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Overview and comparison of the proton pump inhibitors for the treatment of acid-related disorders Author M Michael Wolfe, MD Section Editor Mark Feldman, MD, MACP, AGAF, FACG Deputy Editor Shilpa Grover, MD, MPH, AGAF All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Apr 2017. | This topic last updated: Apr 04, 2017. INTRODUCTION — The introduction of proton pump inhibitors (PPIs)

in the late 1980s optimized the medical treatment of acid-related disorders. In addition, PPIs have allowed clinicians to evaluate the role of gastric acid in several extraesophageal manifestations of gastroesophageal reflux disease, including noncardiac chest pain and tracheopulmonary diseases [1-4].

This topic review will provide an overview of the pharmacology and clinical efficacy of the proton pump inhibitors for a variety of acid-related disorders and address issues related to the comparison of these agents. It will also discuss issues related to stopping these medications. The pharmacology of other drugs used in the treatment of acid-related diseases is presented separately. (See "Antiulcer medications: Mechanism of action, pharmacology, and side effects".)

PHYSIOLOGY OF ACID SECRETION — The normal human stomach contains approximately one billion parietal cells that secrete 0.16 M hydrochloric acid (HCl) into the gastric lumen in response to three principal physiological stimuli: acetylcholine, histamine, and gastrin (figure 1). (See "Physiology of gastric acid secretion".)

● Acetylcholine is the chief neurocrine transmitter, which is released by vagal postganglionic neurons and appears to stimulate hydrogen ion generation directly via a parietal cell muscarinic M3 receptor. ● Histamine is the primary paracrine transmitter that binds to H2-specific receptors on the parietal cell basolateral membrane, while gastrin, secreted from antral G-cells, comprises the primary endocrine pathway. ● Gastrin stimulates the generation of hydrogen ions both directly and indirectly, the latter by stimulating histamine secretion from enterochromaffin-like (ECL) cells in the proximate vicinity of parietal cells. Although interactions among these three pathways are coordinated to promote or inhibit hydrogen ion generation, histamine appears to represent the dominant route as gastrin stimulates acid secretion principally by promoting the release of histamine from ECL cells [5]. Because of the dominance of this pathway, H2-receptor blockade became the principal means by which acid secretion was inhibited in

the mid-1970s.

During the unstimulated (basal) state, a large percentage of the parietal cell volume is occupied by tubulovesicles, which are elongated tubes with smooth surface membranes, and by the secretory canaliculus, a small invaginated area of the apical membrane. Upon meal stimulation, these tubulovesicles decrease in number and become transformed into microvilli around the secretory canaliculus, which serves to greatly expand the surface area of the parietal cell in preparation for the active transport of large quantities of hydrogen ions against a 3,000,000:1 ionic gradient [5]. Hydrogen ions are actively secreted in exchange for potassium ions by means of an H-K-ATPase, the so-called proton pump located on the apical surface of the parietal cell. H-K-ATPase comprises the final pathway by which HCl is secreted into the gastric lumen, where it serves to both hydrolyze dietary protein and maintain a sterile environment.

Structure of the parietal cell H-K-ATPase — The parietal cell H-K-ATPase is a member of the family of ion-motive transport enzymes that includes F1, V, and P ATPases. The last is further divided into P1 or P2 types based either on the transport of transition metals (P1) or small cations (P2) or alternatively on the number of transmembrane segments [1]. The P2 family possesses one catalytic subunit with 10 transmembrane segments and a beta subunit with one transmembrane segment, and exists as two principal forms: H-K-ATPase and Na-K-ATPase. These isoforms are tightly bound to a beta-subunit that is smaller than the catalytic alpha-subunit and are glycosylated to a different extent depending upon the isoform.

PHARMACOLOGY OF THE PROTON PUMP INHIBITORS — The recognition that H-K-ATPase was the final step of acid secretion culminated in the development of a class of drugs, the proton pump inhibitors (PPIs), which are targeted at inhibiting this enzyme. PPIs all share a common structural motif, but vary in terms of their substitutions. They are all weak protonatable pyridines, with a pKa of about 4.0 for omeprazole/esomeprazole and lansoprazole/dexlansoprazole, about 3.9 for pantoprazole, and about 5.0 for rabeprazole (table 1). As a result, they accumulate specifically and selectively in the secretory canaliculus, the highly acid space of the parietal cell [1]. Within that space, PPIs undergo an acid catalyzed conversion to a reactive species, the thiophilic sulfenamide, which are permanent cations.

The rate of conversion varies among the compounds and is inversely

proportional to the pKa of the benzimidazole [6]: rabeprazole > omeprazole/esomeprazole = lansoprazole/dexlansoprazole > pantoprazole. 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 by the thiophilic sulfenamide results in a specific and long-lasting impairment of gastric acid secretion.

In vitro studies using rat microsomal membrane preparations containing H-K-ATPase have demonstrated that, in addition to cysteine 813, pantoprazole binds to cysteine 822, which is situated deeper in the membrane domain TM6 [7]. Recovery of acid secretion following pantoprazole was prolonged compared to other PPIs possibly as a result of its binding to cysteine 822. Neither in vivo nor clinical studies have been performed to determine whether these observations are clinically relevant.

The PPIs are the most potent inhibitors of gastric acid secretion available [1]. They 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]. PPIs should not be given concomitantly with H2-antagonists, prostaglandins, somatostatin analogues (eg, octreotide), or other antisecretory agents because of the marked reduction in their acid inhibitory effects when administered simultaneously [1,8]. An H2 antagonist can be used with a PPI provided that there is a sufficient time interval between administration of the H2 antagonist and the PPI (although the precise minimal time interval has not been established). As an example, an H2 antagonist 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.

During meals, neither all parietal cells nor all proton pumps are active. 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.

Once-daily PPI dosing inhibits maximal acid output by about 66 percent after five days. 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]. Because of the delay in optimal acid inhibition, the initial use of twice-daily PPI dosing (for the first two to three days) may be helpful in achieving more rapid inhibition of gastric acid secretion. In addition to their delay in onset, and because PPI-derived thiophilic sulfenamides bind covalently to H-K-ATPase, the restoration of acid secretion will likewise be delayed, depending upon enzyme turnover and the biological reversibility of the disulfide bond. Maximal acid secretory capacity may not be restored for 24 to 48 hours after discontinuing PPIs [1].

Rebound acid hypersecretion — Rebound acid hypersecretion after withdrawal of PPIs is described separately. (See "Physiology of gastric acid secretion".)

TREATMENT OF ACID-RELATED DISORDERS — The PPIs are effective for treatment of all acid-related disorders. The following sections will summarize data demonstrating the efficacy of the PPIs in a variety of clinical settings. Detailed discussions on each of these disorders are also presented separately on the corresponding topic reviews.

Peptic ulcer disease — PPIs heal gastroduodenal ulcers more rapidly than H2-receptor antagonists. A meta-analysis comparing the healing of duodenal ulcers found that 20 mg of omeprazole every morning for four weeks was superior to both 300 mg of ranitidine and 800 mg of cimetidine, both administered at bedtime [9]. Similarly, another meta-analysis found that 30 mg of lansoprazole every morning healed significantly more ulcers than 300 mg of ranitidine and 40 mg of famotidine, both administered at bedtime [10]. The pooled healing rates were 60 and 85 percent for lansoprazole at two and four weeks, respectively, while the corresponding figures for the H2-antagonists were 40 and 75 percent. (See "Peptic ulcer disease: Management".)

Pantoprazole and rabeprazole have also demonstrated superior and accelerated ulcer healing compared with H2-antagonists [11,12]. The optimal duration of therapy with PPIs should be four and eight weeks for acute duodenal ulcer and gastric ulcer, respectively [12].

Eradication of Helicobacter pylori — The role of PPIs in treatment of Helicobacter pylori (H. pylori) is discussed separately. (See "Treatment regimens for Helicobacter pylori".)

Treatment and prevention of gastroduodenal ulcers associated with NSAIDs — A number of studies have demonstrated that the PPIs are more effective than H2 antagonists for healing gastroduodenal ulcers associated with nonsteroidal anti-inflammatory drugs (NSAIDs) when NSAIDs cannot be discontinued. PPIs also appear to be as or more effective than misoprostol. PPIs are also effective for primary prevention of NSAID-associated ulcers. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity".)

Zollinger-Ellison syndrome — The goal of therapy in individuals with Zollinger-Ellison syndrome (ZES) is surgical gastrinoma excision, which is possible in about 50 percent of those with sporadic disease. However, all patients with ZES require antisecretory therapy after the diagnosis is established and during tumor localization. (See "Management and prognosis of the Zollinger-Ellison syndrome (gastrinoma)".)

Treatment of gastroesophageal reflux disease — Numerous studies have documented the marked efficacy of PPIs in controlling symptoms of gastroesophageal reflux disease (GERD) and healing esophagitis. Comparative trials show a clear advantage of PPIs over H2-antagonists. As a general rule, doses of PPIs recommended by the manufacturers all administered before breakfast will relieve symptoms and heal esophagitis in approximately 85 to 90 percent of patients. (See "Medical management of gastroesophageal reflux disease in adults".)

At least 10 to 15 percent of patients with GERD respond suboptimally to PPIs, particularly those with more advanced grades of esophagitis. The reasons for such failures are not entirely clear but may often be due to their suboptimal administration [13]. Another potential reason stems from the variable antisecretory properties of PPIs based on individual pharmacogenomic differences [14]. Polymorphisms in the CYP2C19 gene, which encodes the cytochrome P450 isoenzyme that metabolizes different PPI preparations, are common in Asian and other

populations [14]. 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 GERD patients.

A careful history regarding the timing of PPI administration should be obtained in individuals who do not respond to PPIs [13]. As noted above, the optimal time is immediately before breakfast. Once the correct timing is established, a second dose of the PPI (before the evening meal) may be helpful. (See "Approach to refractory gastroesophageal reflux disease in adults".)

New PPI prodrugs with longer biological half-lives are under development and may address some of the present shortcomings of PPIs. Like all PPIs, these prodrugs are converted to active thiophilic sulfenamides within the highly acidic milieu of the secretory canaliculus [15]. The substitution of a benzimidazole with an imidazopyridine moiety [4-6,15] reduces the rate of metabolism, increasing both the plasma and biological half-lives significantly, the former from approximately 60 to 90 minutes to 9.3 hours [15]. The ultimate benefit of such preparations, if any, will require careful examination.

Maintenance therapy — Most patients with GERD, particularly those with grade III and IV esophagitis, will relapse once therapy is discontinued [16]. A landmark study of maintenance therapy compared five regimens: ranitidine, cisapride (no longer available by prescription in the United States and several other countries), ranitidine plus cisapride, omeprazole, and omeprazole plus cisapride [17]. All patients had esophagitis on initial endoscopy and were treated with omeprazole 40 mg daily for eight weeks before initiating one of the maintenance regimens. After 12 months of treatment, remission was maintained in 80 to 90 percent of the omeprazole groups, versus 49 to 60 percent in the other groups. This study demonstrated the superiority of PPIs in maintaining remission and further showed that effective prophylactic doses are generally the same as those required for initial healing. (See "Medical management of gastroesophageal reflux disease in adults".)

Complications of GERD — PPIs are effective in treating a number of complications related to GERD:

● Esophageal strictures – PPIs decrease the eventual number of esophageal dilations required to relieve dysphagia more effectively than H2 antagonists [18,19]. (See "Complications of gastroesophageal reflux in adults".) ● Barrett's esophagus – PPIs are frequently used in patients with Barrett's metaplasia, although no studies have shown unequivocal regression of Barrett's esophagus or a decrease in the risk of esophageal malignancy with any medical or surgical therapy. PPI doses are generally the same as those used for healing esophagitis without metaplasia. Individuals with Barrett's metaplasia require continued surveillance for the development of dysplasia or frank adenocarcinoma. (See "Barrett's esophagus: Surveillance and management".) ● Extraesophageal symptoms – A number of extraesophageal symptoms can occur as a result of acid reflux. As an example, acid reflux is the most common cause of noncardiac chest pain, accounting for 25 to 50 percent of cases in several studies [20]. The association of GERD with other extraesophageal disorders such as idiopathic hoarseness, chronic laryngitis, asthma, and cough has also been suggested in a number of studies. However, because these disorders and GERD are very common, an etiologic relationship has been difficult to establish unequivocally. (See "Complications of gastroesophageal reflux in adults".) See other appropriate topic reviews. COMPARISON OF PROTON PUMP INHIBITORS — The preceding discussion underscores that the proton pump inhibitors (PPIs) are similar in structure and mechanism of action, although different doses of the available PPIs are recommended (table 2).

The PPIs differ in their pKa, bioavailability, peak plasma levels, and route of excretion, with lansoprazole/dexlansoprazoleand pantoprazole being the most bioavailable and achieving the highest plasma levels (table 1). Because of its higher pKa, rabeprazole possesses a slightly faster onset of action, while pantoprazole is often touted as being the most "gastro-specific" because of its binding only to cysteine residues 813 and 822 within the alpha-subunit of the proton pump. However, the clinical relevance of these differences has not been established.

A number of studies have compared the various proton pump inhibitors to one another [21-34]. While some differences have been reported, the magnitude of differences has been small and of uncertain clinical importance. In particular, the degree to which any of the reported differences would justify the selection of one versus another PPI, particularly when considering cost-effectiveness, is unclear [33]. One trial that looked at cost-effectiveness found the following:

● In the randomized trial, 1564 patients with GERD symptoms despite treatment with a PPI or H2 receptor antagonist were assigned to switch to esomeprazole or to continue on their current medication(s) [35]. At baseline, 73 percent of the patients were taking a PPI. After four weeks of treatment, patients who switched to esomeprazole had a statistically higher mean quality-adjusted life month (QALM) gain compared with patients who did not switch (0.86 versus 0.82 QALM). The mean cost in Canadian dollars was $763 per QALM gained. However, the mean QALM gain was lower among patients on a PPI at baseline (0.84 for those switched to esomeprazole versus 0.81 for the controls), and the mean cost per QALM gained was $1213. It is important to note that the advantage of switching to esomeprazole was quite small (an additional 0.03 to 0.04 QALMs gained compared with controls) and came at a significant cost. Importantly, most of the comparative trials evaluated doses of the various PPIs that have been approved by the United States Food and Drug Administration (FDA). However, the doses of various PPIs that would be considered pharmacologically equivalent have not been well established and thus it is possible that all the various PPIs could be equivalent when administered at certain doses. A systematic review of the various PPI comparisons prepared on behalf of the Agency for Healthcare Research and Quality is available on the internet [36].

A separate question is the effectiveness of substituting one PPI for another in patients who have stabilized on therapy. This issue is important since substitution may be required when health plans change their formulary based upon cost considerations. This issue was examined in a study involving 105 patients with GERD who had stabilized on omeprazole but were converted to lansoprazole in equivalent doses by their health plan [37]. A telephone assessment suggested that following conversion the mean symptom severity score increased significantly. Furthermore, 33 percent of patients consumed more over-the-counter heartburn medications, 13 percent changed

their diet more frequently due to heartburn, and overall patient satisfaction decreased significantly. These results should be interpreted cautiously since the study was uncontrolled and subject to a number of biases, which were acknowledged by the authors. As an example, patients could have been dissatisfied with the substitution since it may have been perceived as a cost-cutting measure; as a result, they may have been influenced to report negative outcomes on the self-reported questionnaire. Despite these limitations, the study suggests that the similar efficacy of PPIs that has been observed in controlled clinical trials may not necessarily translate into equivalent effectiveness when these drugs are substituted for one another.

Over-the-counter and on-demand PPIs — Two unpublished, randomized controlled trials led to the approval of omeprazole magnesium (Prilosec-OTC) for use without a prescription. The studies, involving a total of 1047 subjects with frequent heartburn, compared Prilosec-OTC once daily with placebo for 14 days. On day 14, significantly more patients taking omeprazole were free of heartburn (approximately 70 versus 43 percent). The incidence of heartburn was similar to placebo within five days of stopping the drug.

Other studies of "on-demand" use of PPIs have suggested they can help maintain symptom control better than placebo in patients with mild or no esophagitis [34,38-40]. However, the clinical endpoints of such "on-demand" trials have not defined success as timely, complete relief of heartburn, which could be considered the most important objective in patients with intermittent symptoms. Rather, they have compared overall assessments of heartburn and medication use at various time points.

Furthermore, heartburn control is less effective than with continuous therapy, even though intermittent dosing may be associated with greater overall satisfaction compared with regular use of a PPI [38]. A meta-analysis evaluated the rapidity of heartburn control with PPIs [41]. Complete heartburn relief occurred in approximately 30 percent of patients after their first PPI dose compared with 9 percent of patients receiving placebo (RR 0.41, 95% CI 0.28-0.58). The authors concluded that most patients will not have symptom relief after one to two days of PPI therapy. Most studies that the authors included assessed heartburn relief at 24 hours. The 21 percent benefit compared with placebo may be even less important clinically when considering that patients with intermittent symptoms seek rapid relief of heartburn (within minutes) and it is not clear what proportion of

patients achieve such timely relief after taking a PPI.

As noted in the discussions above, the pharmacokinetics of the PPIs suggest that they are best suited for long-term prevention of heartburn rather than for treatment of acute symptoms. However, labeling of Prilosec-OTC warns against its use for more than 14 days. Similar considerations apply to other PPIs targeted for the OTC market. Finally, a survey that compared PPI use by consumers with GERD with PPI use by those prescribed these drugs by physicians found that patients receiving prescription PPIs from a gastroenterologist were far more likely to be optimal users of the medication with a lower disease burden, while consumers were more likely to be suboptimal users with a higher disease burden [13].

Thus, the role of PPIs in the treatment of patients with troubling, intermittent heartburn is uncertain. H2 receptor antagonists may be better suited for this role. No studies have directly compared "on-demand" use of PPIs with H2RAs.

Three other issues related to the comparison of these drugs are relevant clinically: safety, convenience, and cost.

The long-term safety of these drugs has been best established with omeprazole since it was the first to become available clinically. These data suggest that its use for more than 15 years is safe, although some risks have been described. (See 'Safety' below.)

Differences in drug metabolism and drug interactions — While overall proton pump inhibitors are an extremely safe class of drugs, differences in their metabolism may lead to specific drug interactions.

As discussed above, some differences among the PPIs do exist with regard to the pKa, bioavailability, peak plasma levels, and route of excretion (table 1). In addition, PPIs are metabolized by somewhat different routes, which might affect their clinical efficacy in certain ethnic groups and potentially lead to differences in drug interactions [42].

PPIs are metabolized via hepatic cytochrome P450 enzymes, with CYP2C19 having the dominant role. However, the dominance of this route varies significantly among the PPIs. The activity of CYP2C19 is determined to some extent by gene polymorphism, and two known inactivating mutations which occur most commonly in Asian populations have been described [42]. Five percent of Caucasians are

homozygous for this mutation; as a result, the metabolism of drugs by this route may be delayed in these individuals. About two-thirds of Caucasians are homozygous for the wild type gene; such persons rapidly metabolize drugs, while heterozygotes are intermediate metabolizers.

Plasma levels of PPI correlate with their metabolism, and differences may contribute to dose requirements and clinical efficacy [42]. As an example, one study examined the effect of variable metabolism of omeprazole when using this agent to treat H. pylori in Japanese patients [42]. 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. Another report from Japan evaluated the efficacy of lansoprazole in the treatment of GERD [43]. Slow metabolizers were much more likely to be cured than heterozygotes and wild type homozygotes (85 versus 68 and 46 percent, respectively). The cure rate was only 16 percent in wild type homozygotes who had severe GERD. Furthermore, wild type homozygotes (rapid metabolizers) had the lowest plasma lansoprazole concentrations.

Although the presence of a CYP2C19 gene mutation may appear beneficial because of higher plasma levels, deleterious consequences may ensue. If this metabolic pathway becomes saturated, the isoenzyme may become a major target for interactions with many drugs, including warfarin, diazepam, clopidogrel and phenytoin (table 3). CYP3A4-mediated metabolism also may be activated under such conditions and may become the principal route of drug elimination. Furthermore, induction of CYP1A, another P450 isoenzyme, may occur in CYP2C19 deficient or saturated individuals, making them susceptible to interference with theophylline metabolism (table 3).

The specific P450 enzymes involved in PPI metabolism and the potential for interactions among these agents varies considerably (table 4) [44-50].

● Omeprazole and esomeprazole are metabolized largely via CYP2C19, and the potential for interactions thus appears to be the greatest among the PPIs. However, R-omeprazole is a more potent inhibitor of CYP2C19 than the S-enantiomer, and thus esomeprazole appears to interfere to a lesser extent with the metabolism of other drugs metabolized by this route than the racemic mixture comprising

omeprazole. ● While rabeprazole is also metabolized by this isoenzyme, it apparently possesses significant affinity for CYP3A4; in any event, very few interactions have been documented with this agent. ● Although lansoprazole/dexlansoprazole is a potent inhibitor of CYP2C19, as well as other cytochrome P450 isoforms, it is metabolized in vivo principally via CYP3A4, and as predicted, interactions with theophylline have been reported. ● Although the metabolism of pantoprazole primarily involves CYP2C19 O-demethylation, this step is followed rapidly by sulfate conjugation. As a result, significant CYP3A4 and CYP1A induction is not apparent, and this agent has the lowest potential for P450 metabolism and drug interactions. Despite these differences in drug metabolism, for the most part significant and clinically relevant interactions are uncommon. However, there is particular concern regarding the potential for interactions between PPIs and clopidogrel. Clinicians and patients should be cognizant of possible interactions. (See "Overview of the non-acute management of unstable angina and non-ST elevation myocardial infarction", section on 'Gastrointestinal prophylaxis'.)

None of the PPIs require dose-adjustment for hepatic or renal insufficiency. PPIs may decrease the absorption of certain HIV protease inhibitors. (See "Overview of antiretroviral agents used to treat HIV", section on 'Protease inhibitors (PIs)'.)

Convenience — Most of the PPIs are available in oral, delayed release formulations. An exception is Zegerid (a formulation of omeprazole-sodium bicarbonate), which is designed for immediate release. There appears to be little, if any, benefit from this formulation except possibly in the occasional patient unable to swallow pills or capsules; other choices under such circumstances include lansoprazole (Prevacid SoluTab) or intravenous PPIs.

Intravenous formulations — Pantoprazole and esomeprazole are the only PPIs available as an intravenous formulation in the United

States; intravenous omeprazole is used in other countries, and intravenous lansoprazole has been removed from the world market. Although intravenous PPIs have been approved for the treatment of erosive esophagitis in patients unable to tolerate oral treatment, they are more frequently used in management of patients with bleeding peptic ulcers and for the prevention of stress-related mucosal damage. (See "Overview of the treatment of bleeding peptic ulcers".)

Costs — A major issue related to the choice among the various PPIs is their relative costs. The costs to the patient and the health plan vary locally depending upon contracting and whether use of over-the-counter (rather than prescription) PPIs is required. In addition, most of the PPIs are now available in the generic form, which is generally less costly.

SAFETY — Maintenance antisecretory therapy is used in many patients, particularly those with gastroesophageal reflux disease. With the long-term use of any medication, drug safety becomes an important issue. The three main concerns regarding the long-term safety of proton pump inhibitors (PPIs) include the effects of prolonged hypochlorhydria and hypergastrinemia, and the possible association of PPIs with gastric atrophy. In particular, hypochlorhydria is of concern since it may predispose to infections and malabsorption. (See "Physiology of gastrin", section on 'Causes of hypergastrinemia'.)

After a critical review of all available safety data, a 2008 guideline on gastroesophageal reflux disease (GERD) management developed by the American Gastroenterological Association Institute found insufficient evidence to recommend for or against bone density studies, calcium supplementation, H. pylori screening, or any other routine precaution in patients taking proton pump inhibitors [51]. However, studies subsequent to that guideline continue to raise concerns about possible infectious complications, electrolyte disturbances, and metabolic bone disease associated with PPI use. PPIs should be used at the lowest possible dose and for shortest duration needed.

Infections — A concern with any form of gastric acid inhibition is an increased risk of enteric infections since gastric acidity normally protects against these infections. In addition, a reduction in gastric acid secretion permits pathogens to more easily colonize the upper gastrointestinal tract, which may predispose to pneumonia.

Clostridium difficile and other enteric infections — The best

documented association of PPI use with enteric infections has been with C. difficile diarrhea, even in patients not exposed to antibiotics [52-58]. C. difficile is an anaerobic organism that sporulates; acid-resistant spores are presumed to be the major vector of disease transmission. The role of potent acid suppression and the pathophysiologic mechanisms involved in increasing the risk of C. difficile by PPI use are unclear.

Three meta-analyses of observational studies have demonstrated an increased risk of C. difficile infections in patients treated with PPIs [59-61]. A 2012 meta-analysis of 42 observational studies that included 313,000 patients found that PPI use was significantly associated with an increased risk of both incident and recurrent C. difficile infection (odds ratio [OR] 1.7; 95% CI 1.5-2.9 and 2.5; 95% CI 1.2-5.4, respectively) [60]. However, significant heterogeneity was noted among the studies included in the meta-analysis. Both this study and a 2007 meta-analysis found that the risk of C. difficile infection was greater with PPIs than with H2 receptor antagonists [59,60]. (See "Clostridium difficile in adults: Epidemiology, microbiology, and pathophysiology", section on 'Gastric acid suppression'.)

The US Food and Drug Administration (FDA) has issued a safety alert encouraging providers to consider a diagnosis of C. difficile-associated disease in PPI users with persistent diarrhea [62]. Given the potential risk of C. difficile infection, the FDA has also recommended that providers prescribe the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

Associations with other enteric infections, including Campylobacter and Salmonella, have also been reported [63-66], but the magnitude of risk is unclear [63,67].

Pneumonia — The risk of pneumonia in PPI users may be increased due to a reduction in gastric acid secretion, permitting pathogens to more easily colonize the upper gastrointestinal tract. The increased risk has been seen with both community-acquired pneumonia (CAP) and health care associated pneumonia (HCAP) [68-70]. (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'.)

A meta-analysis of 31 studies found that patients taking PPIs or H2 receptor antagonists (H2RAs) were at increased risk for pneumonia,

with an odds ratio of 1.27 (95% CI 1.11-1.46) with PPIs and 1.22 (95% CI 1.09-1.36) with H2RAs [71]. One large case-control study found an increased risk of CAP only among patients who started a PPI within the previous 30 days and particularly in those who initiated therapy within the previous 48 hours [70]. The significance of this finding is uncertain since maximum anti-secretory effects take at least one week to develop.

While these 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 [72-74]. To overcome the limitations of prior studies, a 2013 meta-analysis included eight cohort studies with 4,238,504 new users of nonsteroidal anti-inflammatory drugs (NSAIDs) of which 96,870 were treated with PPIs prophylactically and 47,344 were treated with H2RAs [75]. On adjusted analysis, the use of PPIs or H2RAs was not associated with an increased risk of hospitalization for CAP during the six months following initiation of NSAIDs.

Malabsorption — Concern has been expressed regarding the effects of long-term PPI use on iron and vitamin B12 absorption, though any effects are generally mild, clinically insignificant, and addressed by supplement therapy [76]. On the other hand, magnesium and calcium malabsorption may be bigger problems, predisposing to hypomagnesia and metabolic bone disease.

Magnesium absorption — Hypomagnesemia due to reduced intestinal absorption has been described with PPI use [77]. In March 2011, the FDA issued a safety alert warning providers of the risk of hypomagnesemia in patients who have been on PPIs long-term (generally longer than one year) [78]. The FDA suggests that providers consider obtaining serum magnesium levels prior to starting a PPI in patients who are expected to be on the medication for long periods of time, or in patients who take PPIs in conjunction with other medications associated with hypomagnesemia (eg, digoxin or diuretics). The FDA also suggests that providers consider obtaining levels periodically in such patients while they are taking a PPI. (See "Causes of hypomagnesemia".)

Hip fracture and calcium malabsorption — Long-term use of PPIs may influence bone metabolism. Hypochlorhydria could theoretically reduce calcium absorption [79] and inhibit osteoclastic activity

[80,81], thereby decreasing bone density. A case-control trial suggested that long-term use of PPIs was associated with a slightly increased risk of hip fractures in those older than 50 years of age and that the magnitude of the risk increase was proportional to both PPI dose and duration of therapy [82]. In another case control study, excess fracture risk for PPI use was only present among persons with at least one other fracture risk factor [83]. However, in a prospective cohort study, chronic PPI use was not associated with osteoporosis or accelerated bone mineral density loss [84,85]. (See "Drugs that affect bone metabolism", section on 'Proton pump inhibitors'.)

A meta-analysis that included 11 cohort and case-control studies examined the risk of fractures associated with PPI use [86]. The 11 studies included 1,084,560 patients with 62,210 PPI users, 71,339 patients with hip fractures, 161,179 patients with any-site fractures, and 5728 patients with spine fractures. The risk of hip fracture was increased among PPI users compared with nonusers (relative risk [RR] 1.30, 95% CI 1.19-1.43). There was also an increased risk of spine fracture (RR 1.56, 95% CI 1.31-1.85) and any-site fracture (RR 1.16, 95% CI 1.02-1.32).

Subsequent to the meta-analysis, the Nurses' Health Study reported on the association of hip fracture with PPI use [87]. The study included 79,899 postmenopausal women with 565,786 person-years of follow-up. The absolute risk of hip fracture was 2.02 events per 1000 person-years among regular PPI users, compared with 1.51 events per 1000 person-years for nonusers. The risk of hip fracture was 36 percent higher among women who regularly used PPIs for at least two years compared with nonusers (adjusted hazard ratio [HR] 1.36; 95% CI 1.13-1.63). The difference was more pronounced in current and former smokers, where PPI use was associated with a 51 percent increase in hip fracture (HR 1.51; 95% CI 1.20-1.91). On the other hand, there was no significant increase in hip fracture risk among nonsmokers who used PPIs (HR 1.06; 95% CI 0.77-1.46). The authors then performed a meta-analysis that included these results and 10 prior studies and found that the pooled odds ratio for hip fracture associated with PPI use was 1.30 (95% CI 1.25-1.36).

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 [88]. The FDA also recommends that healthcare professionals who prescribe PPIs consider whether a lower dose or shorter duration of therapy would adequately treat the

patient's condition. (See "Medical management of gastroesophageal reflux disease in adults".)

Vitamin B12 malabsorption — Long-term therapy with omeprazole has been associated with vitamin B12 malabsorption [89,90]. Thus, it is reasonable to assess vitamin B12 levels periodically (eg, annually) in patients who are on long-term treatment with PPIs [91].

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 [76,92-94]. 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 [94,95]. (See "Treatment of iron deficiency anemia in adults", section on 'Dosing and administration (oral iron)'.)

Hypergastrinemia — An initial concern with omeprazole was the induction of hypergastrinemia and gastric carcinoid tumors in rats, changes also demonstrated with chronic ranitidine exposure or subtotal resection of the gastric fundus [96]. However, these observations have not generalized to species with gastrin physiology more analogous to humans [96]. While patients treated with omeprazole for up to 11 years have shown some argyrophil cell hyperplasia, no dysplasia or neoplastic changes have been observed [97].

The clinical significance of other theoretical risks related to hypergastrinemia (such as colon cancer) has not been established. One study found no increased risk of colon cancer in long-term users of a PPI [98]. (See "Physiology of gastrin".)

Atrophic gastritis — Patients receiving maintenance therapy have a propensity to develop chronic atrophic gastritis. Although the risk of atrophic gastritis in this context remains unclear, it could theoretically lead to an increased incidence of gastric cancer. (See "Risk factors for gastric cancer".)

In one study, for example, atrophy developed in over 30 percent of patients after omeprazole therapy for a five-year period, changes not evident in a cohort of Scandinavians treated with antireflux surgery [99]. However, since the omeprazole-treated patients developed atrophy only in the presence of a concomitant H. pylori infection, it was suggested that only the H. pylori infected group was at risk.

Thus, an argument can be made for the detection and eradication of H. pylori in patients who will be given maintenance therapy with a PPI. Although some clinicians subsequently adopted this practice, an FDA panel reviewing these data in November 1996 concluded that there was insufficient evidence to warrant that approach. This recommendation was supported by a subsequent controlled trial involving 155 patients who were randomly assigned to antireflux surgery or omeprazole [100]. After three years, no significant differences were observed in the development of gastric glandular atrophy or the occurrence of intestinal metaplasia, irrespective of H. pylori status. Furthermore, follow-up data (up to 10 years) from the study discussed above [99] revealed that although the annual incidence of gastric corpus mucosal atrophy was higher in H. pylori-positive patients (4.7 versus 0.7 percent), corpus intestinal metaplasia was rare, and no dysplasia or neoplasms were observed [97].

Thus, we do not routinely test for H. pylori in patients who require long-term therapy with a proton pump inhibitor since the risk of atrophic gastritis is small and, in the uncommon patient who develops it, the clinical consequences are uncertain.

Kidney disease — PPIs have been associated with acute interstitial nephritis (AIN) [101-104]. Drug-induced AIN is not dose-dependent, and recurrence or exacerbation can occur with a second exposure to the same or a related drug. PPI use has also been associated with an increased risk of incident chronic kidney disease (CKD), CKD progression, and end-stage renal disease [105,106].

Data were analyzed from the Atherosclerosis Risk in Communities (ARIC) study, including 10,482 individuals with eGFR ≥60 mL/min/1.73 m2 who were followed for a median of 13.9 years [106]. In an analysis adjusted for demographic, socioeconomic, clinical variables (including but not limited to baseline eGFR, proteinuria, and BMI), comorbidities, and concurrent medications, PPI use was associated with increased risk of CKD (hazard ratio [HR] 1.5, 95% CI 1.14-1.96). When directly compared with H2 receptor antagonists, PPI use was also associated with an increased risk of CKD (adjusted HR 1.39, 95% CI 1.01-1.91). In the same study, similar results were obtained from an analysis of data from 248,751 individuals with eGFR >60 mL/min/1.73 m2 who were identified from a large, integrated health system in the United States and followed up for a median of 6.2 years. In the latter analysis, twice-daily PPI dosing was associated with a higher risk (adjusted HR 1.46, 95% CI 1.28-1.67) than once-

daily dosing (adjusted HR 1.15, 95% CI 1.09-1.21).

An association between PPI use and CKD was also suggested by a study of 173,321 new PPI users and 20,270 new H2 receptor antagonist users who were identified from the Department of Veterans Affairs national database and followed for five years [105]. Compared with the H2 receptor antagonist group and adjusted for demographic, eGFR, and comorbidities, the PPI group had an increased risk of incident eGFR <60 mL/min/1.73 m2 (HR 1.22, 95% CI 1.18-1.26). PPI users were also at higher risk for CKD, as defined by two eGFR measurements <60 mL/min/1.73 determined at least 90 days apart (HR 1.28, 95% CI 1.23-1.34), and for end-stage renal disease (ESRD; HR 1.96, 95% CI 1.21-3.18). Furthermore, compared with PPI use for ≤30 days, PPI exposure for 31 to 90, 91 to 180, 181 to 360, and 360 to 720 days was associated with a progressively higher CKD risk (HRs of 1.82, 2.00, 2.16, and 1.96, respectively).

Although these studies suggest an association between PPI use and CKD, the mechanism underlying the association between PPI use and risk of CKD is not known, nor is it clear whether decreasing PPI use decreases the risk of CKD. Moreover, PPIs are commonly used to prevent gastroduodenal mucosal injury associated with the use of NSAIDs. Only one of the two studies evaluated NSAID use [106]. In this study, NSAID use in PPI users was increased significantly as compared with nonusers in one of the cohorts examined. However, the study did not assess the dose or length of exposure to NSAIDs, both of which are critical factors in the development of CKD associated with the use of these agents [107,108]. Thus, while it might be prudent to monitor eGFR in patients taking PPIs long-term, further studies are needed to help better define an etiologic relationship between PPI use and the development and worsening of CKD.

(See "Clinical manifestations and diagnosis of acute interstitial nephritis", section on 'Drugs'.)

Dementia — Although some studies have found a significant association between use of PPIs and incident dementia, additional studies are needed to determine whether the relationship is causal [109,110]. The association between PPI use and dementia is discussed in detail, separately. (See "Epidemiology, pathology, and pathogenesis of Alzheimer disease".)

Drug-induced lupus — In postmarketing safety surveillance, new onset of cutaneous lupus erythematosus (CLE) and systemic lupus

erythematosus (SLE), and exacerbation of existing disease have been reported in patients on PPIs [111-113]. 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 primary treatment and typically presents with a rash. Most patients improve within 4 to 12 of discontinuation of PPI therapy. (See "Drug-induced lupus", section on 'Causative drugs'.)

Drug interactions — Clinically important drug interactions with PPIs are rare. However, some data suggest decreased activation of clopidogrel when used in conjunction with omeprazole on the basis of a shared hepatic metabolic pathway. Other mechanisms by which PPIs might negatively impact cardiovascular outcomes have also been proposed [114]. However, the relevance of these data remains highly controversial. In 2009, the US Food and Drug Administration 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 [115,116]. (See "Clopidogrel resistance and clopidogrel treatment failure" and 'Differences in drug metabolism and drug interactions' above.)

DISCONTINUING PROTON PUMP INHIBITORS — Many patients with gastroesophageal reflux disease (GERD) and dyspepsia are maintained on proton pump inhibitors (PPIs), but some concerns have been expressed regarding the long-term safety of these medications, as well as potentially important drug interactions. As a result, some asymptomatic patients who do not have other indications for being on a PPI may be candidates for having their PPI discontinued, though many relapse once the medication is stopped. (See 'Safety' above and "Medical management of gastroesophageal reflux disease in adults", section on 'Management of recurrent symptoms and maintenance therapy' and "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity" and "Clopidogrel resistance and clopidogrel treatment failure", section on 'Interaction with other drugs'.)

Previous studies have demonstrated rebound gastric acid hypersecretion following the discontinuation of PPIs in patients managed for prolonged periods of time with these agents. 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].

As discussed below, no specific method for discontinuing the use of

PPIs has been proven effective, and no approach is universally accepted. Moreover, despite the definition of "prolonged therapy" being likewise unclear, patients treated for a period of six months might be considered candidates for dose tapering. The following are general guidelines that may be employed when stopping a PPI:

● Patients with GERD or dyspepsia are considered for a taper after being asymptomatic for a minimum of three months. ● Patients treated for acute duodenal and gastric ulcers for four to eight weeks do not require a taper. ● Patients receiving a PPI as part of a course of treatment for H. pylori do not require a taper. ● For patients on a moderate- to high-dose PPI (eg, omeprazole 40 mg daily or twice daily), we cut 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 stop the medication. Data are limited regarding the success of attempts at stopping therapy.

● In one randomized trial, 97 patients on a long-term PPI were assigned to either omeprazole 20 mg daily for three weeks, or omeprazole 20 mg daily for one week, followed by 10 mg daily for one week, followed by 10 mg every other day for one week [117]. At the end of three weeks the PPI was stopped. After one year of follow-up, 26 patients (27 percent) remained off of PPIs, two of whom used H2 receptor antagonists occasionally. Patients with GERD were more likely to resume taking a PPI compared with patients taking a PPI for dyspepsia or another indication (79, 67, and 42 percent, respectively). No significant difference in the rate of PPI resumption was detected based upon the discontinuation strategy (tapering versus nontapering).

● A second, earlier trial evaluated the feasibility of step-down therapy in 71 patients with uncomplicated GERD [118]. Step-down therapy consisted of a 50 percent reduction in the prescribed dose of PPI, unless the patient was already on the lowest dose available, in which case it was stopped. If symptoms returned during a two-week period, the PPI was resumed at the original dose. If no GERD symptoms were reported, the medication was stopped. If symptoms recurred after two weeks, patients were initially treated with high-dose H2 receptor antagonists, followed by the addition of/switchto a prokinetic agent (cisapride or metoclopramide) if needed. If those measures failed, the patient’s PPI was resumed (at the pre-study dose). After one year of follow-up, 41 patients (58 percent) were asymptomatic either on non-PPI therapy (30 patients) or no therapy (11 patients). However, it must be emphasized that cisapride is no longer available, and the long-term use of metoclopramide is generally not recommended because of the drug's serious adverse effects. For patients in whom step-down therapy failed, the median time to resumption of the PPI was 14 days (all but one of these patients had recurrent symptoms within four months of follow-up). 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 (gastroesophageal reflux disease) in adults (The Basics)")

● Beyond the Basics topics (see "Patient education: Acid reflux (gastroesophageal reflux disease) in adults (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS

● H-K-ATPase comprises the final pathway by which HCl is secreted into the gastric lumen, where it serves to both hydrolyze dietary protein and maintain a sterile environment. Proton pump inhibitors (PPIs) inhibit this enzyme. The PPIs are the most potent inhibitors of gastric acid secretion available. (See 'Pharmacology of the proton pump inhibitors' above.) ● PPIs are effective for treatment of all acid-related disorders including peptic ulcer disease, gastroesophageal reflux disease (GERD), and Zollinger-Ellison syndrome. They are also effective in treating and preventing nonsteroidal anti-inflammatory drug-associated gastroduodenal mucosal injury and, when used in combination with various antimicrobial agents, in eradicating Helicobacter pylori infection. (See 'Treatment of acid-related disorders' above.) ● A number of studies have compared the various proton pump inhibitors to one another. While some differences have been reported, the magnitude of differences has been small and of uncertain clinical importance. In particular, the degree to which any of the reported differences would justify the selection of one versus another PPI, particularly when considering cost-effectiveness, is unclear. (See 'Comparison of proton pump inhibitors' above.) The main concerns regarding the long-term safety of the PPIs include the effects of prolonged hypochlorhydria and hypergastrinemia, and the possible association of PPIs with gastric atrophy. In particular, hypochlorhydria is of concern since it may predispose to infections and malabsorption. (See 'Safety' above.) Due to a possible increased risk of fractures, it is recommended that healthcare professionals who prescribe PPIs consider whether a lower dose or shorter duration of therapy would adequately treat the

patient's condition. (See 'Hip fracture and calcium malabsorption' above.) PPI use may increase the risk of C. difficile-associated diarrhea. In 2012, the US Food and Drug Administration (FDA) issued a safety alert encouraging providers to consider C. difficile infection in PPI users with persistent diarrhea. Given the potential risk of C. difficile infection, the FDA has also recommended that providers prescribe the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. (See 'Clostridium difficile and other enteric infections' above.) Hypomagnesemia due to reduced intestinal absorption has been described with PPI use. It is recommended that serum magnesium levels be obtained prior to starting a PPI when patients are expected to be on the medication for long periods of time, or in patients who take PPIs in conjunction with other medications associated with hypomagnesemia (eg, digoxin or diuretics). The FDA also suggests that providers consider obtaining magnesium levels periodically in such patients while they are on a PPI. (See 'Magnesium absorption' above.) ● In patients treated with PPIs for a period of six months or longer, a dose taper should be considered prior to discontinuation. Patients with GERD or dyspepsia should also be considered for a taper after being asymptomatic for a minimum of three months. For patients on a moderate- to high-dose PPI (eg, omeprazole 40 mg daily or twice daily), we reduce the dose by 50 percent every week until the patient is on the lowest dose of the medication. Once on the lowest dose for one week, the patient is instructed to stop the medication. (See 'Discontinuing proton pump inhibitors' above.) Use of UpToDate is subject to the Subscription and License Agreement.

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