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A Closer Look At Proton Pump
Inhibitors, Or PPIs

Proton Pump Inhibitors (PPIs) are a staple in managing gastroesophageal reflux disease (GERD) and other acid-related disorders. These potent agents significantly reduce acid secretion by irreversibly binding to H+/K+ adenosine triphosphatase, or the proton pump, located in the parietal cells. 


PPIs have proven to be very effective and safe in managing GERD, healing peptic ulcer disease, and reducing the incidence of nonsteroidal anti-inflammatory drug–associated gastropathy, becoming one of the most-prescribed medications by healthcare providers. Their superb efficacy and low toxicity resulted in the approval of the first OTC product in 2003, providing patients with an option other than antacids and H2-receptor antagonists for self-medication of ailments such as heartburn and other related symptomatology. 


The advantages of PPIs have also contributed to their overuse and misuse. Healthcare providers often prescribe these agents for prolonged – even lifetime – use, and many patients take the OTC agents beyond the recommended course of therapy without any supervision. 


Over the years, there has been growing concern over potential adverse effects of long-term therapy. Since 2010, the FDA has issued various safety warnings regarding the potential effects of long-term use of PPIs. These can include decreased calcium absorption, magnesium, iron, vitamin B12, minerals, and acid suppression. 

PPIs Associate Adverse Events (PAAE) For Long-term Use

  • Increased risk of fractures, osteoporosis, and myopathy

  • Increased risk of arrhythmias, MI, and CVA

  • Renal effects leading to acute interstitial nephritis and chronic kidney disease

  • Increased risk for anemia

  • Increased risk for gastric and colon cancer

  • Increased PH, allowing overgrowth of bacterial infections (e.g., Salmonella, Campylobacter, C-diff). Aspiration of gastric content leading to pneumonia. 

  • Increased risk for seizures and dementia 

How Long Should Patients Be On PPIs?

PPIs are typically prescribed for 1-2 weeks to treat H. Pylori infections, in addition to antibiotics. A PPI course of 4-12 weeks may be prescribed for patients with GI ulcers or for esophagitis.

Best Practice Recommendations

  • For all patients on PPIs, primary care physicians should regularly review ongoing indications for use and document any indication for continued use.


  • De-prescribing should be considered for any patients on chronic PPIs without a definitive indication. 


  • The majority of patients on twice-daily PPI dosing should be considered for once-daily step-down dosing.


  • PPI should not be discontinued for those with eosinophilic esophagitis, erosive esophagitis, esophageal ulcers, Zollinger-Ellison syndrome, idiopathic pulmonary fibrosis, or Barrett's esophagus. 


  • PPI users should be assessed for upper gastrointestinal bleeding risk using an evidence-based strategy before de-prescribing.


  • Patients who discontinue long-term PPI therapy should be advised that they may develop transient upper gastrointestinal symptoms due to rebound acid hypersecretion.


  • Abrupt discontinuation or dose tapering can be used to de-prescribe PPIs. Consider overlapping discontinuation of PPI, with H2 Blockers to decrease rebound symptoms.


  • The decision to discontinue PPIs should be based solely on the lack of an indication for PPI use, and not because of concern for PAAEs. 

Alternative Therapies To PPIs

Non-PPI options include histamine blockers, antacids, probiotics, and lifestyle changes (weight management, dietary behaviors, relaxation strategies, and awareness about the brain-gut axis relationship to patients with reflux symptoms). In addition, the elevation of the head of the bed by 6-9 inches may decrease GI Reflux.


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