Perils and Pitfalls of Long-term Effects of Proton Pump Inhibitors

Sheila M Wilhelm; Ryan G Rjater; Pramodini B Kale-Pradhan


Expert Rev Clin Pharmacol. 2013;6(4):443-451. 

In This Article

Abstract and Introduction


This review summarizes the literature regarding long-term adverse effects of proton pump inhibitors (PPIs). A PubMed search (1966 to February 2013) for English language studies was conducted using key terms PPI: omeprazole, esomeprazole, pantoprazole, lansoprazole, dexlansoprazole, rabeprazole, pneumonia, Clostridium difficile, osteoporosis, risk of fractures, thrombocytopenia, rhabdomyolysis, anemia, iron deficiency, hypomagnesemia, vitamin B12 and nephritis. The risk of pneumonia was increased 27–39% in short-term use of PPIs in three meta-analyses. C. difficile infections were also associated with the use of PPIs (odds ratio: 2.15; 95% CI: 1.81–2.55; p < 0.00001). This effect appears to be dose related. The US FDA has recently issued a warning regarding fractures and the impaired magnesium absorption associated with the use of PPI. Thrombocytopenia, iron deficiency, vitamin B12 deficiency, rhabdomyolysis and acute interstitial nephritis have also been reported with the use of PPIs. There is mounting evidence that PPIs are associated with serious adverse effects. Practitioners should be vigilant and counsel patients accordingly.


The secretion of gastric acid is a complex and continuous process incorporating neuronal, paracrine and endocrine pathways.[1] These separate signaling mechanisms converge at a common endpoint to promote the secretion of hydrogen ions by gastric parietal cells. Since proton pump inhibitors (PPIs) block acid secretion from all three pathways simultaneously, they are considered the most potent medications available to reduce gastric acid secretion. There are currently six PPIs available for use: omeprazole (Prilosec®, AstraZeneca, London, UK), lansoprazole (Prevacid®, Takeda Pharmaceuticals, Tokyo, Japan), pantoprazole (Protonix®, Wyeth Pharmaceuticals, NJ, USA), esomeprazole (Nexium®, AstraZeneca, London, UK), rabeprazole (AcipHex®, Eisai, Tokyo, Japan) and dexlansoprazole (Dexilant®, Takeda Pharmaceuticals). Despite their efficacy, long-term use of PPIs has been associated with several potential adverse effects including increased Clostridium difficile infections (CDI), risk of fractures and acute interstitial nephritis (AIN). With the prevalent use of PPIs and the availability of omeprazole and lansoprazole over-the-counter, the long-term use of PPIs and related safety issues are concerning.[2–4]