Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders

INTRODUCTION — Proton pump inhibitors (PPIs) effectively block gastric acid secretion by irreversibly binding to and inhibiting the hydrogen-potassium ATPase pump that resides on the luminal surface of the parietal cell membrane.

This topic review will provide an overview of the mechanism of action, pharmacokinetics, administration, and adverse effects of PPIs. The use and efficacy of PPIs in specific acid-related disorders is presented separately. (See "Antiulcer medications: Mechanism of action, pharmacology, and side effects".)

INDICATIONS FOR PPI THERAPY — Proton pump inhibitor (PPI) therapy is indicated in the following clinical situations:

●Peptic ulcer disease – PPIs are first-line antisecretory therapy in the treatment of peptic ulcer disease. (See "Peptic ulcer disease: Treatment and secondary prevention", section on 'Initial antisecretory therapy'.)

●Gastroesophageal reflux disease – PPIs are indicated in patients with gastroesophageal reflux disease, including for the treatment of erosive esophagitis and as maintenance therapy in patients with severe erosive esophagitis or Barrett’s esophagus. (See "Medical management of gastroesophageal reflux disease in adults", section on 'Severe or frequent symptoms or erosive esophagitis'.)

●Zollinger-Ellison syndrome – PPIs, often in high doses, are required to control gastric acid hypersecretion in patients with gastrin-secreting tumors. (See "Management and prognosis of the Zollinger-Ellison syndrome (gastrinoma)", section on 'Proton pump inhibitors'.)

●NSAID-associated ulcers – PPIs are indicated in the primary prevention of gastroduodenal ulcers associated with NSAID use. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity".)

●Eradication of Helicobacter pylori – PPIs are a component of several first-line and salvage therapy regimens for H. pylori infection. (See "Treatment regimens for Helicobacter pylori in adults".)

PHARMACOLOGY

●Mechanism of action – Proton pump inhibitors (PPIs) inhibit H-K-ATPase, the final step of gastric acid secretion by parietal cells.

PPIs are benzimidazole prodrugs which accumulate specifically and selectively in the secretory canaliculus of the parietal cell [1]. Within that space, they undergo an acid catalyzed conversion to a reactive species, the thiophilic sulfonamides, which are permanent cations. The rate of conversion varies among the compounds and is inversely proportional to the pKa of the benzimidazole (rabeprazole >omeprazole, esomeprazole, and lansoprazole >pantoprazole) (table 1) [2]. The reactive species interacts with the external surface of the H-K-ATPase that faces the lumen of the secretory space of the parietal cell, resulting in disulfide bond formation with cysteine 813 located within the alpha-subunit of the enzyme; this is the residue that is intimately involved in hydrogen ion transport. This covalent inhibition of the enzyme results in a specific and long-lasting impairment of gastric acid secretion. (See "Physiology of gastric acid secretion".)

●Pharmacokinetics – Although PPIs are similar in structure and mechanism of action, there are differences in their pharmacokinetic properties including bioavailability, peak plasma levels, half-life, and pKa (table 1). The magnitude of these differences are small, and their clinical relevance has not been established.

In general, PPIs are rapidly absorbed following oral administration. If taken with food, peak plasma concentrations may be delayed and bioavailability altered (ie, increased or decreased), depending upon the individual PPI. Most PPIs are formulated within an enteric-coating or other delayed-release system, which enables the prodrug to withstand high acidity of the gastric lumen and pass intact to absorption sites within the duodenum. Upon entering the systemic circulation, the PPI prodrug is protonated to become the active (thiophilic sulfenamide) moiety within highly acidic activated secretory canaliculus of parietal cells [1,3].

PPIs are metabolized in the liver primarily by cytochrome P450 2C19, and to a lesser extent by CYP3A4, to inactive metabolites, which are excreted mainly in the urine and bile. The degree to which individual PPIs are dependent upon CYP2C19 activity for degradation varies and is reported to be from most to least: omeprazole/esomeprazole > pantoprazole > lansoprazole > rabeprazole [4,5]. Despite their dependence on CYP2C19 for degradation, PPIs are themselves targets of relatively few clinically significant drug interactions. (See 'Drug interactions' below.)

CYP2C19 activity is determined to an extent by genetic polymorphism. Approximately 5 percent of White patients and up to 20 to 30 percent of patients within certain South and East Asian populations are homozygous for a CYP2C19 mutation, thereby conferring low CYP2C19 activity (ie, slow metabolizers) [6]. Slow metabolism of PPIs may lead to a greater duration of suppression of gastric acidity and contribute to decreased dose requirements. (See 'Dose and timing of administration' below.)

As an example, one study examined the effect of variable metabolism of omeprazole when using this agent to treat H. pylori in 62 Japanese patients [7]. While eradication was achieved in all individuals homozygous for a CYP2C19 mutation (ie, slow metabolizers), successful treatment was achieved in only 60 and 29 percent of heterozygotes and wild type homozygotes, respectively. In another study that evaluated the efficacy of lansoprazole in the treatment of 65 patients with gastroesophageal reflux disease (GERD), slow metabolizers were much more likely to be asymptomatic as compared with heterozygotes and wild type homozygotes (85 versus 68 and 46 percent, respectively) [8]. The response rate in wild type homozygotes with severe GERD was only 16 percent. Wild type homozygotes (rapid metabolizers) also had the lowest plasma lansoprazole concentrations. (See 'Dose and timing of administration' below.)

Following metabolism in the liver, PPIs are excreted as inactive metabolites in urine and in bile (table 1). PPI half-life (T½) is typically reported as ranging from 0.5 to 2.5 hours, which refers to half-life of the prodrug. The elimination half-life (T ½) of the active (thiophilic sulfonamide) form is greater and likely to be in the range of 12 to 18 hours. The duration of antisecretory effect of PPIs exceeds that predicted by their elimination half-life due to the stability of binding at the site of action [1,3].

Pharmacokinetic properties of the PPIs are listed in a table (table 1).

●Pharmacodynamics - PPIs are most effective when the parietal cell is stimulated to secrete acid postprandially, a relationship that has important clinical implications for timing of administration. Because the amount of H-K-ATPase present in the parietal cell is greatest after a prolonged fast, PPIs should be administered before the first meal of the day. In most individuals, once-daily dosing is sufficient to produce the desired level of acid inhibition, and a second dose, which is occasionally necessary, should be administered before the evening meal [1]. (See 'Dose and timing of administration' below.)

Once-daily PPI dosing for five days inhibits maximal gastric acid output by approximately 66 percent. Since PPIs inhibit only activated enzyme present in the canalicular membrane, the reduction of gastric acid secretion after an initial dose will probably be suboptimal. As inactive enzyme is recruited into the secretory canaliculus, acid secretion will resume, albeit at a reduced level. After the second dose is given on the next day, more H-K-ATPase will have been recruited and subsequently inhibited, and after the third dose, additional recruitment and further acid inhibition will probably occur. Thus, the occasional use of a PPI taken on an "as needed" basis does not reliably provide adequate acid inhibition and does not produce a consistent or satisfactory clinical response (in contrast to the H2 antagonists, which have a more rapid onset of action) [1].

Restoration of acid secretion after discontinuing PPIs depends upon enzyme turnover and the biological reversibility of the disulfide bond. Maximal acid secretory capacity may not be restored for 24 to 48 hours [1]. (See 'Discontinuing PPIs' below.)

PRETREATMENT CONSIDERATIONS AND MONITORING

Drug interactions — Although the proton pump inhibitors (PPIs) are rarely the target of clinically relevant drug-drug interactions, UpToDate suggests avoiding their administration at the same time as antisecretory agents (eg, histamine-2 receptor antagonists [H2RAs]) due to decreased acid-inhibitory effects (see 'Avoidance of concurrent antisecretory agents' below). Furthermore, strong inducers of CYP2C19 (eg, rifampin) can result in decreased efficacy of some of the PPIs (omeprazole, esomeprazole, lansoprazole); coadministration of these PPIs with rifampin should be avoided [9,10].

PPIs are implicated in decreasing the oral bioavailability of some co-medications via modulation of gastric acidity and, in some cases, can interact via inhibition of CYP2C19 metabolism. Illustrative examples of impaired absorption of an oral co-medication due to PPI modulation of gastric acidity include:

●Azole antifungals (some) – PPIs can decrease oral bioavailability of certain azole formulations: posaconazole oral suspension and conventional itraconazole capsules (Sporanox brand) [11-13]. (See "Pharmacology of azoles", section on 'Drug interactions'.)

●HCV direct acting antivirals (some) – PPIs can decrease absorption of velpatasvir- and ledipasvir-containing regimens. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection".)

●HIV antiretrovirals (some) – Due to impaired absorption of rilpivirine, combined use with a PPI is contraindicated; the use of atazanavir should be avoided in patients who require omeprazole dose of >20 mg daily or equivalent. (See "Overview of antiretroviral agents used to treat HIV".)

●Mycophenolate mofetil – PPIs can decrease absorption of mycophenolate mofetil (MMF) by 25 percent or more [14]. Enteric-coated mycophenolate sodium (EC-MPS) formulation appears less likely to interact. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases", section on 'Drug interactions'.)

●Tyrosine kinase inhibitors (TKIs) (several) – Diminished total exposure (AUC_0-24) by up to 78 percent has been reported for the TKI dasatinib when coadministered with a PPI [15]. This interaction may also occur with other TKIs that require gastric acidity to solubilize and become absorbed (eg, acalabrutinib capsules [acalabrutinib tablets do not interact with PPIs], bosutinib, dacomitinib, erlotinib, gefitinib, infigratinib, neratinib, nilotinib, pazopanib, pexidartinib). Additional information is available elsewhere. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor", section on 'Erlotinib'.)

Additional information on drug interactions due to PPI gastric acidity modulation is provided in a table (table 2).

Illustrative examples of altered exposure of a co-medication due to PPI inhibition of CYP2C19 metabolism include:

●Clopidogrel – Clopidogrel requires conversion to its active form via CYP2C19 metabolism. Some data suggest decreased activation of clopidogrel when used in conjunction with omeprazole due to shared hepatic CYP2C19 metabolism. Pantoprazole, lansoprazole, and rabeprazole appear less likely to interact. In 2009, the US Food and Drug Administration (FDA) concluded that patients taking clopidogrel should consult with their clinician if they are taking or considering taking a PPI, including over-the-counter PPI preparations [16,17]. However, the relevance of these data remains highly controversial. We advise patients requiring PPI therapy who take clopidogrel not to use omeprazole or esomeprazole and to take the PPI in the morning and clopidogrel at least four hours later, eg, at bedtime [18]. Additional detail of this interaction is provided separately. (See "Clopidogrel resistance and clopidogrel treatment failure", section on 'Interaction with other drugs'.)

●Citalopram – Omeprazole can increase total exposure (AUC_0-24 hours) to the active form of citalopram by 90 percent via inhibition of CYP2C19 metabolism [19]. The labeling recommends limiting the citalopram dose to 20 mg/day if used with omeprazole.

●Cilostazol – Omeprazole can increase serum concentrations of cilostazol via inhibition of CYP2C19 metabolism [20]. A dose adjustment of cilostazol is recommended if used with omeprazole.

Other drug interactions observed with PPIs include the following; the mechanism for these interactions is not well established:

●Methotrexate – Coadministration of PPIs with high dose methotrexate appears to be correlated with delayed methotrexate elimination and potentially may lead to methotrexate toxicity if not monitored appropriately [21]. (See "Therapeutic use and toxicity of high-dose methotrexate", section on 'Potential drug-drug-interactions'.)

●Warfarin – Lansoprazole and omeprazole have been associated with modest increases in serum concentrations of R-warfarin (ie, less active warfarin enantiomer) in a number of case reports [22-24].

Additional information on drug interactions due to PPI inhibition of CYP2C19 metabolism and other mechanisms is provided in a table (table 2).

This is not a complete list of PPI drug interactions. For additional information on specific drug interactions, use the drug interactions program included within UpToDate.

Laboratory testing — We limit routine laboratory testing to selected patients on PPI therapy.

●Magnesium – We obtain serum magnesium levels prior to starting a PPI in patients who are expected to be on long-term (≥1 year) treatment or in patients who take PPIs in conjunction with other medications associated with hypomagnesemia (eg, diuretics). In addition, we obtain magnesium levels periodically in such patients while they are taking a PPI. The frequency of testing is based on the clinical history and the presence of symptoms of hypomagnesemia. As an example, in patients with a history of arrhythmias or QT interval prolongation, we monitor magnesium levels every six months. The management of hypomagnesemia is discussed in detail separately. (See "Hypomagnesemia: Evaluation and treatment".)

●Vitamin B12 – We also obtain vitamin B12 levels yearly in patients on long-term PPIs [25]. However, routinely monitoring vitamin B12 levels is controversial. (See 'Magnesium malabsorption' below and 'Vitamin B12 malabsorption' below.)

There are insufficient evidence to support routine bone density monitoring or calcium supplementation due to proton pump inhibitor use alone [26].

ADMINISTRATION

Intravenous regimen — IV PPIs are indicated prior to endoscopic evaluation in patients with clinically significant upper gastrointestinal bleeding from a suspected peptic ulcer. Pantoprazole and esomeprazole are the only PPIs available as an IV formulation in the United States; IV omeprazole is available in other countries. The use of PPIs in the treatment of bleeding peptic ulcers and the duration of treatment is discussed in detail separately. (See "Overview of the treatment of bleeding peptic ulcers", section on 'Oral versus intravenous dosing' and "Approach to acute upper gastrointestinal bleeding in adults", section on 'Acid suppression'.)

Oral regimen

Selecting a PPI — The choice of a specific oral PPI and whether over-the-counter (rather than prescription) PPIs are prescribed are often determined by patient preference and payer coverage. A systematic review of 12 randomized trials examining the relative effectiveness of different PPI doses and dosing regimens found no consistent difference in symptom resolution and esophagitis healing rates [27].

In patients unable to swallow pills or capsules, options include an orally disintegrating tablet (ODT) of lansoprazole, delayed-release granules (packets) of omeprazole and pantoprazole for oral suspension, and a rabeprazole capsule that can be opened and sprinkled on soft food.

Dose and timing of administration — PPIs should be administered 30 to 60 minutes before breakfast for maximal inhibition of proton pumps. (See 'Pharmacology' above.)

Dose reduction, particularly for maintenance of healing of erosive esophagitis may be possible in Asian populations. Polymorphisms in the CYP2C19 gene, which encodes the cytochrome P450 isoenzyme that metabolizes different PPI preparations, are common in Asian and other populations [28]. Such gene mutations would render an individual a "slow metabolizer" and prolong the antisecretory effect of PPIs. In contrast, the duration of acid inhibition would be decreased in a "rapid metabolizer," and differences in PPI metabolism might account for incomplete inhibition of acid secretion and a high prevalence of nocturnal breakthrough symptoms in gastroesophageal reflux disease patients. (See 'Pharmacology' above and "Approach to refractory gastroesophageal reflux disease in adults", section on 'Differences in PPI metabolism'.)

Avoidance of concurrent antisecretory agents — PPIs should not administered concomitantly with antisecretory agents including histamine-2 receptor antagonists (H2RAs), analogues of prostaglandin E (eg, misoprostol), and somatostatin analogues (eg, octreotide), because of the marked reduction in acid inhibitory effects [1,29]. Antisecretory drugs can be used with a PPI provided that there is a sufficient time interval between their administration. As an example, an H2RA can be taken before bedtime or during the night by individuals who report nocturnal breakthrough symptoms such as heartburn after taking a PPI in the morning or before dinner.

Switching between PPIs — Switching PPIs is a reasonable strategy in patients with side-effects to an individual PPI and may be necessary due to cost differences. Although there is significant interindividual and intraindividual variability in intragastric pH control between PPIs, there are no consistent difference in relation to symptom resolution and esophagitis healing rates [27]. Switching PPIs in patients with well-controlled symptoms may also be associated with increased symptom severity and decreased patient satisfaction [30]. (See "Approach to refractory gastroesophageal reflux disease in adults", section on 'Subsequent management'.)

Discontinuing PPIs — PPIs should be prescribed at the lowest dose and for the shortest duration appropriate to the condition being treated. (See 'Indications for PPI therapy' above.)

We gradually taper PPI therapy in patients treated with PPIs for longer than six months. For patients on a standard or high-dose PPI (eg, omeprazole 40 mg daily or twice daily), we decrease the dose by 50 percent every week. For patients on twice daily dosing, the initial reduction can be accomplished by decreasing the dosing to once in the morning before breakfast until the patient is on the lowest dose of the medication. Once on the lowest dose for one week, the patient is instructed to discontinue the PPI. However, no specific method for discontinuing PPI therapy has been proven effective, and no approach is universally accepted. [31,32].

Studies have demonstrated rebound gastric acid hypersecretion following discontinuation of PPIs in patients with long-term use. The reasons are not entirely clear, but appear to be due in part to the suppression of antral somatostatin expression, resulting in an increase in antral gastrin release and subsequent disruption of normal pH-related feedback inhibition of acid secretion that occurs after a meal [1]. (See "Physiology of gastric acid secretion", section on 'Tolerance'.)

ADVERSE EFFECTS — Long-term PPI use has been associated with several safety concerns. However, few of these concerns are supported by consistent data demonstrating a causal relationship. (See "Physiology of gastrin", section on 'Hypergastrinemia'.)

Gastrointestinal effects

Clostridioides difficile and other enteric infections — PPI use has been associated with an increased risk of C. difficile infection, even in the absence of antibiotic use [33-43]. Associations with other enteric infections, including salmonellosis and campylobacteriosis, have also been reported [44-49]. However, the pathophysiologic mechanism involved in the increased risk of infection is unclear.

A 2017 meta-analysis of 50 observational studies found that PPI use was significantly associated with an increased risk of C. difficile infection (relative risk [RR] 1.3; 95% CI 1.1-14). The risk of C. difficile infection appears to be greater with PPIs as compared to histamine-2 receptor antagonists (H2RAs) [40,41].

PPI use has also been associated with an increased risk of recurrent C. difficile infection [41]. In a 2017 meta-analysis of 16 observational studies that included 7703 patients with C. difficile infection of whom 1525 (20 percent) had recurrent C. difficile infection, gastric acid suppression was significantly associated with an increased risk of recurrent C. difficile infection (odds ratio [OR] 1.5; 95% CI 1.2-1.9) [50]. There was significant heterogeneity among the studies included in the meta-analysis. In adjusted analysis using data from nine studies, PPI use was associated with an increased risk of recurrent C. difficile infection after controlling for patient age and other co-morbid conditions (OR 1.4; 95% CI 1.1-1.8). (See "Clostridioides difficile infection in adults: Epidemiology, microbiology, and pathophysiology", section on 'Gastric acid suppression'.)

Microscopic colitis — PPI use has been associated with microscopic colitis, including lymphocytic and collagenous colitis. In a case-control study that included 95 cases of microscopic colitis, exposure to PPIs was significantly higher in patients with microscopic colitis as compared with controls (38 versus 13 percent, OR 4.5, 95% CI 2.0-9.5) [51]. Similar results have been reported in other case-control studies, however, it is unclear if this association varies by PPI and if there is a dose-response relationship in either dose or duration of use [52,53]. (See "Microscopic (lymphocytic and collagenous) colitis: Clinical manifestations, diagnosis, and management", section on 'Medications'.)

Hypergastrinemia — Induction of hypergastrinemia has been associated with gastric carcinoid tumors in rats. However, these observations are not generalizable to species with gastrin physiology more analogous to humans [54]. While patients treated with omeprazole for up to 11 years have shown some enterochromaffin-like cell hyperplasia, no dysplasia or neoplastic changes have been observed [55]. An increased risk of colon cancer due to hypergastrinemia has also not been established [56]. (See "Physiology of gastrin".)

Atrophic gastritis — Patients on long-term PPI therapy have a propensity to develop chronic atrophic gastritis. However, the risk of atrophic gastritis is small, and in the rare patient who develops atrophic gastritis, the clinical consequences are uncertain [55,57,58]. (See "Risk factors for gastric cancer".)

Intestinal colonization of multi-drug resistant organisms — PPIs may increase the risk of intestinal colonization with multi-drug resistant organisms. In a meta-analysis of 12 observational studies that included 22,305 patients, after adjusting for potential confounders, acid suppression increased the odds of intestinal carriage of multi-drug resistant organisms of the Enterobacterales order (producing extended-spectrum beta-lactamases, carbapenemases, or plasmid-mediated AmpC beta-lactamases) and of vancomycin-resistant enterococci (OR 1.74; 95% CI 1.4-2.2) [59]. Possible mechanisms include an increase in bacteria that survive transit from the stomach to the intestine due to reduction in gastric acid by PPIs and direct alteration of the composition of intestinal microbiota, leading to a decrease in mean species diversity.  

Inflammatory bowel disease — In a study that pooled data from three observational cohorts and included >600,000 individuals followed for a median of 12 years, the risk of inflammatory bowel disease (IBD) was increased in regular PPI users as compared with nonusers (hazard ratio [HR] 1.42; 95% CI 1.22–1.65) [60]. However, the absolute risk of IBD was low, with a number needed to harm of 3770. In addition, absence of data on PPI dosing precluded assessment of a dose-response relationship between PPI use and IBD.

Malabsorption of minerals and vitamins

Magnesium malabsorption — PPIs can cause hypomagnesemia due to reduced intestinal absorption [61]. A meta-analysis of nine observational studies that included a total of 109,798 patients found that those who took a PPI had a significantly higher risk (RR 1.43; 95% CI 1.08-1.88) of developing hypomagnesemia as compared with those who did not [62]. Clinical manifestations of hypomagnesemia include neuromuscular excitability (eg, tremor, tetany, convulsions), weakness, and apathy. Severe PPI-induced hypomagnesemia has been associated with QT interval prolongation and torsades de pointes [63,64]. The risk of hypomagnesemia appears to be mainly in patients who have been on PPIs long-term (generally longer than one year) but cases have been reported within one year of starting PPI therapy [63,65]. This potential risk has led to recommendations to monitor serum magnesium levels in specific patients at high risk for hypomagnesemia. Monitoring for hypomagnesemia in patients on PPIs is discussed in detail separately. (See 'Laboratory testing' above and "Hypomagnesemia: Clinical manifestations of magnesium depletion", section on 'Overview of clinical manifestations'.)

Calcium and fracture risk — Although hypochlorhydria could theoretically reduce calcium absorption, the effect appears to be relevant only for the absorption of water insoluble calcium (eg, calcium carbonate) and can be overcome by ingestion of a slightly acidic meal [66]. The absorption of water-soluble calcium salts or calcium in dairy products are not impacted by PPI-induced hypochlorhydria. When calcium supplementation is necessary in patients taking PPIs, we use calcium supplements that do not require acid for absorption, such as calcium citrate. (See 'Laboratory testing' above and "Drugs that affect bone metabolism", section on 'Proton pump inhibitors'.)

PPI-induced hypochlorhydria can augment osteoclastic activity, thereby decreasing bone density [67,68]. Although an association between PPI use and bone fracture is plausible, causality has not been established [69]. Nonetheless, the FDA has mandated revised safety information on all PPIs about a possible increased risk of fractures of the hip, wrist, and spine with the use of these medications [70]. The association between PPIs and bone metabolism and risk of fracture are discussed in detail separately. (See "Drugs that affect bone metabolism", section on 'Proton pump inhibitors'.)

Vitamin B12 malabsorption — Long-term therapy with PPIs has been associated with vitamin B12 malabsorption [71,72]. However, absorption of oral B12 supplements is not affected. (See 'Laboratory testing' above and "Treatment of vitamin B12 and folate deficiencies", section on 'Treatment of vitamin B12 deficiency'.)

Iron malabsorption — Gastric acid plays a role in the absorption of nonheme iron, and the use of PPIs has been associated with decreased iron absorption [73-77]. However, in most cases the decreased absorption does not appear to be of clinical significance. One exception may be in patients who require oral iron supplementation [76,78]. Such patients may need a higher dose or longer duration of supplementation [76]. (See "Treatment of iron deficiency anemia in adults", section on 'Dosing and administration (oral iron)'.)

Kidney disease — PPIs can cause acute interstitial nephritis (AIN) [79-82]. Similar to other cases of drug-induced AIN, AIN due to PPI use is not dose-dependent, and recurrence or exacerbation can occur with a second exposure to the same or a related drug. (See "Clinical manifestations and diagnosis of acute interstitial nephritis", section on 'Drugs'.)

PPI use has also been associated with an increased risk of incident chronic kidney disease (CKD), CKD progression, and end-stage kidney disease [83-86]. However, the mechanism underlying the association between PPI use and risk of CKD is not known, and it is possible that the weak association observed in these studies is due to methodological limitations (residual confounding) [83,84,87]. Further studies are needed to help better define an etiologic relationship between PPI use and the development and worsening of CKD.

Drug-induced lupus — In postmarketing safety surveillance, new onset of cutaneous lupus erythematosus and systemic lupus erythematosus (SLE), and exacerbation of existing disease have been reported in patients on PPIs [88-90]. Most cases of CLE-associated with PPI use are subacute and occur within weeks to years after continuous PPI therapy. PPI-associated SLE usually occurs days to years after initiating PPI treatment and typically presents with a rash. Most patients improve within 4 to 12 weeks of discontinuation of PPI therapy. (See "Drug-induced lupus", section on 'Causative drugs'.)

Other associations of unclear significance

COVID-19 — It is unclear if PPI use is associated with an increased risk of COVID-19. In a cross-sectional survey of 86,602 individuals, 53,130 reported prior abdominal pain, acid reflux, heartburn, and regurgitation symptoms and provided data on H2RA and PPI use. Of these, 3386 individuals (6.4 percent) self-reported a positive COVID-19 test [91]. In analyses adjusted for socioeconomic, lifestyle, and clinical comorbidities, patients who reported PPI use were significantly more likely to report a positive COVID-19 test with a dose-dependent increase in odds of reporting a positive test (PPI once-daily OR 2.15, 95% CI 1.9-2.4; PPI twice-daily OR 3.7, 95% CI 2.9-4.6). It is possible that this association is due to residual confounding.

Other studies have demonstrated that patients taking PPIs are at increased risk for severe clinical outcomes of COVID-19 but have not demonstrated an increase in susceptibility to SARS-CoV-2 infection [92]. These data require further validation.

Dementia — Although some studies have found a significant association between use of PPIs and incident dementia, others have not found an association between PPI use and cognitive function [93-98]. The association between PPI use and dementia may reflect residual confounding by factors related to both use of PPIs and the development of dementia and is discussed in detail, separately. (See "Epidemiology, pathology, and pathogenesis of Alzheimer disease", section on 'Medications'.)

Pneumonia — While observational studies suggest an association between PPI use and pneumonia, the observed association may be due to confounding such that individuals prescribed PPIs may be more likely to have other unobserved health characteristics that predispose them to pneumonia as compared with nonusers [99-106]. (See "Epidemiology, pathogenesis, and microbiology of community-acquired pneumonia in adults", section on 'Predisposing host conditions' and "Risk factors and prevention of hospital-acquired and ventilator-associated pneumonia in adults", section on 'Role of gastric pH'.)

Mortality — It is unclear if PPI use is associated with an increase in risk of death. In an observational cohort study that included 275,977 new PPI users and 73,335 new histamine-2 receptor antagonist (H2RA) users, over a median follow-up of 5.7 years, the incident death rate among new PPI users was higher as compared to those receiving H2RA (4.5 versus 3.3 per 100 person-years) [107]. New PPI users were significantly older as compared with new users of H2RAs at the time of study entry (61.7 versus 58.5 years). However, after adjusting for potential confounders, PPI use was associated with an increase in all-cause mortality as compared with H2RA use (HR 1.25, 95% CI 1.23-1.28). PPI users also had an increase in risk of death as compared with individuals without any PPI use and individuals without any acid suppression use (HR 1.15, 95% CI 1.14-1.15; HR 1.23, 95% CI 1.22-1.24, respectively). Among new PPI users, the risk of death increased with the duration of PPI use. Limitations of the study include its generalizability as the study cohort primarily consisted of older White males, and lack of data on the cause of mortality. The underlying basis for this apparent increased risk of death with PPI use are not known and further studies are needed to evaluate whether this epidemiologic association is due to unmeasured confounding.

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SUMMARY AND RECOMMENDATIONS

●Indications for proton pump inhibitors – Indications include the treatment of peptic ulcer disease, gastroesophageal reflux disease, and Zollinger-Ellison syndrome. Proton pump inhibitors (PPIs) are effective in the prevention of nonsteroidal anti-inflammatory drug-associated gastroduodenal mucosal injury and are an important component of several antimicrobial regimens used in the treatment of Helicobacter pylori infection. (See 'Indications for PPI therapy' above.)

●Pharmacology – PPIs effectively block gastric acid secretion by irreversibly binding to and inhibiting the hydrogen-potassium ATPase pump that resides on the luminal surface of the parietal cell membrane. Genetically determined variability in the PPI metabolism can influence their efficacy. The presence of a CYP2C19 gene mutation can result in higher plasma PPI levels in homozygous individuals. PPI metabolism via hepatic cytochrome P450 enzymes may lead to specific drug interactions in some individuals. However, clinically important drug interactions with PPIs are infrequent. (See 'Pharmacology' above.)

●Administration – Oral PPIs should be administered 30 to 60 minutes before breakfast for maximal inhibition of proton pumps. PPIs should not be administered concomitantly with histamine-2 receptor antagonists (H2RAs), and prostaglandins or somatostatin analogues. The magnitude of pharmacokinetic differences between PPIs is small and the clinical relevance of these differences has not been established (table 1). Intravenous PPI therapy is indicated in patients with clinically significant upper gastrointestinal bleeding prior to endoscopy for treatment of suspected bleeding peptic ulcers. In general, PPIs should be prescribed at the lowest dose and for the shortest duration appropriate to the condition being treated. When discontinuing PPI therapy, we taper the dose gradually in patients on PPIs for longer than six months. (See 'Administration' above.)

●Adverse effects

•Gastrointestinal – PPI use has been associated with an increased risk of Clostridioides difficile infection, other enteric infections, and microscopic colitis. C. difficile infection with diarrhea may occur even in the absence of antibiotic use. (See 'Gastrointestinal effects' above.)

•Malabsorption of minerals and vitamins

-PPIs can cause hypomagnesemia due to reduced intestinal absorption. Long-term therapy with PPIs has been associated with vitamin B12 malabsorption. We obtain serum magnesium levels prior to starting a PPI in patients who are expected to be on long-term (≥1 year) treatment, or in patients who take PPIs in conjunction with other medications associated with hypomagnesemia. In addition, we also monitor magnesium and vitamin B12 levels in patients on long-term PPIs. (See 'Pretreatment considerations and monitoring' above and 'Magnesium malabsorption' above and 'Vitamin B12 malabsorption' above.)

-Although an association between PPIs and bone fracture is plausible, causality has not been established. PPIs can decrease the absorption of water insoluble calcium (eg, calcium carbonate). When calcium supplementation is necessary in patients taking PPIs, we use calcium supplements that do not require acid for absorption, such as calcium citrate. (See 'Calcium and fracture risk' above.)

•Kidney disease – PPIs can cause acute interstitial nephritis. PPI use has also been associated with an increased risk of incident chronic kidney disease (CKD), CKD progression, and end-stage renal disease. However, further studies are needed to help better define an etiologic relationship between PPI use and the development and worsening of CKD. (See 'Kidney disease' above.)

•Associations of unclear significance – There are conflicting data on the association between PPI use and risk of dementia and pneumonia. It is also unclear if PPI use is associated with an increased risk of death. It is possible that these associations are due to residual confounding and more studies are needed. (See 'Kidney disease' above and 'Dementia' above and 'Mortality' above.)