, and sometimes cytopenia
  • Most patients improve within 4-12 weeks after discontinuation 1

Drug Interactions

• Clopidogrel interaction:
  • PPIs (particularly omeprazole and esomeprazole) may inhibit CYP2C19
  • This can reduce the effectiveness of clopidogrel by impairing its metabolism to the active form
  • Consider alternative anti-platelet therapy when using omeprazole 7
  • The European Society of Cardiology notes that univocal effects of these combinations on the risk of ischemic events or stent thrombosis have not been clearly demonstrated 7

Special Considerations

Duration of Use

• The American Gastroenterological Association recommends:
  • All patients on PPIs should have regular review of ongoing indications
  • Patients without definitive indications should be considered for de-prescribing
  • Most patients on twice-daily dosing should be considered for step-down to once-daily 7

Patients Who Should NOT Discontinue PPIs

• Patients with complicated GERD (severe erosive esophagitis, esophageal ulcer, peptic stricture)
• Patients with Barrett's esophagus, eosinophilic esophagitis, or idiopathic pulmonary fibrosis
• Patients at high risk for upper gastrointestinal bleeding 7, 6

Clinical Approach to PPI Use

1. Prescribe PPIs only when clearly indicated
2. Use the lowest effective dose for the shortest duration possible
3. Regularly reassess the need for continued therapy
4. Monitor for potential adverse effects in long-term users:
   • Periodic assessment of renal function
   • Vitamin B12 levels after 3+ years of use
   • Magnesium levels
   • Bone health in those at risk for osteoporosis

Important Caveats

• Most evidence for adverse effects comes from observational studies with potential for confounding
• The decision to discontinue PPIs should be based on lack of indication, not solely on concerns about adverse effects 7
• When discontinuing PPIs, patients may experience rebound acid hypersecretion and transient upper GI symptoms 7
• For patients requiring antithrombotic therapy who are at increased risk of GI bleeding, gastric protection with PPIs is still recommended despite potential risks 7