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Overview of pp is

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  • 1. Last literature review version 19.2: May 2011 | This topic last updated: June 7, 2011 (More)INTRODUCTION — The introduction of proton pump inhibitors (PPIs) in the late 1980soptimized the medical treatment of acid-related disorders. In addition, the PPIs allowedclinicians to evaluate the role of gastric acid in several extraesophageal manifestations ofgastroesophageal reflux disease, including noncardiac chest pain and tracheopulmonarydiseases [1-4].This topic review will provide an overview of the pharmacology and clinical efficacy of theproton pump inhibitors for a variety of acid-related disorders and address issues related to thecomparison 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 presentedseparately. (See "Pharmacology of antiulcer medications".)PHYSIOLOGY OF ACID SECRETION — The normal human stomach containsapproximately one billion parietal cells that secrete 0.16 M hydrochloric acid (HCl) into thegastric 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 inhibithydrogen ion generation, histamine appears to represent the dominant route as gastrinstimulates 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 principalmeans by which acid secretion was inhibited in the mid-1970s.During the unstimulated (basal) state, a large percentage of the parietal cell volume isoccupied by tubulovesicles, which are elongated tubes with smooth surface membranes, andby the secretory canaliculus, a small invaginated area of the apical membrane. Upon mealstimulation, these tubulovesicles decrease in number and become transformed into microvilliaround the secretory canaliculus, which serves to greatly expand the surface area of theparietal cell in preparation for the active transport of large quantities of hydrogen ions againsta 3,000,000:1 ionic gradient [5]. Hydrogen ions are actively secreted in exchange forpotassium ions by means of an H-K-ATPase, the so-called proton pump located on the apicalsurface of the parietal cell. H-K-ATPase comprises the final pathway by which HCl issecreted into the gastric lumen, where it serves to both hydrolyze dietary protein and maintaina sterile environment.Structure of the parietal cell H-K-ATPase — The parietal cell H-K-ATPase is a member ofthe family of ion-motive transport enzymes that includes F1, V, and P ATPases. The last isfurther divided into P1 or P2 types based either on the transport of transition metals (P1) or
  • 2. small cations (P2) or alternatively on the number of transmembrane segments [1]. The P2family possesses one catalytic subunit with 10 transmembrane segments and a beta subunitwith 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 catalyticalpha-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 ofdrugs, the proton pump inhibitors (PPIs), which are targeted at inhibiting this enzyme. PPIsall share a common structural motif, but vary in terms of their substitutions. They are allweak protonatable pyridines, with a pKa of about 4.0 for omeprazole/esomeprazole andlansoprazole/dexlansoprazole, about 3.9 for pantoprazole, and about 5.0 forrabeprazole (table 1). As a result, they accumulate specifically and selectively in the secretorycanaliculus, the highly acid space of the parietal cell [1]. Within that space, PPIs undergo anacid catalyzed conversion to a reactive species, the thiophilic sulfenamide, which arepermanent cations.The rate of conversion varies among the compounds and is inversely proportional to the pKaof the benzimidazole [6]: rabeprazole > omeprazole/esomeprazole =lansoprazole/dexlansoprazole > pantoprazole. The reactive species interacts with the externalsurface 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 ofthe enzyme; this is the residue that is intimately involved in hydrogen ion transport. Thiscovalent 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 havedemonstrated that, in addition to cysteine 813, pantoprazole binds to cysteine 822, which issituated deeper in the membrane domain TM6 [7]. Recovery of acid secretion followingpantoprazole was prolonged compared to other PPIs possibly as a result of its binding tocysteine 822. Neither in vivo nor clinical studies have been performed to determine whetherthese observations are clinically relevant.The PPIs are the most potent inhibitors of gastric acid secretion available [1]. They are mosteffective when the parietal cell is stimulated to secrete acid postprandially, a relationship thathas 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 beadministered before the first meal of the day. In most individuals, once-daily dosing issufficient to produce the desired level of acid inhibition, and a second dose, which isoccasionally necessary, should be administered before the evening meal [1]. PPIs shouldnot be given concomitantly with H2-antagonists, prostaglandins, or other antisecretory agentsbecause of the marked reduction in their acid inhibitory effects when administeredsimultaneously [1,8]. An H2 antagonist can be used with a PPI provided that there is asufficient time interval between administration of the H2 antagonist and the PPI (although theprecise minimal time interval has not been established). As an example, an H2 antagonist canbe taken before bedtime or during the night by individuals who report nocturnal breakthroughsymptoms such as heartburn after taking a PPI in the morning.During meals, neither all parietal cells nor all proton pumps are active. Since PPIs inhibitonly activated enzyme present in the canalicular membrane, the reduction of gastric acid
  • 3. secretion after an initial dose will probably be suboptimal. As inactive enzyme is recruitedinto the secretory canaliculus, acid secretion will resume, albeit at a reduced level. After thesecond dose is given on the next day, more H-K-ATPase will have been recruited andsubsequently inhibited, and after the third dose, additional recruitment and further acidinhibition 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 provideadequate acid inhibition and does not produce a consistent or satisfactory clinical response (incontrast to the H2 antagonists, which have a more rapid onset of action) [1]. Because of thedelay in optimal acid inhibition, the initial use of twice-daily PPI dosing (for the first two tothree days) may be helpful in achieving more rapid inhibition of gastric acid secretion. Inaddition to their delay in onset, and because PPI-derived sulfonamides bind covalently to H-K-ATPase, the restoration of acid secretion will likewise be delayed, depending upon enzymeturnover and the biological reversibility of the disulfide bond. Maximal acid secretorycapacity may not be restored for 24 to 48 hours after discontinuing PPIs [1].Rebound acid hypersecretion — Rebound acid hypersecretion after withdrawal of PPIs isdescribed separately. (See "Physiology of gastric acid secretion".)TREATMENT OF ACID-RELATED DISORDERS — The PPIs are effective for treatmentof all acid-related disorders. The following sections will summarize data demonstrating theefficacy of the PPIs in a variety of clinical settings. Detailed discussions on each of thesedisorders are also presented separately on the corresponding topic reviews.Peptic ulcer disease — PPIs heal gastroduodenal ulcers more rapidly than H2-receptorantagonists. A meta-analysis comparing the healing of duodenal ulcers found that 20 mg ofomeprazole every morning for four weeks was superior to both 300 mg of ranitidine and 800mg of cimetidine, both administered at bedtime [9]. Similarly, another meta-analysis foundthat 30 mg of lansoprazole every morning healed significantly more ulcers than 300 mg ofranitidine and 40 mg of famotidine, both administered at bedtime [10]. The pooled healingrates were 60 and 85 percent for lansoprazole at two and four weeks, respectively, while thecorresponding figures for the H2-antagonists were 40 and 75 percent. (See "Overview of thenatural history and treatment of peptic ulcer disease".)Pantoprazole and rabeprazole have also demonstrated superior and accelerated ulcer healingcompared with H2-antagonists [11,12]. The optimal duration of therapy with PPIs should befour and eight weeks for acute duodenal ulcer and gastric ulcer, respectively [12].Eradication of Helicobacter pylori — The role of PPIs in treatment of H. pylori is discussedseparately. (See "Treatment regimens for Helicobacter pylori".)Treatment and prevention of gastroduodenal ulcers associated with NSAIDs — A number ofstudies have demonstrated that the PPIs are more effective than H2 antagonists for healinggastroduodenal ulcers associated with nonsteroidal antiinflammatory drugs (NSAIDs) whenNSAIDs cannot be discontinued. PPIs also appear to be as or more effective thanmisoprostol. PPIs are also effective for primary prevention of NSAID-associated ulcers. (See"NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity".)
  • 4. Zollinger-Ellison syndrome — The goal of therapy in individuals with Zollinger-Ellisonsyndrome (ZES) is surgical gastrinoma excision, which is possible in about 50 percent ofthose with sporadic disease. However, all patients with ZES require antisecretory therapyafter the diagnosis is established and during tumor localization. (See "Management andprognosis of the Zollinger-Ellison syndrome (gastrinoma)".)Treatment of gastroesophageal reflux disease — Numerous studies have documented themarked 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 alladministered before breakfast will relieve symptoms and heal esophagitis in approximately85 to 90 percent of patients. (See "Medical management of gastroesophageal reflux disease inadults".)At least 10 to 15 percent of patients with GERD respond suboptimally to PPIs, particularlythose with more advanced grades of esophagitis. The reasons for such failures are not entirelyclear but may often be due to their suboptimal administration. Another potential reason stemsfrom the variable antisecretory properties of PPIs based on individual pharmacogenomicdifferences [13]. Polymorphisms in the CYP2C19 gene, which encodes the cytochrome P450isoenzyme that metabolizes different PPI preparations, are common in Asian and otherpopulations [13]. Such gene mutations would render an individual a "slow metabolizer" andprolong the antisecretory effect of PPIs. In contrast, the duration of acid inhibition would bedecreased in a "rapid metabolizer", and differences in PPI metabolism might account forincomplete inhibition of acid secretion and a high prevalence of nocturnal breakthroughsymptoms in GERD patients.A careful history regarding the timing of PPI administration should be obtained in individualswho do not respond to PPIs. As noted above, the optimal time is immediately beforebreakfast. Once the correct timing is established, a second dose of the PPI (before the eveningmeal) may be helpful. (See "Approach to refractory gastroesophageal reflux disease inadults".)New PPI prodrugs with longer biological half-lives are under development and may addresssome of the present shortcomings of PPIs. These prodrugs are converted to activesulfenamides by acid in the secretory canaliculus [14]. The substitution of a benzimidazolewith an imidazo [4-6,14] pyridine moiety reduces the rate of metabolism, increasing both theplasma and biological half-lives significantly, the former from approximately 60 to 90minutes to 9.3 hours [14]. The ultimate benefit of such preparations, if any, will requirecareful examination.Maintenance therapy — Most patients with GERD, particularly those with grade III and IVesophagitis, will relapse once therapy is discontinued [15]. A landmark study of maintenancetherapy compared five regimens: ranitidine, cisapride (no longer available by prescription inthe United States and several other countries), ranitidine plus cisapride, omeprazole, andomeprazole plus cisapride [16]. All patients had esophagitis on initial endoscopy and weretreated with omeprazole 40 mg daily for eight weeks before initiating one of the maintenanceregimens. After 12 months of treatment, remission was maintained in 80 to 90 percent of theomeprazole groups, versus 49 to 60 percent in the other groups. This study demonstrated thesuperiority of PPIs in maintaining remission and further showed that effective prophylactic
  • 5. doses are generally the same as those required for initial healing. (See "Medical managementof gastroesophageal reflux disease in adults".)Complications of GERD — PPIs are effective in treating a number of complications relatedto GERD: Esophageal strictures – PPIs decrease the eventual number of esophageal dilations required to relieve dysphagia more effectively than H2 antagonists [17,18]. (See "Complications of gastroesophageal reflux in adults".) Barretts esophagus – PPIs are frequently used in patients with Barretts metaplasia, although no studies have shown unequivocal regression of Barretts 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 Barretts metaplasia require continued surveillance for the development of dysplasia or frank adenocarcinoma. (See "Management of Barretts esophagus".) 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 [19]. 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 discussionunderscores that the proton pump inhibitors 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, withlansoprazole/dexlansoprazole and pantoprazole being the most bioavailable and achieving thehighest plasma levels (table 1). Because of its higher pKa, rabeprazole possesses a slightlyfaster 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 theproton 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 [20-33]. While some differences have been reported, the magnitude of differences has been smalland of uncertain clinical importance. In particular, the degree to which any of the reporteddifferences would justify the selection of one versus another PPI, particularly whenconsidering cost-effectiveness, is unclear [32]. One trial that looked at cost-effectivenessfound 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) [34]. 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
  • 6. 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 beenapproved by the United States Food and Drug Administration (FDA). However, the doses ofvarious PPIs that would be considered pharmacologically equivalent have not been wellestablished and thus it is possible that all the various PPIs could be equivalent whenadministered at certain doses. A systematic review of the various PPI comparisons preparedon behalf of the Agency for Healthcare Research and Quality is available on the internet [35].A separate question is the effectiveness of substituting one PPI for another in patients whohave stabilized on therapy. This issue is important since substitution may be required whenhealth plans change their formulary based upon cost considerations. This issue was examinedin a study involving 105 patients with GERD who had stabilized on omeprazole but wereconverted to lansoprazole in equivalent doses by their health plan [36]. A telephoneassessment suggested that following conversion the mean symptom severity score increasedsignificantly. Furthermore, 33 percent of patients consumed more over-the-counter heartburnmedications, 13 percent changed their diet more frequently due to heartburn, and overallpatient satisfaction decreased significantly. These results should be interpreted cautiouslysince the study was uncontrolled and subject to a number of biases, which wereacknowledged by the authors. As an example, patients could have been dissatisfied with thesubstitution since it may have been perceived as a cost-cutting measure; as a result, they mayhave been influenced to report negative outcomes on the self-reported questionnaire. Despitethese limitations, the study suggests that the similar efficacy of PPIs that has been observed incontrolled clinical trials may not necessarily translate into equivalent effectiveness whenthese drugs are substituted for one another.Over-the-counter and on-demand PPIs — Two unpublished, randomized controlled trials ledto 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 takingomeprazole were free of heartburn (approximately 70 versus 43 percent). The incidence ofheartburn 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 symptomcontrol better than placebo in patients with mild or no esophagitis [33,37-39]. However, theclinical endpoints of such "on-demand" trials have not defined success as timely, completerelief of heartburn, which could be considered the most important objective in patients withintermittent symptoms. Rather, they have compared overall assessments of heartburn andmedication use at various time points.Furthermore, heartburn control is less effective than with continuous therapy, even thoughintermittent dosing may be associated with greater overall satisfaction compared with regularuse of a PPI [37]. A meta-analysis evaluated the rapidity of heartburn control with PPIs [40].Complete heartburn relief occurred in approximately 30 percent of patients after their firstPPI 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
  • 7. days of PPI therapy. Most studies that the authors included assessed heartburn relief at 24hours. The 21 percent benefit compared with placebo may be even less important clinicallywhen 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 aftertaking a PPI.As noted in the discussions above, the pharmacokinetics of the PPIs suggest that they are bestsuited 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. Similarconsiderations apply to other PPIs targeted for the OTC market.Thus, the role of PPIs in the treatment of patients with troubling, intermittent heartburn isuncertain. H2 receptor antagonists may be better suited for this role. No studies have directlycompared "on-demand" use of PPIs with H2RAs.Three other issues related to the comparison of these drugs are relevant clinically: safety,convenience, and cost.Safety — The proton pump inhibitors are an extremely safe class of drugs. However,differences in their metabolism may lead to specific drug interactions. The long-term safetyof these drugs has been best established with omeprazole since it was the first to becomeavailable clinically. These data suggest that its use for more than 15 years is safe, althoughsome risks have been described. (See "Medical management of gastroesophageal refluxdisease in adults", section on Safety.)Differences in drug metabolism and drug interactions — As discussed above, somedifferences among the PPIs do exist with regard to the pKa, bioavailability, peak plasmalevels, and route of excretion (table 1). In addition, PPIs are metabolized by somewhatdifferent routes, which might affect their clinical efficacy in certain ethnic groups andpotentially lead to differences in drug interactions [41].PPIs are metabolized via hepatic cytochrome P450 enzymes, with CYP2C19 having thedominant 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 twoknown inactivating mutations which occur most commonly in Asian populations have beendescribed [41]. Five percent of Caucasians are homozygous for this mutation; as a result, themetabolism of drugs by this route may be delayed in these individuals. About two-thirds ofCaucasians 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 doserequirements and clinical efficacy [41]. As an example, one study examined the effect ofvariable metabolism of omeprazole when using this agent to treat H. pylori in Japanesepatients [41]. While eradication was achieved in all individuals homozygous for a CYP2C19mutation (ie, poor metabolizers), successful treatment was achieved in only 60 and 29 percentof heterozygotes and wild type homozygotes, respectively. Another report from Japanevaluated the efficacy of lansoprazole in the treatment of GERD [42]. Poor metabolizers weremuch more likely to be cured than heterozygotes and wild type homozygotes (85 versus 68and 46 percent, respectively). The cure rate was only 16 percent in wild type homozygotes
  • 8. who had severe GERD. Furthermore, wild type homozygotes (fast metabolizers) had thelowest plasma lansoprazole concentrations.Although the presence of a CYP2C19 gene mutation may appear beneficial because of higherplasma levels, deleterious consequences may ensue. If this metabolic pathway becomessaturated, the isoenzyme may become a major target for interactions with many drugs,including warfarin, diazepam, clopidogrel and phenytoin (table 3). CYP3A4-mediatedmetabolism also may be activated under such conditions and may become the principal routeof drug elimination. Furthermore, induction of CYP1A, another P450 isoenzyme, may occurin CYP2C19 deficient or saturated individuals, making them susceptible to interference withtheophylline metabolism (table 3).The specific P450 enzymes involved in PPI metabolism and the potential for interactionsamong these agents varies considerably (table 4) [43-49]. 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 clinicallyrelevant interactions are uncommon. However, there is particular concern regarding thepotential for interactions between PPIs and clopidogrel. Physicians and patients should becognizant of possible interactions. (See "Nonresponse and resistance to aspirin andclopidogrel", section on Proton pump inhibitors and "Overview of the non-acutemanagement of unstable angina and acute non-ST elevation myocardial infarction", sectionon Gastrointestinal prophylaxis.)None of the PPIs require dose-adjustment for hepatic or renal insufficiency. PPIs maydecrease the absorption of certain HIV protease inhibitors. (See "HIV protease inhibitors".)Long-term safety — The three main concerns regarding the long-term safety of the PPIsinclude the effects of prolonged hypergastrinemia, the possible association of PPIs withgastric atrophy, and the effects of chronic hypochlorhydria. Modest elevations in gastrin areoften seen with PPI use (generally 200 to 400 pg/mL). (See "Medical management ofgastroesophageal reflux disease in adults", section on Safety and "Physiology of gastrin",section on Causes of hypergastrinemia.)
  • 9. A possible increased risk of fractures prompted the FDA to recommend that healthcareprofessionals who prescribe proton pump inhibitors should consider whether a lower dose orshorter duration of therapy would adequately treat the patients condition [50]. (See "Medicalmanagement of gastroesophageal reflux disease in adults".)There is inconclusive evidence to suggest that PPI use may increase the risk of Clostridiumdifficile-associated disease [51-54]. C. difficile is an anaerobic organism that sporulates;acid-resistant spores are presumed to be the major vector of disease transmission. Althoughthe spores may survive in an alkaline environment, there is little epidemiological evidencelinking PPI use to C. difficile infection [51]. Despite the role of gastric acidity in maintaininga sterile environment in the upper GI tract, any significant effects on other enteric infectionshas not been detected [55].Hypomagnesemia due to reduced intestinal absorption has been described with PPI use.Hypomagnesemia can result in muscle spasms, cardiac arrhythmias, and seizures. In March2011, the US Food and Drug Administration (FDA) issued a safety alert warning providers ofthe risk of hypomagnesemia in patients who have been on PPIs long-term (generally longerthan one year) [56]. The FDA suggests that providers consider obtaining serum magnesiumlevels prior to starting a PPI in patients who are expected to be on the medication for longperiods of time, or in patients who take PPIs in conjunction with other medications associatedwith hypomagnesemia (eg, digoxin or diuretics). The FDA also suggests that providersconsider obtaining levels periodically in such patients while they are on a PPI. (See "Causesof hypomagnesemia", section on Proton pump inhibitors.)Finally, although some concern has been expressed regarding the effects of long-term PPI useon iron and vitamin B12 absorption, any effects are generally mild, clinically insignificant,and addressed by supplement therapy [57]. (See "Medical management of gastroesophagealreflux disease in adults", section on Safety.)Convenience — Most of the PPIs are available in oral, delayed release formulations. Anexception is Zegerid (a formulation of omeprazole-sodium bicarbonate), which is designedfor immediate release. There appears to be little, if any, benefit from this formulation exceptpossibly in the occasional patient unable to swallow pills or capsules; other choices undersuch circumstances include lansoprazole (Prevacid SoluTab) or intravenous PPIs.Intravenous formulations — Pantoprazole, lansoprazole, and esomeprazole are the only PPIsavailable as an intravenous formulation in the United States; intravenous omeprazole is usedin other countries. Although intravenous PPIs have been approved for the treatment oferosive esophagitis in patients unable to tolerate oral treatment, they are more frequently usedin management of patients with bleeding peptic ulcers and for the prevention of stress-relatedmucosal damage. (See "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 andwhether use of over-the-counter (rather than prescription) PPIs is required.DISCONTINUING PROTON PUMP INHIBITORS — Many patients with gastroesophagealreflux disease (GERD) and dyspepsia are maintained on proton pump inhibitors (PPIs), butsome concerns have been expressed regarding the long-term safety of these medications, aswell as potentially important drug interactions. As a result, some asymptomatic patients who
  • 10. do not have other indications for being on a PPI may be candidates for having their PPIdiscontinued, though many relapse once the medication is stopped. (See Safety above and"Nonresponse and resistance to aspirin and clopidogrel", section on Proton pumpinhibitors and "Medical management of gastroesophageal reflux disease in adults", sectionon Maintenance therapy and "NSAIDs (including aspirin): Primary prevention ofgastroduodenal toxicity".)Previous studies have demonstrated rebound gastric acid hypersecretion following thediscontinuation 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 antralsomatostatin expression, resulting in an increase in antral gastrin release and subsequentdisruption 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 proveneffective, and no approach is universally accepted. Moreover, despite the definition of―prolonged therapy‖ being likewise unclear, patients treated for a period of six months mightbe considered candidates for dose tapering. The following are general guidelines that may beemployed 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 randomizedtrial, 97 patients on a long-term PPI were assigned to either [58]: 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 weekAt the end of three weeks the PPI was stopped. After one year of follow-up, 26 patients (27percent) 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 aPPI for dyspepsia or another indication (79, 67, and 42 percent, respectively). No significantdifference 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 withuncomplicated GERD [59]. Step-down therapy consisted of the following:
  • 11. The prescribed dose of PPI was decreased by 50 percent, unless the patient was already on the lowest dose available, in which case it was stopped. Two weeks later, patients were assessed for GERD symptoms. If symptoms returned during the two-week period, the PPI was resumed at the original dose. If no GERD symptoms were reported, the medication was stopped. Patients were then followed at three-month intervals. If symptoms recurred during that time, patients were initially treated with high-dose H2 receptor antagonists, followed by the addition of/switch to 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-PPItherapy (30 patients) or no therapy (11 patients). However, it must be emphasized thatcisapride is no longer available, and the long-term use of metoclopramide is generally notrecommended because of the drug’s association with significant, occasionally serious adverseeffects, principally consisting of extrapyramidal events.For patients in whom step-down therapy failed, the median time to resumption of the PPI was14 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 educationmaterials, "The Basics" and "Beyond the Basics." The Basics patient education pieces arewritten in plain language, at the 5th to 6th grade reading level, and they answer the four orfive key questions a patient might have about a given condition. These articles are best forpatients who want a general overview and who prefer short, easy-to-read materials. Beyondthe Basics patient education pieces are longer, more sophisticated, and more detailed. Thesearticles are written at the 10th to 12th grade reading level and are best for patients who wantin-depth information and are comfortable with some medical jargon.Here are the patient education articles that are relevant to this topic. We encourage you toprint or e-mail these topics to your patients. (You can also locate patient education articles ona variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient information: Acid reflux (gastroesophageal reflux disease) (The Basics)") Beyond the Basics topics (see "Patient information: Acid reflux (gastroesophageal reflux disease) in adults")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 and Zollinger-Ellison syndrome. (See Treatment of acid-related disorders above.)
  • 12. 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. 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. (See Comparison of proton pump inhibitors above.)Use of UpToDate is subject to the Subscription and License Agreement.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. Harding SM, Richter JE, Guzzo MR, et al. Asthma and gastroesophageal reflux: acid suppressive therapy improves asthma outcome. Am J Med 1996; 100:395. 3. Wo JM, Grist WJ, Gussack G, et al. Empiric trial of high-dose omeprazole in patients with posterior laryngitis: a prospective study. Am J Gastroenterol 1997; 92:2160. 4. Fass R, Fennerty MB, Ofman JJ, et al. The clinical and economic value of a short course of omeprazole in patients with noncardiac chest pain. Gastroenterology 1998; 115:42. 5. Wolfe MM, Soll AH. The physiology of gastric acid secretion. N Engl J Med 1988; 319:1707. 6. 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. 7. Shin JM, Sachs G. Restoration of acid secretion following treatment with proton pump inhibitors. Gastroenterology 2002; 123:1588. 8. 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. 9. Holt S, Howden CW. Omeprazole. Overview and opinion. Dig Dis Sci 1991; 36:385. 10. Poynard T, Lemaire M, Agostini H. Meta-analysis of randomized clinical trials comparing lansoprazole with ranitidine or famotidine in the treatment of acute duodenal ulcer. Eur J Gastroenterol Hepatol 1995; 7:661. 11. Dekkers CP, Beker JA, Thjodleifsson B, et al. Comparison of rabeprazole 20 mg versus omeprazole 20 mg in the treatment of active duodenal ulcer: a European multicentre study. Aliment Pharmacol Ther 1999; 13:179. 12. Bader JP, Delchier JC. Clinical efficacy of pantoprazole compared with ranitidine. Aliment Pharmacol Ther 1994; 8 Suppl 1:47. 13. Wolfe MM, Lowe RC. Investing in the future of GERD. J Clin Gastroenterol 2007; 41:S209. 14. Shin JM, Homerin M, Domagala F, et al. Characterization of the inhibitory activity of tenatoprazole on the gastric H+,K+ -ATPase in vitro and in vivo. Biochem Pharmacol 2006; 71:837.
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  • 15. 47. Lew EA. Review article: pharmacokinetic concerns in the selection of anti-ulcer therapy. Aliment Pharmacol Ther 1999; 13 Suppl 5:11.48. Li XQ, Andersson TB, Ahlström M, Weidolf L. Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metab Dispos 2004; 32:821.49. Liu KH, Kim MJ, Shon JH, et al. Stereoselective inhibition of cytochrome P450 forms by lansoprazole and omeprazole in vitro. Xenobiotica 2005; 35:27.50. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedi calProducts/ucm213321.htm (Accessed on June 02, 2010).51. 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.e1.52. Howell MD, Novack V, Grgurich P, et al. Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection. Arch Intern Med 2010; 170:784.53. 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.

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