Proton-pump inhibitors (PPIs) are a class of medications that cause a profound and prolonged reduction of stomach acid production. They do so by irreversibly inhibiting the stomach's H+/K+ ATPase proton pump. The body eventually synthesizes new proton pumps to replace the irreversibly inhibited ones—a process driven by normal cellular turnover, which gradually restores acid production. Proton-pump inhibitors have largely superseded the H2-receptor antagonists, a group of medications with similar effects but a different mode of action, and heavy use of antacids. Potassium-competitive acid blockers (PCABs) have entered the market since the 2010s. PPIs are among the most widely sold medications in the world. The class of proton-pump inhibitor medications is on the World Health Organization's List of Essential Medicines, omeprazole being the specific listed example.
Medical uses These medications are used in the treatment of many conditions, such as:
Dyspepsia Peptic ulcer disease including after endoscopic treatment for bleeding As part of Helicobacter pylori eradication therapy Gastroesophageal reflux disease (GERD or GORD) including symptomatic endoscopy-negative reflux disease and associated laryngopharyngeal reflux causing laryngitis and chronic cough Barrett's esophagus Eosinophilic esophagitis Stress gastritis and ulcer prevention in critical care Gastrinomas Zollinger–Ellison syndrome (often 2–3× the regular dose is required) Specialty professional organizations recommend that people take the lowest effective PPI dose to achieve the desired therapeutic result when used to treat gastroesophageal reflux disease long-term. In the United States, the Food and Drug Administration (FDA) has advised that over-the-counter PPIs, such as Prilosec OTC, should be used no more than three 14-day treatment courses over one year. Despite their extensive use, the quality of the evidence supporting their use in some of these conditions is variable. The effectiveness of PPIs has not been demonstrated for every case. For example, although they reduce the incidence of esophageal adenocarcinoma in Barrett's oesophagus, they do not change the length affected. In addition, research in the UK has suggested that PPIs are not effective at treating persistent throat symptoms.
Indications for stopping PPIs PPIs are often used longer than necessary. In about half of people who are hospitalized or seen at a primary care clinic there is no documented reason for their long-term use of PPIs. Some researchers believe that, given the little evidence of long-term effectiveness, the cost of the medication and the potential for harm means that clinicians should consider stopping PPIs in many people.
Adverse effects In general, proton pump inhibitors are well tolerated, and the incidence of short-term adverse effects is relatively low. The range and occurrence of adverse effects are similar for all of the PPIs, though they have been reported more frequently with omeprazole. This may be due to its longer availability and, hence, clinical experience. Common adverse effects include headache, nausea, diarrhea, abdominal pain, fatigue, and dizziness. Infrequent adverse effects include rash, itch, flatulence, constipation, anxiety, and depression. Also infrequently, PPI use may be associated with occurrence of myopathies, including the serious reaction rhabdomyolysis. Long-term use of PPIs requires assessment of the balance of the benefits and risks of the therapy. As of March 2017, various adverse outcomes have been associated with long-term PPI use in several primary reports, but reviews assess the overall quality of evidence in these studies as "low" or "very low". They describe inadequate evidence to establish causal relationships between PPI therapy and many of the proposed associations, due to study design and small estimates of effect size. As of March 2017, benefits outweighed risks when PPIs are used appropriately, but when used inappropriately, modest risks become important. They recommend that PPIs should be used at the lowest effective dose in people with a proven indication, but discourage dose escalation and continued chronic therapy in people unresponsive to initial empiric therapy. With regard to iron and vitamin B12, the data is weak and several confounding factors have been identified. Low levels of magnesium can be found in people on PPI therapy and these can be reversed when they are switched to H2-receptor antagonist medications.
Bone High dose or long-term use of PPIs carries an increased risk of bone fractures which was not found with short-term, low dose use; the FDA included a warning regarding this on PPI drug labels in 2010. In infants, acid suppression therapy is frequently prescribed to treat symptomatic gastroesophageal reflux in otherwise healthy infants (i.e., infants without gastroesophageal reflux disease). A study from 2019 showed that PPI use alone and together with histamine H2-receptor antagonists was associated with an increased bone fracture hazard, which was amplified by days of use and earlier initiation of therapy. The reason is not clear; increased bone breakdown by osteoclasts has been suggested. A recent 2024 study published in the Journal of Clinical Endocrinology & Metabolism found that chronic use of PPIs in men is linked to lower trabecular bone quality. Specifically, PPI use was associated with reduced lumbar spine trabecular bone score (TBS), as well as lower bone mineral density (BMD) T-scores in the lumbar spine, total hip, and femoral neck.
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