Official reprint from UpToDate®

[Link] © 2025 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Proton pump inhibitors: Overview of use and adverse

effects in the treatment of acid related disorders
AUTHOR: M Michael Wolfe, MD
SECTION EDITOR: Loren Laine, MD
DEPUTY EDITORS: Claire Meyer, MD, Sara Swenson, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Mar 2025.

This topic last updated: Apr 15, 2025.

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

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
'Complicated ulcer'.)

● 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 "Initial management
of gastroesophageal reflux disease in adults", section on 'Severe or frequent symptoms'.)
● 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 gastrinoma (Zollinger-Ellison syndrome)", 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 of Helicobacter pylori infection in
adults".)

PHARMACOLOGY
● Mechanism of action – 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 is 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 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 (AUC0-24) 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, 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 'Less preferred options'.)

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 (AUC0-24 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 PPI 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 '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 'Gastric acid 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 'Gastric acid 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]. Other studies have shown no increased incidence of worsening kidney
function after adjusting for confounders [88]. 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 [89-91]. 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 [92]. 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 [93]. 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 [94-99]. 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 [100-107]. (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 'Other risk factors'.)

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) [108]. 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.

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics."
The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer
short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topics (see "Patient education: Acid reflux and GERD in adults (The Basics)")

● Beyond the Basics topics (see "Patient education: Gastroesophageal reflux disease in adults
(Beyond the Basics)")

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 kidney 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.)

ACKNOWLEDGMENT
We are saddened by the death of Mark Feldman, MD, who passed away in March 2024.
UpToDate gratefully acknowledges Dr. Feldman’s role as a Section Editor on this topic and his
dedicated and longstanding involvement with the UpToDate program.
 Use of UpToDate is subject to the Terms of Use.

REFERENCES

1. Wolfe MM, Sachs G. Acid suppression: optimizing therapy for gastroduodenal ulcer healing,
gastroesophageal reflux disease, and stress-related erosive syndrome. Gastroenterology
2000; 118:S9.
2. Shin JM, Cho YM, Sachs G. Chemistry of covalent inhibition of the gastric (H+, K+)-ATPase by
proton pump inhibitors. J Am Chem Soc 2004; 126:7800.
3. Shin JM, Kim N. Pharmacokinetics and pharmacodynamics of the proton pump inhibitors. J
Neurogastroenterol Motil 2013; 19:25.
4. Wedemeyer RS, Blume H. Pharmacokinetic drug interaction profiles of proton pump
inhibitors: an update. Drug Saf 2014; 37:201.
5. Fock KM, Ang TL, Bee LC, Lee EJ. Proton pump inhibitors: do differences in
pharmacokinetics translate into differences in clinical outcomes? Clin Pharmacokinet 2008;
47:1.
6. Koopmans AB, Braakman MH, Vinkers DJ, et al. Meta-analysis of probability estimates of
worldwide variation of CYP2D6 and CYP2C19. Transl Psychiatry 2021; 11:141.
7. Furuta T, Ohashi K, Kamata T, et al. Effect of genetic differences in omeprazole metabolism
on cure rates for Helicobacter pylori infection and peptic ulcer. Ann Intern Med 1998;
129:1027.
8. Furuta T, Shirai N, Watanabe F, et al. Effect of cytochrome P4502C19 genotypic differences
on cure rates for gastroesophageal reflux disease by lansoprazole. Clin Pharmacol Ther
2002; 72:453.
9. Park GJ, Bae SH, Park WS, et al. Drug-drug interaction of microdose and regular-dose
omeprazole with a CYP2C19 inhibitor and inducer. Drug Des Devel Ther 2017; 11:1043.
10. Kanebratt KP, Diczfalusy U, Bäckström T, et al. Cytochrome P450 induction by rifampicin in
healthy subjects: determination using the Karolinska cocktail and the endogenous CYP3A4
marker 4beta-hydroxycholesterol. Clin Pharmacol Ther 2008; 84:589.
11. Krishna G, Moton A, Ma L, et al. Pharmacokinetics and absorption of posaconazole oral
suspension under various gastric conditions in healthy volunteers. Antimicrob Agents
Chemother 2009; 53:958.
12. Jaruratanasirikul S, Sriwiriyajan S. Effect of omeprazole on the pharmacokinetics of
itraconazole. Eur J Clin Pharmacol 1998; 54:159.
13. Johnson MD, Hamilton CD, Drew RH, et al. A randomized comparative study to determine
the effect of omeprazole on the peak serum concentration of itraconazole oral solution. J
Antimicrob Chemother 2003; 51:453.
14. Schaier M, Scholl C, Scharpf D, et al. Proton pump inhibitors interfere with the
immunosuppressive potency of mycophenolate mofetil. Rheumatology (Oxford) 2010;
49:2061.
15. Yago MR, Frymoyer A, Benet LZ, et al. The use of betaine HCl to enhance dasatinib
absorption in healthy volunteers with rabeprazole-induced hypochlorhydria. AAPS J 2014;
16:1358.
16. Information for Healthcare Professionals: Update to the labeling of Clopidogrel Bisulfate
(marketed as Plavix) to alert healthcare professionals about a drug interaction with omepra
zole (marketed as Prilosec and Prilosec OTC). Available on the US Food and Drug Administr
ation (FDA) web site: [Link]
orHumanMedicalProducts/[Link] (Accessed on November 18, 2009).
17. FDA's MedWatch Safety Alerts: November 2009. Plavix and Prilosec Drug Interaction. Availa
ble at: [Link]
ilosecDrugInteraction (Accessed on January 26, 2009).
18. Juurlink DN. Proton pump inhibitors and clopidogrel: putting the interaction in perspective.
Circulation 2009; 120:2310.
19. Rocha A, Coelho EB, Sampaio SA, Lanchote VL. Omeprazole preferentially inhibits the
metabolism of (+)-(S)-citalopram in healthy volunteers. Br J Clin Pharmacol 2010; 70:43.
20. Suri A, Bramer SL. Effect of omeprazole on the metabolism of cilostazol. Clin
Pharmacokinet 1999; 37 Suppl 2:53.
21. Beorlegui B, Aldaz A, Ortega A, et al. Potential interaction between methotrexate and
omeprazole. Ann Pharmacother 2000; 34:1024.
22. Hata M, Hayasaka M, Sezai A, et al. Proton pump inhibitors may increase the risk of delayed
bleeding complications after open heart surgery if used concomitantly with warfarin.
Thorac Cardiovasc Surg 2008; 56:274.
23. Unge P, Svedberg LE, Nordgren A, et al. A study of the interaction of omeprazole and
warfarin in anticoagulated patients. Br J Clin Pharmacol 1992; 34:509.
24. Ahmad S. Omeprazole-warfarin interaction. South Med J 1991; 84:674.
25. Laine L, Ahnen D, McClain C, et al. Review article: potential gastrointestinal effects of long-
term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther 2000; 14:651.
26. Freedberg DE, Kim LS, Yang YX. The Risks and Benefits of Long-term Use of Proton Pump
Inhibitors: Expert Review and Best Practice Advice From the American Gastroenterological
Association. Gastroenterology 2017; 152:706.
27. Ip S, Bonis P, Tatsioni A, et al. Comparative Effectiveness of Management Strategies for Gast
roesophageal Reflux Disease. Evidence Report/Technology Assessment No. 1. (Prepared by
Tufts-New England Medical Center. Evidence-based Practice Center under Contract No. 290-
02-0022.) Rockville, MD: Agency for Healthcare Research and Quality. December 2005 www.
[Link]/reports/[Link] (Accessed on December 05, 2007).
28. Wolfe MM, Lowe RC. Investing in the future of GERD. J Clin Gastroenterol 2007; 41:S209.
29. De Graef J, Woussen-Colle MC. Influence of the stimulation state of the parietal cells on the
inhibitory effect of omeprazole on gastric acid secretion in dogs. Gastroenterology 1986;
91:333.
30. Nelson WW, Vermeulen LC, Geurkink EA, et al. Clinical and humanistic outcomes in patients
with gastroesophageal reflux disease converted from omeprazole to lansoprazole. Arch
Intern Med 2000; 160:2491.
31. Björnsson E, Abrahamsson H, Simrén M, et al. Discontinuation of proton pump inhibitors in
patients on long-term therapy: a double-blind, placebo-controlled trial. Aliment Pharmacol
Ther 2006; 24:945.
32. Inadomi JM, Jamal R, Murata GH, et al. Step-down management of gastroesophageal reflux
disease. Gastroenterology 2001; 121:1095.
33. Naggie S, Miller BA, Zuzak KB, et al. A case-control study of community-associated
Clostridium difficile infection: no role for proton pump inhibitors. Am J Med 2011;
124:276.e1.
34. Howell MD, Novack V, Grgurich P, et al. Iatrogenic gastric acid suppression and the risk of
nosocomial Clostridium difficile infection. Arch Intern Med 2010; 170:784.
35. Aseeri M, Schroeder T, Kramer J, Zackula R. Gastric acid suppression by proton pump
inhibitors as a risk factor for clostridium difficile-associated diarrhea in hospitalized
patients. Am J Gastroenterol 2008; 103:2308.
36. Vaishnavi C. Established and potential risk factors for Clostridum difficile infection. Indian J
Med Microbiol 2009; 27:289.
37. Dial S, Alrasadi K, Manoukian C, et al. Risk of Clostridium difficile diarrhea among hospital
inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ 2004;
171:33.
38. Cunningham R, Dale B, Undy B, Gaunt N. Proton pump inhibitors as a risk factor for
Clostridium difficile diarrhoea. J Hosp Infect 2003; 54:243.
39. Dial S, Delaney JA, Barkun AN, Suissa S. Use of gastric acid-suppressive agents and the risk
of community-acquired Clostridium difficile-associated disease. JAMA 2005; 294:2989.
40. Leonard J, Marshall JK, Moayyedi P. Systematic review of the risk of enteric infection in
patients taking acid suppression. Am J Gastroenterol 2007; 102:2047.
41. Kwok CS, Arthur AK, Anibueze CI, et al. Risk of Clostridium difficile infection with acid
suppressing drugs and antibiotics: meta-analysis. Am J Gastroenterol 2012; 107:1011.
42. Janarthanan S, Ditah I, Adler DG, Ehrinpreis MN. Clostridium difficile-associated diarrhea
and proton pump inhibitor therapy: a meta-analysis. Am J Gastroenterol 2012; 107:1001.
43. Cao F, Chen CX, Wang M, et al. Updated meta-analysis of controlled observational studies:
proton-pump inhibitors and risk of Clostridium difficile infection. J Hosp Infect 2018; 98:4.
44. Neal KR, Scott HM, Slack RC, Logan RF. Omeprazole as a risk factor for campylobacter
gastroenteritis: case-control study. BMJ 1996; 312:414.
45. Kader SA, Mansour AM, Mohran Z, et al. A study on the relation between proton pump
inhibitor and gastric giardiasis. J Egypt Soc Parasitol 1998; 28:149.
46. Reynaert H, Fernandes E, Bourgain C, et al. Proton-pump inhibition and gastric giardiasis: a
causal or casual association? J Gastroenterol 1995; 30:775.
47. García Rodríguez LA, Ruigómez A, Panés J. Use of acid-suppressing drugs and the risk of
bacterial gastroenteritis. Clin Gastroenterol Hepatol 2007; 5:1418.
48. Garcia Rodríguez LA, Ruigómez A. Gastric acid, acid-suppressing drugs, and bacterial
gastroenteritis: how much of a risk? Epidemiology 1997; 8:571.
49. Prag C, Prag M, Fredlund H. Proton pump inhibitors as a risk factor for norovirus infection.
Epidemiol Infect 2017; 145:1617.
50. Tariq R, Singh S, Gupta A, et al. Association of Gastric Acid Suppression With Recurrent
Clostridium difficile Infection: A Systematic Review and Meta-analysis. JAMA Intern Med
2017.
51. Keszthelyi D, Jansen SV, Schouten GA, et al. Proton pump inhibitor use is associated with an
increased risk for microscopic colitis: a case-control study. Aliment Pharmacol Ther 2010;
32:1124.
52. Law EH, Badowski M, Hung YT, et al. Association Between Proton Pump Inhibitors and
Microscopic Colitis. Ann Pharmacother 2017; 51:253.
53. Verhaegh BP, de Vries F, Masclee AA, et al. High risk of drug-induced microscopic colitis
with concomitant use of NSAIDs and proton pump inhibitors. Aliment Pharmacol Ther
 2016; 43:1004.
54. Freston JW. Omeprazole, hypergastrinemia, and gastric carcinoid tumors. Ann Intern Med
1994; 121:232.
55. Klinkenberg-Knol EC, Nelis F, Dent J, et al. Long-term omeprazole treatment in resistant
gastroesophageal reflux disease: efficacy, safety, and influence on gastric mucosa.
Gastroenterology 2000; 118:661.
56. van Soest EM, van Rossum LG, Dieleman JP, et al. Proton pump inhibitors and the risk of
colorectal cancer. Am J Gastroenterol 2008; 103:966.
57. Kuipers EJ, Lundell L, Klinkenberg-Knol EC, et al. Atrophic gastritis and Helicobacter pylori
infection in patients with reflux esophagitis treated with omeprazole or fundoplication. N
Engl J Med 1996; 334:1018.
58. Lundell L, Miettinen P, Myrvold HE, et al. Lack of effect of acid suppression therapy on
gastric atrophy. Nordic Gerd Study Group. Gastroenterology 1999; 117:319.
59. Willems RPJ, van Dijk K, Ket JCF, Vandenbroucke-Grauls CMJE. Evaluation of the Association
Between Gastric Acid Suppression and Risk of Intestinal Colonization With Multidrug-
Resistant Microorganisms: A Systematic Review and Meta-analysis. JAMA Intern Med 2020;
180:561.
60. Xia B, Yang M, Nguyen LH, et al. Regular Use of Proton Pump Inhibitor and the Risk of
Inflammatory Bowel Disease: Pooled Analysis of 3 Prospective Cohorts. Gastroenterology
2021; 161:1842.
61. Hess MW, Hoenderop JG, Bindels RJ, Drenth JP. Systematic review: hypomagnesaemia
induced by proton pump inhibition. Aliment Pharmacol Ther 2012; 36:405.
62. Cheungpasitporn W, Thongprayoon C, Kittanamongkolchai W, et al. Proton pump inhibitors
linked to hypomagnesemia: a systematic review and meta-analysis of observational
studies. Ren Fail 2015; 37:1237.
63. Hoorn EJ, van der Hoek J, de Man RA, et al. A case series of proton pump inhibitor-induced
hypomagnesemia. Am J Kidney Dis 2010; 56:112.
64. Hansen BA, Bruserud Ø. Hypomagnesemia as a potentially life-threatening adverse effect
of omeprazole. Oxf Med Case Reports 2016; 2016:147.
65. [Link]
ducts/[Link] (Accessed on March 02, 2011).
66. Recker RR. Calcium absorption and achlorhydria. N Engl J Med 1985; 313:70.
67. Tuukkanen J, Väänänen HK. Omeprazole, a specific inhibitor of H+-K+-ATPase, inhibits bone
resorption in vitro. Calcif Tissue Int 1986; 38:123.
68. Mizunashi K, Furukawa Y, Katano K, Abe K. Effect of omeprazole, an inhibitor of H+,K(+)-
ATPase, on bone resorption in humans. Calcif Tissue Int 1993; 53:21.
69. Khalili H, Huang ES, Jacobson BC, et al. Use of proton pump inhibitors and risk of hip
fracture in relation to dietary and lifestyle factors: a prospective cohort study. BMJ 2012;
344:e372.
70. [Link]
ducts/[Link] (Accessed on June 02, 2010).
71. Marcuard SP, Albernaz L, Khazanie PG. Omeprazole therapy causes malabsorption of
cyanocobalamin (vitamin B12). Ann Intern Med 1994; 120:211.
72. Lam JR, Schneider JL, Zhao W, Corley DA. Proton pump inhibitor and histamine 2 receptor
antagonist use and vitamin B12 deficiency. JAMA 2013; 310:2435.
73. McColl KE. Effect of proton pump inhibitors on vitamins and iron. Am J Gastroenterol 2009;
104 Suppl 2:S5.
74. Hutchinson C, Geissler CA, Powell JJ, Bomford A. Proton pump inhibitors suppress
absorption of dietary non-haem iron in hereditary haemochromatosis. Gut 2007; 56:1291.
75. Sarzynski E, Puttarajappa C, Xie Y, et al. Association between proton pump inhibitor use and
anemia: a retrospective cohort study. Dig Dis Sci 2011; 56:2349.
76. Ajmera AV, Shastri GS, Gajera MJ, Judge TA. Suboptimal response to ferrous sulfate in iron-
deficient patients taking omeprazole. Am J Ther 2012; 19:185.
77. Lam JR, Schneider JL, Quesenberry CP, Corley DA. Proton Pump Inhibitor and Histamine-2
Receptor Antagonist Use and Iron Deficiency. Gastroenterology 2017; 152:821.
78. Sharma VR, Brannon MA, Carloss EA. Effect of omeprazole on oral iron replacement in
patients with iron deficiency anemia. South Med J 2004; 97:887.
79. Sampathkumar K, Ramalingam R, Prabakar A, Abraham A. Acute interstitial nephritis due to
proton pump inhibitors. Indian J Nephrol 2013; 23:304.
80. Ra A, Tobe SW. Acute interstitial nephritis due to pantoprazole. Ann Pharmacother 2004;
38:41.
81. Geevasinga N, Coleman PL, Webster AC, Roger SD. Proton pump inhibitors and acute
interstitial nephritis. Clin Gastroenterol Hepatol 2006; 4:597.
82. Muriithi AK, Leung N, Valeri AM, et al. Biopsy-proven acute interstitial nephritis, 1993-2011:
a case series. Am J Kidney Dis 2014; 64:558.
83. Xie Y, Bowe B, Li T, et al. Proton Pump Inhibitors and Risk of Incident CKD and Progression
to ESRD. J Am Soc Nephrol 2016; 27:3153.
84. Lazarus B, Chen Y, Wilson FP, et al. Proton Pump Inhibitor Use and the Risk of Chronic
Kidney Disease. JAMA Intern Med 2016; 176:238.
85. Kuo HW, Tsai SS, Tiao MM, et al. Analgesic use and the risk for progression of chronic
kidney disease. Pharmacoepidemiol Drug Saf 2010; 19:745.
86. Gooch K, Culleton BF, Manns BJ, et al. NSAID use and progression of chronic kidney disease.
Am J Med 2007; 120:280.e1.
87. Klatte DCF, Gasparini A, Xu H, et al. Association Between Proton Pump Inhibitor Use and
Risk of Progression of Chronic Kidney Disease. Gastroenterology 2017; 153:702.
88. González-Pérez A, Martínez-Domínguez SJ, Lanas Á, et al. Proton Pump Inhibitor Use and
Worsening Kidney Function: A Retrospective Cohort Study Including 122,606 Acid-
Suppressing Users. J Gen Intern Med 2025; 40:818.
89. Aggarwal N. Drug-Induced Subacute Cutaneous Lupus Erythematosus Associated with
Proton Pump Inhibitors. Drugs Real World Outcomes 2016; 3:145.
90. [Link]
[Link] (Accessed on November 09, 2016).
91. [Link] (Accessed on November 09, 201
6).
92. Alamario CV, Chey WD, Spiegel BMR. Increased Risk of COVID-19 Among Users of Proton Pu
mp Inhibitors. AM J Gastro. 2020 [in press]. [Link]
0-1811_R1(PUBLISH%20AS%20WEBPART).pdf (Accessed on July 13, 2020).
93. Lee SW, Ha EK, Yeniova AÖ, et al. Severe clinical outcomes of COVID-19 associated with
proton pump inhibitors: a nationwide cohort study with propensity score matching. Gut
2021; 70:76.
94. Haenisch B, von Holt K, Wiese B, et al. Risk of dementia in elderly patients with the use of
proton pump inhibitors. Eur Arch Psychiatry Clin Neurosci 2015; 265:419.
95. Gomm W, von Holt K, Thome F, et al. Association of proton pump inhibitors with risk of
dementia. JAMA Neurol 2016; epub.
96. Lochhead P, Hagan K, Joshi AD, et al. Association Between Proton Pump Inhibitor Use and
Cognitive Function in Women. Gastroenterology 2017; 153:971.
97. Batchelor R, Gilmartin JF, Kemp W, et al. Dementia, cognitive impairment and proton pump
inhibitor therapy: A systematic review. J Gastroenterol Hepatol 2017; 32:1426.
98. Goldstein FC, Steenland K, Zhao L, et al. Proton Pump Inhibitors and Risk of Mild Cognitive
Impairment and Dementia. J Am Geriatr Soc 2017; 65:1969.
 99. Khan MA, Yuan Y, Iqbal U, et al. No Association Linking Short-Term Proton Pump Inhibitor
Use to Dementia: Systematic Review and Meta-analysis of Observational Studies. Am J
Gastroenterol 2020; 115:671.
100. Gulmez SE, Holm A, Frederiksen H, et al. Use of proton pump inhibitors and the risk of
community-acquired pneumonia: a population-based case-control study. Arch Intern Med
2007; 167:950.
101. Laheij RJ, Sturkenboom MC, Hassing RJ, et al. Risk of community-acquired pneumonia and
use of gastric acid-suppressive drugs. JAMA 2004; 292:1955.
102. Sarkar M, Hennessy S, Yang YX. Proton-pump inhibitor use and the risk for community-
acquired pneumonia. Ann Intern Med 2008; 149:391.
103. Eom CS, Jeon CY, Lim JW, et al. Use of acid-suppressive drugs and risk of pneumonia: a
systematic review and meta-analysis. CMAJ 2011; 183:310.
104. Jena AB, Sun E, Goldman DP. Confounding in the association of proton pump inhibitor use
with risk of community-acquired pneumonia. J Gen Intern Med 2013; 28:223.
105. Freedberg DE, Abrams JA. Does confounding explain the association between PPIs and
Clostridium difficile-related diarrhea? Am J Gastroenterol 2013; 108:278.
106. Myles PR, Hubbard RB, McKeever TM, et al. Risk of community-acquired pneumonia and
the use of statins, ace inhibitors and gastric acid suppressants: a population-based case-
control study. Pharmacoepidemiol Drug Saf 2009; 18:269.
107. Filion KB, Chateau D, Targownik LE, et al. Proton pump inhibitors and the risk of
hospitalisation for community-acquired pneumonia: replicated cohort studies with meta-
analysis. Gut 2014; 63:552.
108. Xie Y, Bowe B, Li T, et al. Risk of death among users of Proton Pump Inhibitors: a
longitudinal observational cohort study of United States veterans. BMJ Open 2017;
7:e015735.
Topic 5 Version 62.0
GRAPHICS

Pharmacokinetic properties of proton pump inhibitors in adults

Time
Regimen Oral to Cmax AUC0-24
Agent
tested bioavailability peak (micrograms/mL) (mg•h/L)
(hours)
Dexlansoprazole 30 mg May be increased 1 to 2 0.7 3.3
once daily if taken with food (peak 1)
4 to 5
(peak 2)

Esomeprazole 20 mg 64% (single 1 to 1.6 2.1 (micromol/L) 4.2

once daily dose); (micromol•h/L)
90% (after
multiple doses if
taken on an
empty stomach;
bioavailability is
reduced by
approximately
50% if taken with
food)
Lansoprazole 30 mg >80% (taken on 1.5 to 3 0.5 to 1.0 3.2
once daily an empty
stomach;
absorption is
reduced by
approximately 50
to 70% if taken
with food)
Omeprazole 20 mg 30 to 45% (single 0.5 to 0.7 3.3
once daily dose) 3.5
(delayed Varies by
release formulation;
capsule) absorption is
significantly
increased after
multiple doses
 Pantoprazole 40 mg Approximately 2.5 2.5 4.8 (range 1.4
once daily 77% to 13.3)

Rabeprazole 20 mg Approximately 2 to 5 0.4 to 0.48 0.9

once daily 52% (delayed
up to 4
hours if
taken
with
high fat
meal)

AUC0-24: cumulative systemic drug exposure as measured by the area under the plasma concentration
versus time curve over 24 hours; Cmax: maximum plasma concentration; pKa: acid dissociation constant
transformed by negative log; PPI: proton pump inhibitor.
* Reported half-lives of 1 to 2 hours refer to conversion of the parent prodrug to active (thiophilic
sulfenamide) form; half-life of the active form is considerably longer. The duration of antisecretory effect
of PPIs exceeds that predicted by half-life due to irreversible binding at site of action (ie, parietal proton
pumps).
¶ PPIs are converted to their active form (ie, protonated) when pH of parietal cell is lower than pKa of the
individual PPI (ie, in presence of gastric acidity). For detail, refer to accompanying text.
Δ Drug metabolism via hepatic CYP2C19 enzymes is polymorphic; thus, PPI systemic exposure (AUC0-24)
can be increased several (ie, 2 to 12) times in patients who are intermediate or poor metabolizers
compared with those who are extensive metabolizers (ie, most patients). Up to 20 to 30% of persons
within certain South and East Asian populations are CYP2C19 poor metabolizer phenotypes. [1]

Reference:
1. Koopmans AB, Braakman MH, Vinkers DJ, et al. Meta-analysis of probability estimates of worldwide variation of CYP2D6
and CYP2C19. Transl Psychiatry 2021; 11:141.
Data from:
1. United States prescribing information available at US National Library of Medicine.
[Link] (Accessed on January 17, 2023).
2. UpToDate Lexidrug. More information available at [Link]

Graphic 72598 Version 10.0

Selected drug interactions of proton pump inhibitors (PPIs) by mechanism

Interacting
Effect Approach to management
medication(s)
Mechanism: Decreased oral bioavailability of co-medication due to PPI modulation of gastric
pH
Posaconazole These specific azole formulations have Consider use of a different formulatio
suspension, decreased oral bioavailability when of these azoles that do not interact
itraconazole coadministered with medications that with PPIs (eg, posaconazole delayed-
capsules (Sporanox elevate gastric pH, particularly PPIs release tablets or itraconazole oral
brand) solution).
(NOTE: Voriconazole
interaction is listed
in the following
section)
Capecitabine Inconsistent evidence of diminished In patients receiving a capecitabine-
capecitabine efficacy potentially due to containing regimen, consider use of
impaired dissolution and absorption alternatives to PPIs where appropriate
Mycophenolate Impaired absorption of Monitor clinical effect and
mofetil mycophenolate mofetil; decreased mycophenolic acid levels (where
bioavailability by 25% or more applicable); enteric-coated
mycophenolate sodium formulation
appears less likely to interact with
PPIs.
HCV direct acting Impaired absorption and decreased In general, avoid use of a PPI in
antivirals: ledipasvir- serum concentrations of ledipasvir or patients receiving ledipasvir or
and velpatasvir- velpatasvir velpatasvir. Refer to UpToDate topic
containing regimens review of direct-acting antivirals for
hepatitis C infection.
HIV antiretrovirals: Impaired dissolution and absorption; In general, the use of atazanavir and
atazanavir, significantly decreased oral rilpivirine is avoided in patients
rilpivirine (orally bioavailability requiring PPI therapy.
administered)
Immune checkpoint Decreased clinical response Refer to UpToDate clinical topics.
inhibitors *
Tyrosine kinase Impaired dissolution and absorption; Refer to UpToDate clinical topics.
inhibitors ¶ significantly decreased oral
bioavailability
Mechanism: Altered metabolism of co-medication due to PPI inhibition of cytochrome P450
2C19 metabolism
 Cilostazol Omeprazole increased the AUC0-24 of In patients receiving omeprazole or
cilostazol and its active metabolites up esomeprazole, consider limiting the
to 69% dose of cilostazol to 50 mg twice daily;
other PPIs appear less likely to
interact.
Citalopram, Omeprazole increased the AUC0-24 of In patients receiving omeprazole or
escitalopram the active form of citalopram (ie, esomeprazole, consider limiting the
escitalopram) by up to 90% dose of citalopram to 20 mg daily or
escitalopram to 10 mg daily; other
PPIs appear less likely to interact.
Clopidogrel Omeprazole may decrease conversion We advise patients requiring PPI
of clopidogrel to its active form and therapy who take clopidogrel not to
diminish antiplatelet efficacy; however, use omeprazole or esomeprazole and
a clinically relevant effect is not well to take the PPI in the morning and
established clopidogrel at least four hours later,
eg, at bedtime. Rabeprazole or
pantoprazole appear less likely to
interact. Refer to UpToDate topic
review of clopidogrel resistance and
treatment failure.
Voriconazole PPIs can moderately increase serum Monitor for signs/symptoms of
(NOTE: Itraconazole concentrations of voriconazole voriconazole toxicity; refer to
and posaconazole UpToDate topic review of
interactions are pharmacology of azoles.
listed above)
Mechanism uncertain
Methotrexate (high Delayed methotrexate elimination Consider temporarily interrupting PPI
dose) potentially leading to methotrexate therapy in patients receiving high-dos
toxicity methotrexate. Monitor for increased
methotrexate toxicity and levels;
adjust therapy as appropriate. Refer to
UpToDate topic review of therapeutic
use and toxicity of high-dose
methotrexate.
Warfarin Lansoprazole and omeprazole Monitor for increased INR and
associated with a modest increase in anticoagulant effect; pantoprazole and
serum concentrations of R-warfarin (ie, rabeprazole appear less likely to
less active warfarin enantiomer) increase INR.

This table lists potentially significant effects of PPI use on co-medications. Although PPIs themselves are
rarely the target of clinically significant interactions, UpToDate suggests avoiding their administration at
the same time as anti-secretory agents (eg, H2RAs) due to decreased acid inhibitory effects. In addition,
strong inducers of CYP2C19 (rifampin) may result in decreased efficacy of omeprazole, esomeprazole,
and lansoprazole.
NOTE: This table does not list all possible PPI interactions. For specific interactions and approach to
management, refer to UpToDate clinical topics and drug interactions program.

AUC0-24: area under curve of serum concentration versus time over 24 hours; H2RA: histamine-2 receptor
antagonist (eg, famotidine); PPI: proton pump inhibitor; TKI: tyrosine kinase inhibitor.
* Immune checkpoint inhibitors that can interact with PPIs include: atezolizumab, avelumab, cemiplimab,
dostarlimab, durvalumab, ipilimumab, nivolumab, pembrolizumab.
¶ TKIs that can interact with PPIs include: acalabrutinib capsules (acalabrutinib tablets do not interact
with PPIs), bosutinib, dacomitinib, erlotinib, gefitinib, infigratinib, neratinib, nilotinib, pazopanib, and
pexidartinib.

Data from: UpToDate Lexidrug. More information available at [Link]

Graphic 53616 Version 6.0

Contributor Disclosures
M Michael Wolfe, MD No relevant financial relationship(s) with ineligible companies to disclose. Loren
Laine, MD Consultant/Advisory Boards: Medtronic [Endoscopic hemostatic therapy]; Phathom
Pharmaceuticals [Gastric acid inhibition medication]. Other Financial Interest: Biohaven [Data safety
monitoring board]; Celgene/Bristol Myers Squibb [Data safety monitoring board]; Intercept [Adjudication
committee to assess liver events in clinical trials]; Merck [Data Safety Monitoring Board]; Pfizer
[Adjudication committee to adjudicate liver events in clinical trials]. All of the relevant financial
relationships listed have been mitigated. Claire Meyer, MD No relevant financial relationship(s) with
ineligible companies to disclose. Sara Swenson, MD No relevant financial relationship(s) with ineligible
companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
Conflict of interest policy