The proton-pump inhibitors: similarities and differences

OBJECTIVE: This paper examines the clinical pharmacology of the proton-pump inhibitors (PPIs) and briefly reviews some comparative studies of these agents. BACKGROUND: PPIs have emerged as the treatment of choice for acid-related diseases, including gastroesophageal reflux disease (GERD) and peptic ulcer disease. Although these drugs-omeprazole, lansoprazole, pantoprazole, and rabeprazole-share a common structure (all are substituted benzimidazoles) and mode of action (inhibition of H+,K+-adenosine triphosphatase [ATPase]), each differs somewhat in its clinical pharmacology. RESULTS: In comparative clinical trials found in MEDLINE, PPIs administered once daily produced endoscopic evidence of healing in >90% of patients with duodenal ulcer after 4 weeks of treatment, in >90% of those with gastric ulcer after 6 weeks of treatment, and in >90% of those with ulcerative or erosive GERD after 8 weeks of treatment. Maintenance therapy with daily doses of a PPI has been shown to be an effective means of preventing GERD relapse. PPIs also inhibit the growth of Helicobacter pylori, now recognized as an important factor in peptic ulcer disease, and, when administered in combination with antibiotics, provide the best treatment for eradication of the bacterium. Rabeprazole has a more rapid onset of H+,K+-ATPase inhibition than the other PPIs and, compared with omeprazole, a greater effect on intragastric pH after the first dose. Omeprazole and lansoprazole have a greater potential for drug-drug interactions than do pantoprazole and rabeprazole. CONCLUSION: Although the individual PPIs have similar efficacy in many cases, differences between them should be considered when choosing a treatment regimen.     

Acid-suppressive strategy against gastroesophageal reflux diseases and non-erosive reflux diseases: the alternative of proton- pump inhibitors or H2 receptor antagonists

Gastroesophageal reflux disease (GERD) is categorized into three distinct entities: erosive reflux diseases(ERD), non -erosive reflux diseases(NERD) and Barrett's esophagus. In ERD, early symptomatic relief as well as healing of the esophageal mucosal injury to prevent complications is the goal of the treatment, whereas in NERD, alleviation of the symptoms leading to better quality of life is the main goal. According to the results of randomized controlled trials comparing proton-pump inhibitors (PPIs) with H2-receptor antagonists (H2RAs) head-to-head, PPIs are superior to H2RAs in the treatment for ERD. However, H2RA was equally effective with PPI to the Japanese ERD patients with low-grade esophageal mucosal breaks and positive Helicobacter pylori (H. pylori) infection. PPIs are also more beneficial than H2RAs in NERD in Western literatures but overall therapeutic gains of PPIs in NERD are lower than those reported in ERD, indicating heterogeneity of NERD pathophysiology. Again, H2RA was reported to show equal effectiveness with PPI in NERD patients with positive H. pylori status in Japan. Thus, on -demand treatment with H2RA in NERD patients with positive H. pylori status could be an alternative option. In conclusion, optimal management of the Japanese GERD patients with acid suppressive therapies should be tailored to individual conditions.     

Soraprazan: setting new standards in inhibition of gastric acid secretion

After treatment of millions of patients suffering from gastroesophageal reflux disease (GERD) and other acid-related ailments with proton pump inhibitors, there are still unmet medical needs such as rapid and reliable pain relief, especially for nocturnal acid breakthrough. In this work, we introduce and characterize the biochemistry and pharmacology of the potassium-competitive acid blocker (P-CAB) soraprazan, a novel, reversible, and fast-acting inhibitor of gastric H,K-ATPase. Inhibitory and binding properties of soraprazan were analyzed together with its mode of action, its selectivity, and its in vivo potency. This P-CAB has an IC(50) of 0.1 microM if measured with ion leaky vesicles and of 0.19 microM in isolated gastric glands. With a K(i) of 6.4 nM, a K(d) of 26.4 nM, and a B(max) of 2.89 nmol/mg, this compound is a highly potent and reversible inhibitor of the H,K-ATPase. Soraprazan shows immediate inhibition of acid secretion in various in vitro models and in vivo and was found to be more than 2000-fold selective for H,K-ATPase over Na,K- and Ca-ATPases. Soraprazan is superior to esomeprazole in terms of onset of action and the extent and duration of pH elevation in vivo in the dog. Rapid and consistent inhibition of acid secretion by soraprazan renders the P-CABs a promising group of compounds for therapy of GERD.     

Developments in the inhibition of gastric acid secretion

Understanding the physiology of gastric acid secretion and the pathophysiology of acid-related diseases (e.g. gastrooesophageal reflux and peptic ulcer) has led to the development of numerous ways to decrease acid exposure. Pharmacologically one can try to neutralize secreted acid by antacids, prevent stimulation of the parietal cell, improve mucosal defences and block the functioning of the proton pump. Proton pump inhibitors (PPIs) inhibit the final step of acid secretion, and are currently the most potent acid inhibitors. Major therapeutic improvement within the PPI class appears unlikely, as agents in this class share similar chemistry, mode of action, and pharmacokinetic profiles. New approaches that block acid secretion are now being developed. Gastrin (CCK2) receptor antagonists and potassium-competitive acid blockers (P-CABs) are in clinical development.     

Overview of medical therapy for gastroesophageal disease

The last twenty years have seen an evolution of much improved strategies in the medical treatment of GERD. Current therapy is targeted at acid suppression, to deal with consequences of mucosal injury and afford resolution of symptoms. Given their modest efficacy, there is no longer much support for initial treatment with H2RAs. PPIs have been shown to provide the highest levels of symptom relief and esophageal healing, in addition to preventing relapse and complications. With this class of agents, the clinician is able to prescribe a drug that is as highly effective as surgery for the purpose intended, without worrying about long term sequelae of acid suppression. It appears that patients with extraesophageal GERD must be treated with higher doses of pharmacologic therapy, principally with the PPIs, for longer periods of time to achieve complete relief of symptoms when compared to patients with heartburn and erosive esophagitis. There is still no clear consensus as to whether aggressive acid suppression alters the natural history of Barrett's esophagus. Based on their initial success, it appears that the next generation of evolving medical therapies will continue to play an important role in the management of GERD. The outcome from medical therapy is the standard against which the results of the novel endoscopy anti-reflux treatments will be measured.     

Effect of Food on the Pharmacokinetics and Pharmacodynamics of a Single Oral Dose of Tegoprazan

PurposeTegoprazan is a potassium-competitive acid blocker (P-CAB) that is designed to treat acid-related diseases through a fundamentally different mechanism than that of proton pump inhibitors (PPIs). Because PPIs inhibit only activated parietal cell H⁺/K⁺ adenosine triphosphatase, stimulation of parietal cells by a meal is necessary for optimal results. In contrast, P-CABs can inactivate proton pumps without acid activation and bind to both activated and inactivated adenosine triphosphatase. This study evaluates the effect of food consumption on the pharmacokinetic and pharmacodynamic properties of tegoprazan after a single oral dose in healthy men.MethodsIn this open-label, 2-period crossover study, 24 healthy men were randomized to 1 of 2 treatment sequence groups: administration of tegoprazan under the fasting condition and administration of tegoprazan under the fed condition. The dosing periods of both sequence groups were separated by a washout period of 7 days. At each dosing period, the participants received a single dose of 200 mg of tegoprazan followed by pharmacokinetic and pharmacodynamic analysis.FindingsAfter the oral administration of 200 mg tegoprazan, the C_max was decreased and delayed under the fed condition compared with that of the fasting condition. However, no significant differences were observed in the AUC and the time of gastric acid suppression (inhibition of integrated acidity) during 24 hours.ImplicationsThe pharmacokinetic and pharmacodynamic properties of tegoprazan are independent of food effect; thus, tegoprazan could be administered regardless of the timing of food consumption in patients. ClinicalTrials.gov identifier: NCT01830309.     

Maintenance therapy of mild form of GERD by H2 receptor antagonists

Because of high relapse rate after the healing by proton pump inhibitor(PPI) or H2 receptor antagonist(H2RA), GERD usually needs long time maintenance therapy. PPI is superior to H2RA in the first line as well as maintenance therapy. PPI is necessary for severe cases of GERD. However, H2RA is sufficient for milder form of GERD patients. Among the H2RA using in Japan, nizatidine has known to stimulate gastric emptying and elevate LES pressure. Nizatidine may be superior to other H2RAs in the treatment of GERD. Recently, nocturnal acid breakthrough which night time acid is secreted even PPI is administered twice daily has been documented. H2RAs are stronger than PPI to inhibit nocturnal acid breakthrough and may be better than night time acid reflux.     

Pathogenesis and treatment of refractory gastroesophageal reflux disease in Japanese patients

Prevalence of refractory gastroesophageal reflux disease (GERD) defined as a patient who have persistent GERD symptoms during treatment with proton pump inhibitor (PPI) is rare in Japanese patinets. Pathogenesis of refractory GERD is associated with several factors including dysfunction of esophageal motility, presence of severe hiatal hernia, complication such as stricture and short esophagus, extensive metabolizer of CYP2C19 genotype, nocturnal gastric acid breakthrough, absence of H. pylori infection, or bile reflux. Examination by 24 hr pH monitoring is necessary to assess refractory GERD and if acid suppression is insufficient, treatment with double doses of PPIs or combination of PPI and H2 blocker is effective. However, most cases of refractory GERD are required surgical treatment. Endoscopic therapy might be useful for refractory GERD in future.     

A Review of the Novel Application and Potential Adverse Effects of Proton Pump Inhibitors

Proton pump inhibitors (PPIs) are known as a class of pharmaceutical agents that target H⁺/K⁺-ATPase, which is located in gastric parietal cells. PPIs are widely used in the treatment of gastric acid-related diseases including peptic ulcer disease, erosive esophagitis and gastroesophageal reflux disease, and so on. These drugs present an excellent safety profile and have become one of the most commonly prescribed drugs in primary and specialty care. Except for gastric acid-related diseases, PPIs can also be used in the treatment of Helicobacter pylori infection, viral infections, respiratory system diseases, cancer and so on. Although PPIs are mainly used short term in patients with peptic ulcer disease, nowadays these drugs are increasingly used long term, and frequently for a lifetime, for instance in patients with typical or atypical symptoms of gastroesophageal reflux disease and in NSAID or aspirin users at risk of gastrotoxicity and related complications including hemorrhage, perforation and gastric outlet obstruction. Long-term use of PPIs may lead to potential adverse effects, such as osteoporotic fracture, renal damage, infection (pneumonia and clostridium difficile infection), rhabdomyolysis, nutritional deficiencies (vitamin B12, magnesium and iron), anemia and thrombocytopenia. In this article, we will review some novel uses of PPIs in other fields and summarize the underlying adverse reactions.     

The antithrombotic activity of EP224283, a neutralizable dual factor Xa inhibitor/glycoprotein IIbIIIa antagonist, exceeds that of the coadministered parent compounds

Inhibition of the gastric H,K-ATPase by the potassium-competitive acid blocker (P-CAB) 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (TAK-438), is strictly K(+)-competitive with a K(i) of 10 nM at pH 7. In contrast to previous P-CABs, this structure has a point positive charge (pK(a) 9.06) allowing for greater accumulation in parietal cells compared with previous P-CABs [e.g., (8-benzyloxy-2-methyl-imidazo(1,2-a)pyridin-3-yl)acetonitrile (SCH28080), pK(a) 5.6]. The dissociation rate of the compound from the isolated ATPase is slower than other P-CABs, with the t(1/2) being 7.5 h in 20 mM KCl at pH 7. The stoichiometry of binding of TAK-438 to the H,K-ATPase is 2.2 nmol/mg in the presence of Mg-ATP, vanadate, or MgP(i). However, TAK-438 also binds enzyme at 1.3 nmol/mg in the absence of Mg(2+). Modeling of the H,K-ATPase to the homologous Na,K-ATPase predicts a close approach and hydrogen bonding between the positively charged N-methylamino group and the negatively charged Glu795 in the K(+)-binding site in contrast to the planar diffuse positive charge of previous P-CABs. This probably accounts for the slow dissociation and high affinity. The model also predicts hydrogen bonding between the hydroxyl of Tyr799 and the oxygens of the sulfonyl group of TAK-438. A Tyr799Phe mutation resulted in a 3-fold increase of the dissociation rate, showing that this hydrogen bonding also contributes to the slow dissociation rate. Hence, this K(+)-competitive inhibitor of the gastric H,K-ATPase should provide longer-lasting inhibition of gastric acid secretion compared with previous drugs of this class.     

A study comparing the antisecretory effect of TAK-438, a novel potassium-competitive acid blocker, with lansoprazole in animals

Proton pump inhibitors (PPIs) are widely used for the treatment of acid-related diseases. However, several medical needs such as suppression of night-time acid secretion and rapid symptom relief remain unmet. In this study, we investigated the effects of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438), a novel potassium-competitive acid blocker, on acid secretion in rats and dogs under various conditions, in comparison with the PPI lansoprazole [2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl] methyl]sulfinyl]-1H-benzimidazole], to characterize the antisecretory action of TAK-438. TAK-438 showed a more potent and longer-lasting inhibitory effect than lansoprazole on the histamine-stimulated gastric acid secretion in rats and dogs. A pharmacokinetic study in rats showed that TAK-438 accumulated and was retained in the gastric tissue for more than 24 h, unlike that in the plasma. TAK-438 showed significant antisecretory activity with or without cimetidine pretreatment, in contrast to lansoprazole, which did not show antisecretory activity after cimetidine pretreatment in rats. TAK-438 increased the pH of the gastric perfusate to 5.7 in an unstimulated condition, and this effect was maintained in the presence of subsequent histamine stimulation. On the other hand, lansoprazole also increased the pH in an unstimulated condition, but this effect diminished after histamine stimulation. These results indicated that TAK-438 exerted a more potent and longer-lasting antisecretory effect than lansoprazole through high accumulation and slow clearance from the gastric tissue. In addition, TAK-438 was unaffected by the gastric secretory state, unlike PPIs. Therefore, TAK-438 can provide a novel mechanism of action to improve the present PPI-based treatment of acid-related diseases.     

Mechanisms of gastric proton pump inhibition by calcium channel antagonists

The inhibitory effects of Ca channel antagonists on gastric acid secretion [[14C]-aminopyrine (AP) uptake ratio] have been analyzed in isolated rabbit parletal cells (PC). Secretagogue-stimulated AP uptake was inhibited by verapamil and diltiazem in a dose-dependent manner with IC50 values of 15 and 100 microM, respectively, both in the presence and absence of extracellular Ca. In contrast, nifedipine had no effect on AP accumulation. Verapamil decreased histamine-stimulated respiration with the same IC50 as observed for AP uptake. Imidazole, a weak base, by buffering the acid spaces in PC, reversed the inhibitory effect of verapamil on respiration. In the bullfrog gastric mucosa, forskolin-stimulated proton transport was inhibited by verapamil (10(-4) M) from the luminal but not the serosal side. This inhibitory effect was reversed by either elevating KCl concentration in, or removing the drug from, the secretory solution. Verapamil inhibited gastric microsomal H+,K(+)-adenosine triphosphatase (H+,K(+)-ATPase) and PC K(+)-stimulated p-nitrophenyl phosphatase activities with a higher potency than diltiazem. Inhibition of these enzymes by verapamil and diltiazem was pH dependent. The drugs competed with K+ in both H+,K(+)-ATPase and K(+)-stimulated p-nitrophenyl phosphatase reactions. Our data suggest that inhibition of the gastric proton pump by verapamil or diltiazem is not due to their Ca channel antagonism but to their interaction with the luminal high affinity K(+)-site of the H+,K(+)-ATPase under acidic conditions.     

Effect of histamine H2-receptor antagonists on vitamin B12 absorption.

OBJECTIVE: To discuss the potential of histamine H2-receptor antagonists (H2RAs) to cause malabsorption of vitamin B12 (cyanocobalamin). DATA SOURCES: Pertinent literature was identified via a MEDLINE search. Journals and references cited in published articles also were used as data sources. STUDY SELECTION: Studies evaluating the effect of H2RAs on vitamin B12 absorption were reviewed. DATA SYNTHESIS: H2RAs decrease acid secretion by the gastric parietal cells. Gastric acid and pepsin produced by these cells are required for the cleavage of vitamin B12 from dietary sources. Intrinsic factor (IF), also produced by gastric parietal cells, is required for vitamin B12 absorption from the gastrointestinal tract. Although H2RAs have not conclusively been shown to decrease IF secretion, studies have demonstrated a significant reduction in food-bound vitamin B12 absorption secondary to decreased acid secretion in patients taking these drugs. CONCLUSIONS: H2RAs have the potential to cause vitamin B12 deficiency. This may be important in patients with inadequate stores of vitamin B12 (e.g., poor diet), particularly those receiving H2RA therapy continuously for more than two years. Healthcare providers should be aware of this potential adverse effect.     

Characteristic features of proton pump inhibitors in the inhibition of gastric acid secretion: long-acting and complete inhibition]

Proton pump inhibitor is a compound recently applied for the treatment of peptic ulcers for its strong action to inhibit the gastric acid secretion. It works through inhibition of H+, K(+)-ATPase, so called proton pump, on the luminal surface of secretory canaliculi in the parietal cells, showing remarkable characteristics in the inhibition of gastric acid secretion; e.g., the long-acting and complete inhibition. At neutral pH, the unionized form of this compound as a weak base is lipophilic, and passes through the cell membrane to accumulate as the ionized form in an acidic environment in the secretory canaliculi of parietal cells, where it is transformed to an active molecule which binds covalently to the active site of H+, K(+)-ATPase, forming a highly stable complex. The long-acting and complete inhibition of gastric acid secretion by this compound is derived from this physico-chemical nature. The above characteristics of the proton pump inhibitor have been confirmed with the basal, stimulated and nocturnal gastric acid secretion and the 24-hour intragastric pH of healthy volunteers by several investigators prior to its nation-wide clinical trial in Japan. On the other hand, the increased endocrine and exocrine secretion, such as pepsin secretion and gastrin release, and the increased turnover of gastrointestinal endocrine cells by this compound have been reported in animal models, probably due to its accumulation in the acidic environment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Proton-pump inhibition for acid-related disease.

Omeprazole and lansoprazole are the forerunners of a group of substituted benzimidazole compounds that block the gastric proton pump. These drugs exert a potent antisecretory effect by blocking the final common pathway of acid secretion. Prolonged, potent reduction of acid secretion using omeprazole has resulted in significant therapeutic advantage over existing antisecretory medication, such as H2 receptor antagonists (H2RAs). Research experience with lansoprazole indicates that it has treatment properties for acid-related disease that are similar to those of omeprazole. Omeprazole has been used successfully in the treatment of reflux esophagitis and the Zollinger-Ellison syndrome in the United States over the past year and has received approval recently as first-line therapy for duodenal ulcer disease. Research involving more than 20,000 individuals, postmarketing surveillance studies, and thorough safety studies in man and animals have shown omeprazole to be well tolerated, with an incidence and spectrum of adverse events in clinical trials similar to those observed with H2RAs.     

Proton-pump inhibitors for stress ulcer prophylaxis in critically ill patients

OBJECTIVE: To evaluate the use of proton-pump inhibitors (PPIs) for stress ulcer prophylaxis in critically ill adults. DATA SOURCES: Computerized biomedical literature search of MEDLINE (1966-June 2002) was conducted using the MeSH headings proton-pump inhibitor, ulcer, critical care, and acid. References of selected articles were reviewed. A manual search of critical care, surgery, trauma, gastrointestinal, and pharmacy journals was conducted to identify relevant abstracts. DATA SYNTHESIS: Traditional medications used for stress ulcer prophylaxis include antacids, histamine(2) receptor antagonists (H(2)RAs), and sucralfate. Few studies have evaluated PPIs for stress ulcer prophylaxis. The majority of studies have demonstrated that enteral or intravenous administration of PPIs to critically ill patients elevates intragastric pH and consistently maintains pH > or =4.0. PPIs are safe and seem to be as efficacious as H(2)RAs or sucralfate for prevention of bleeding from stress-related mucosal damage (SRMD) and they may provide cost minimization. The small patient populations limit the results of comparative studies. CONCLUSIONS: Available data indicate that PPIs are safe and efficacious for elevating intragastric pH in critically ill patients. PPIs should be used only as an alternative to H(2)RAs or sucralfate since the superiority of PPIs over these agents for preventing SRMD-associated gastrointestinal bleeding has not been established. Additional comparative studies with adequate patient numbers and pharmacoeconomic analyses are needed before PPIs are considered the agents of choice for stress ulcer prophylaxis.     

Combination drug therapy for gastroesophageal reflux disease

OBJECTIVE: To evaluate the role of combination therapy with proton-pump inhibitors (PPIs) and histamine(2) receptor antagonists in gastroesophageal reflux disease (GERD). DATA SOURCES: Clinical literature identified through MEDLINE (January 1966-August 2001). Key search terms included gastroesophageal reflux, benzimidazoles; omeprazole; lansoprazole; pantoprazole; rabeprazole; receptor antagonists, histamine(2); therapy, combination drug; therapy, combined modality; and combinations, drug. DATA SYNTHESIS: Approximately 80-90% of patients show healing of reflux esophagitis after 8 weeks of once-daily PPI therapy. Patients taking PPI therapy twice daily still have nocturnal acid breakthrough (periods of gastric pH <4 lasting for > or =60 min during the night) as much as 70% of the time. The clinical application of this finding has not been shown. One trial has shown that omeprazole in the morning plus ranitidine at bedtime is not as effective as omeprazole twice daily given before the morning and evening meals at controlling nocturnal acid breakthrough. Further, 1 small trial in healthy subjects without GERD showed that the addition of a 1-time dose of ranitidine at bedtime to a twice-daily regimen of omeprazole may decrease the occurrence of nocturnal acid breakthrough. However, the clinical significance of this finding is not clear. CONCLUSIONS: No studies in patients with GERD demonstrate that the addition of histamine(2) receptor antagonists to twice-daily PPI therapy provides any further benefit above that derived from PPIs alone. The parameter used to measure the efficacy of combination regimens for GERD thus far--nocturnal acid breakthrough--has not been proven to correlate with improvement of GERD symptoms in any controlled or prospective clinical trials. Further investigation is needed to determine optimal therapy in patients refractory to standard doses of PPIs.     

Proton pump inhibitors and gastritis

Proton pump inhibitors (PPIs) are novel compounds that strongly inhibit the H(+)/K(+)-ATPase in the gastric parietal cells to cause profound suppression of acid secretion. Acid-generating ATPase, also known as vacuolar-type ATPase, is located in the lysozomes of leukocytes and osteoclasts and its activity is also reportedly influenced by treatment with PPIs. This concept is supported by the results of studies using autoradiography in which (3)H-Lansoprazole uptake sites were clearly detected in the cytoplasmic granules of neutrophils infiltrating the gastric mucosa. In vitro studies indicate that PPIs increase the intra-vacuolar pH in the lysosomes of purified neutrophils and attenuate the adherence of neutrophils to the vascular endothelium. In clinical practice, the acidic environment in the stomach plays a critical role in the development of gastritis induced by Helicobacter pylori (H. pylori). This is worthy of note, because persistent gastritis often results in atrophic and metaplastic changes in the gastric mucosa, which are believed to be preneoplastic abnormalities. In patients with H. pylori-infection, PPI therapy causes corpus-predominant gastritis, which is frequently found in the background mucosa in patients with gastric cancer. The efficacy and safety of long-term PPI-treatment have not been conclusive, thus we need to pay more attention to the additional pharmacological actions of PPIs.     

Primary care for GEDR

Current approach for the treatment of gastroesopageal reflux disease (GERD) was reviewed. The most effective treatment of erosive esophagitis or symptomatic GERD is to reduce gastric acid secretion with either an H2 receptor antagonists (H2RA) or a proton pump inhibitor (PPI). The PPI lead to more rapid healing and symptom relief than H2RA. Despite treatment with PPI, some patients with GERD continue to have symptoms or endoscopic evidence of esophagitis. Nocturnal acid breakthrough may be one of the mechanisms responsible for the refractory GERD. There are two approaches to the initial medical treatment of gastroesophageal reflux disease ('step down' therapy or 'step up' approach). Although there are arguments in favour of both approaches, the former is considered to be preferable these days.