proton pump inhibitors (PPIs)

see also peptic ulcer disease; gastro-oesophageal reflux; pharmacology main index

• acid pump (gastric H+,K+ ATPase) inhibitors
  • result in decreased basal & stimulated gastric acid secretion irrespective of stimuli;

• 1st PPI
• PU dose:
  • 20mg daily (single dose)
    • ⇒ more rapid/complete healing than ranitidine 300mg/d;
    • ⇒ most PU healed in 4-8wks (20-40mg/d) & maint.Rx → few rec.;
• Erosive or ulcerative oesophagitis dose:
  • 20-40mg/d
    • ⇒ 80% pts healed by 4wks Rx;
    • ⇒ > 80% pts with severe reflux oes. unresp. to H2 antag heal 8wk
    • ⇒ maint. Rx 20mg/d prevents relapse in 80% over 12mths;
• Z-E syndrome:
  • 20-360mg/d (median 60-70mg)
    • ⇒ decrease basal gastric acid to < 10mmol/hr during Rx up to 4yrs;
    • ⇒ best pharmacologic option in this disease;
• NSAID gastric mucosal injury:
  • 40mg/d for > 4D ⇒ signif. decrease injury;

• well tolerated if < 12wks Rx → 1% serious side effects which were similar spectrum as with H2 antag.:
  • no long term ECL cell dysplasia or neoplasia observed at 5.5yrs Rx;
• dosage adjustments not needed in elderly, renal or liver impairment;
• as interferes with a spec.P450 liver system:
  • ⇒ decrease metab. of R-warfarin, R-diazepam, R-phenytoin but not signif.?
• 2017: BMJ long term use > 1-2yrs associated with increased dementia, 50% increase in premature death, etc compared to those on H2 antagonists ALTHOUGH the PPI group were marginally older and sicker but this was thought not enough to account for the differences
• MJA 2009 - risks of PPI's: what every doctor should know (editorial)
  • PPIs are safe relative to most other medications we prescribe, but suppressing gastric acid is not physiological
  • a low level of gastric acid promotes the growth of swallowed and enteric flora in the proximal gut, and these bacteria may be aspirated during episodes of physiological reflux.
  • PPI Rx appears to increase risk of pneumonia by 16-50% and may be responsible for up to 4% of all community acquired pneumonia although causal effect has not yet been proven as other concurrent factors in these patients taking PPIs may be important such as alcohol abuse, morbid obesity, PH stroke (CVA), or impaired immunity due to chronic illness.
  • PPI Rx appears to increase risk of Cl. difficile infection with an odds ratio of 3.5 (95% CI 2.3-5.2)
  • achlorhydria is a risk factor for Salmonella infection
  • potential for risk of osteoporosis:
    • An acid environment is needed for insoluble calcium absorption, but the effects of PPI on dietary calcium absorption are uncertain. Increasing dietary calcium intake and taking calcium citrate as a supplement (which does not require gastric acid for absorption) is not established practice for patients who are prescribed acid-suppressing medications.
    • PPI Rx appears to increase risk of hip fracture with odds ratio of 1.44 (95% CI, 1.30–1.59)
    • about 1263 patients over the age of 50 would need to be treated with PPIs for a year to identify one excess hip fracture.
  • long-term acid suppression has been linked to malabsorption of vitamin B12, especially in older people
  • patients infected with Helicobacter pylori and who are taking long-term PPI therapy are at increased risk of developing gastric atrophy, but the exact clinical significance remains uncertain
  • gastrin release increases with PPI therapy because of acid suppression, but there is no evidence this leads to neoplastic changes in the stomach.
    • it seems long term use of PPIs is associated with 2.4x risk of stomach cancer, and 4.5x risk if used daily compared to those who use it weekly, while risk appears to rise 8x if used for 3 or more years ¹⁾
• interstitial nephritis (rare HS reaction):
  • appears to be a class effect
  • presenting as malaise, LOW,fever & nausea, & rarely the classic triad of fever, rash & eosinophilia
  • lab Ix usually shows raised urea &/or CRM +/- haematuria or proteinuria but may be unremarkable.
  • diagnosis only confirmed on renal biopsy
  • median age 68yrs (47-86yrs)
  • median time to onset 3mths (12d - 12mths)
  • may not reverse on cessation of PPI
  • NB. interstitial nephritis is also assoc. with b-lactams, sulphonamides, diuretics, NSAIDs, allopurinol and rifampicin.