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proton pump inhibitor

Indications: 1) peptic ulcer [5]; more effective than H2 blockers 2) short-term treatment of severe erosive esophagitis 3) short-term treatment of gastroesophageal reflux disease - patients who respond should attempt to reduce dose or discontinue PPI [59] 4) indications for long-term use of PPI [72] a) *pathologic hypersecretory conditions - Zollinger-Ellison syndrome b) long-term antiplatelet therapy if: [7] - history of peptic ulcer - history of gastrointestinal bleeding - *dual antiplatelet therapy or concomitant anticoagulation - *additional risk factors (age >= 60, steroid use, dyspepsia, or gastroesophageal reflux) c) Barrett's esophagus & symptomatic GERD [59] d) eosinophilic esophagitis e) peptic stricture f) possibly idiopathic pulmonary fibrosis 7) component of combination therapy for Helicobacter pylori Contraindications: - probably not indicated for routine treatment of asthma [9] - not effective for unexplained throat symptoms (pain, hoarseness, excessive mucus, globus sensation) [70] - probably overprescribed [14] - not effective in infants [16]; may be effective in children & adolescents - not effective in prevention of GI bleeding due to warfarin [39] - patients with advanced cirrhosis or ascites [77] - discontinue if indication has resolved [19] Benefit/risk: - proton pump inhibitor of no benefit for acute peptic ulcer bleeding or other cause of acute upper GI bleed before [24] or after endoscopy [25] - post-endoscopy acute peptic ulcer bleeding - number needed to treat (NNT) - no benefit for reducing - mortality - neeed for blood transfusion - need for repeat endoscopy - need for surgery - length of hospital stay [25] - 15 to prevent rebleeding - no harm noted [25] - number needed to harm - 286 for 1 year to cause 1 case of chronic renal failure Dosage: 1) administer in AM, 20-45 minutes before 1st meal - efficacy of PPI maximum when taken before meals [63] 2) pantoprazole (Protonix) available for IV injection 3) omeprazole may be available for IV injection 4) intravenous & oral administration equally effective [18,31] even for bleeding peptic ulcer [44] 5) very high high doses (> 60 mg omeprazole) do not provide better acid suppression than lower doses [52] 6) TID dosing has no benefit over BID dosing [52] 7) BID dosing has no benefit over QD dosing [19] 7) generic forms of PPIs most cost-effective [52] 8) use lowest effective dose [59] 9) for patients without esophagitis, attempt to discontinue or reduce dose of PPI after 1 year [19]* * * see deprescribing proton-pump inhibitors Pharmacokinetics: 1) bioavailability 35-90% 2) highly protein bound (90-97%) 3) rapidly metabolized in the liver (cyt P450) 4) elimination 1/2life of 1-1.5 hours 4) duration of acid inhibition: 48-72 hours Monitor: - 24 hour esophageal pH monitoring not routinely indicated [19] - pharmacy guidelines require reassessmen5 or need after 8 weeks Adverse effects: 1) most common a) headache, diarrhea, abdominal pain (dyspepsia), constipation b) switching to another PPI is generally sufficient to reduce or eliminate the adverse effect(s) [19] 2) increased risk of C difficile colitis [4,17,45] 3) increased risk for pneumonia a) increased risk of community-acquired pneumonia - increased risk likely due to confounding factors [41] b) increased risk of nosocomial pneumonia (HR=2.5) [11,12] - increased risk of nosocomial pneumonia in stroke patients [22] c) no data shows stopping PPI reduces risk of pneumonia [35] 4) increased risk of serious infection, including severe or fatal COVID-19 (RR=1.46) [69], hepatic encephalopathy & bacterial peritonitis in cirrhotic patients with ascites [10,40] - H2 receptor antagonists apparently safe [10] 5) increased risk for multidrug-resistant organisms [68] 6) rebound gastric hyperacidity may occur in patients when proton pump inhibitor is stopped after 2 months of use; best managed with antiacids [13] 7) increased risk of acute interstitial nephritis [19,21,32] (hypersensitivity) 8) increased risk for chronic renal failure (14.2 vs 10.7 per 1000 person-years, RR=1.3, NNH=286 for 1 year) [29] - RR=1.3 for 2-fold increase in serum creatinine or 30% decrease in eGFR [47] - 0.5% excess absolute risk for >50% reduction in GFR within 5 years [49] 9) 2-fold increase in cardiovascular mortality with PPI use - increased risk in MI (RR=1.16) [27] - no increased risk in MI [54] - H2-blockers not associated with increased risk - increased risk of stroke within 180 days of initiation of PPI therapy (RR=1.28, RR=1.77 within 30 days) [46] - not associated with increased risk for stroke [55] - increase risk of all-cause mortality relative to use of H2-blockers or no acid suppression (RR=1.25) [48] - excess mortality from CV disease & chronic kidney disease [65] 10) increased risk of dementia in the elderly (RR=1.44) [30] - increased risk for dementia (RR=1.85) [75] - longer use of PPI associated with increased risk of dementia [76] - no increased risk for Alzheimer's disease [50] - PPI use associated with diminished risk of cognitive impairment [51] - no increased risk of dementia [56,67] 11) hypomagnesemia [19] 12) increased risk of fundic gland polyps (RR=2.46) [38] 13) increased risk of gastric cancer - 2-fold independent of prior H pylori infection [53] - RR=1.45, number needed to harm 2100 in 5 years [71] 14) not associated with changes in bone mineral density [42] - association with risk of hip fracture inconsistent [19] - no increased risk of hip fracture [57] - fracture risk increased at higher PPI doses & for duration of therapy > 1 year [19] 15) increased risk for iron deficiency anemia (RR=2.5) [43] 16) vitamin B12 deficiency [19] 17) use during the 1st 6 months of life associated with increased risk for food allergy during childhood (RR=2.6) [58] 18) long-term use of PPIs is associated with increased risk of type 2 diabetes [74] 19) long-term use of PPIs is associated with increased risk of NAFLD non-alcoholic fatty liver disease (RR=2.0 for use > 5 years) [73] 20) 5-12 years of continuous PPI therapy presents no major safety concerns [26] Drug interactions: - proton pump inhibitors may inhibit absorption of levothyroxine in tablet form [23] - switching to oral solution corrects impaired absorption - no increase in risk for adverse cardiovascular events with addition of a PPI to clopidogrel [28] Laboratory: - elevated serum gastrin [71] Mechanism of action: 1) covalent binding to cysteine residues of the H+/K+ ATPase (proton pump) 2) inhibition of the proton pump & gastric acid secretion 3) esomeprazole (active stereoisomer of omeprazole) may be most effective PPI [3] 4) no convincing evidence that any PPI more effective than another for any indication [34] 5) more effecting than H2 blockers to peptic ulcer bleeding [5] 6) PPIs don't provide continuous acid suppression... even with BID dosing - nighttime acid breakthrough occurs in > 70% of patients 7) acid secretion triggered by histamine may not be effectively inhibited by proton pump inhibitors [6]

Interactions

drug interactions drug adverse effects of proton pump inhibitors (PPI)

Specific

dexlansoprazole (Kapidex, Dexilant) lansoprazole (Prevacid) omeprazole (Prilosec, Zegerid, Losec, Medral) pantoprazole (Protonix) rabeprazole (Aciphex)

General

antiulcer agent enzyme inhibitor

References

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