ChemInform Abstract: The Mechanism of Action of the Gastric Acid Secretion Inhibitor Omeprazole.

Lindberg, Per; Nordberg, Peter; Alminger, Tomas; Braendstroem, A.; Wallmark, Björn

doi:10.1002/chin.198704211

Cited by 53 publications

(73 citation statements)

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“…The pKa2 determines the activation rate of PPIs and affects the stability of acid suppression. The active form of the drug forms covalent disulphide bonds with cysteines accessible from the exoplasmic surface of the enzyme thus inhibiting it; studies by Sachs et al showed that proton pump inhibition is not irreversible (9)(10)(11)(12)(13)(14).…”

Section: Mechanism Of Action Of Ppismentioning

confidence: 99%

Proton pump inhibitors in gastroesophageal reflux disease: a custom-tailored therapeutic regimen

Sobrino-Cossío

López-Alvarenga

Remes-Troche

et al. 2012

Rev. esp. enferm. dig.

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The Montreal Definition and Classification divides Gastroesophageal Reflux Disease (GERD) into esophageal symptomatic syndromes (and with mucosal damage) and extraesophageal syndromes (with acid established association and proposed association). In typical GERD symptoms, an 8-week treatment with PPIs is satisfactory in most cases (> 90%). Response rates to PPIs in GERD are highly variable, as they also rely on an appropriate clinical diagnosis of the disease; endoscopy differentiates the macroscopic GERD phenotype. The non-erosive variety (50-70% prevalence) has a different symptomatic response rate, as gastric acid is not the sole etiology of symptoms. The possible explanations of treatment failure include treatment adherence, PPI metabolism alterations and characteristics, and inadequate diagnosis. Refractory symptoms are related to gastric content neutralization by the chronic use of PPIs.Extraesophageal manifestations are associated with other pathophysiological mechanisms where an autonomic nervous system disturbance gives rise to symptoms. In these clinical entities, the relationship between symptoms and acid needs to be established in order to determine the use of PPIs, or consider other drugs. In other words, so as to "custom-tailor the best-fitting therapy" we need to answer the questions for whom, for what, how and for how long. Finally, PPI safety and tolerability are factors to be considered in elderly patients requiring chronic PPI use, who usually have chronic concomitant illnesses.

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Section: Mechanism Of Action Of Ppismentioning

confidence: 99%

Proton pump inhibitors in gastroesophageal reflux disease: a custom-tailored therapeutic regimen

Sobrino-Cossío

López-Alvarenga

Remes-Troche

et al. 2012

Rev. esp. enferm. dig.

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“…37 This would involve the rearrangement of the PPI to form a permanent action with the N of the pyridine now linked directly to the 2C of the benzimidazole (please see below). The protonation of the pyridine moiety was accepted for many years as the protonation reaction that initiated activation of the PPIs, [37][38][39] but the experiments on this were performed initially at acidic pH and with high cysteine concentrations present and omeprazole was the only PPI on which these experiments were performed. With the introduction of other PPIs with generally similar pyridine pK a s, different rates of activation were found which cannot be explained as being due to the pyridine.…”

Section: Hk Atpase Inhibitors Ppismentioning

confidence: 99%

The Gastric H,K ATPase as a Drug Target

Sachs¹,

Shin²,

Vagin³

et al. 2007

Journal of Clinical Gastroenterology

139

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The recent progress in therapy if acid disease has relied heavily on the performance of drugs targeted against the H,K ATPase of the stomach and the H2 receptor antagonists. It has become apparent in the last decade that the proton pump is the target that has the likelihood of being the most sustainable area of therapeutic application in the regulation of acid suppression. The process of activation of acid secretion requires a change in location of the ATPase from cytoplasmic tubules into the microvilli of the secretory canaliculus of the parietal cell. Stimulation of the resting parietal cell, with involvement of F-actin and ezrin does not use significant numbers of SNARE proteins, because their message is depleted in the pure parietal cell transcriptome. The cell morphology and gene expression suggest a tubule fusion-eversion event. As the active H,K ATPase requires efflux of KCl for activity we have, using the transcriptome derived from 99% pure parietal cells and immunocytochemistry, provided evidence that the KCl pathway is mediated by a KCQ1/KCNE2 complex for supplying K + and CLIC6 for supplying the accompanying Cl − . The pump has been modeled on the basis of the structures of different conformations of the sr Ca ATPase related to the catalytic cycle. These models use the effects of site directed mutations and identification of the binding domain of the K competitive acid pump antagonists or the defined site of binding for the covalent class of proton pump inhibitors. The pump undergoes conformational changes associated with phosphorylation to allow the ion binding site to change exposure from cytoplasmic to luminal exposure. We have been able to postulate that the very low gastric pH is achieved by lysine 791 motion extruding the hydronium ion bound to carboxylates in the middle of the membrane domain. These models also allow description of the K + entry to form the K + liganded form of the enzyme and the reformation of the ion site inward conformation thus relating the catalytic cycle of the pump to conformational models. The mechanism of action of the proton pump inhibitor class of drug is discussed along with the cysteines covalently bound with these inhibitors. The review concludes with a discussion of the mechanism of action and binding regions of a possible new class of drug for acid control, the K + competitive acid pump antagonists.Keywords the H; K ATPase; acid secretion; acid pump antagonist; proton pump inhibitor Acid secretion by the human stomach results in a median diurnal pH of 1.4. At the turn of the 19th century, it was recognized that acid secretion is involved in peptic ulcer disease Reprints: Dr George Sachs, DSc, MD, Membrane Biology, Bldg 113, Rm 324, 11301 Wilshire Blvd., Los Angeles, CA 90073 (gsachs@ucla.edu). Until the introduction of cimetidine, a histamine-2 receptor blocker, 3 there was no therapy that was effective in suppressing acid secretion acceptable to patients. The introduction of this medication and other histamine-2 receptor antagonists revolutionized the t...

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“…It was postulated that this class of compound acted as a prodrug that only reacted with the ATPase after this acid catalyzed conversion to an active form, perhaps the sulfenic acid or sulfenamide [33,34]. Later, it was shown that the final structure generated in acidic solutions was a rearranged planar tetracyclic compound containing a highly -SH reactive sulfenamide group [35]. It is not clear whether the sulfenic acid or its dehydro form, the sulfonamide is responsible for covalent binding to the H,K-ATPase.…”

Section: The Proton Pump Inhibitorsmentioning

confidence: 99%

“…These active forms, either the cyclic sulfenamide or the sulfenic acid is very reactive with the thiol groups of cysteine which can then form a disulfide bond with inhibition [35].…”

Section: Cellular Mechanismmentioning

confidence: 99%

Gastric H,K-ATPase as a Drug Target

Shin

Sachs

2006

Dig Dis Sci

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ChemInform Abstract: The Mechanism of Action of the Gastric Acid Secretion Inhibitor Omeprazole.

Abstract: 211ChemInform Abstract Omeprazole (I) is transformed by gastric acid, producing a mixture of the isomeric thiadiazine derivatives (II).

Cited by 53 publications

References 1 publication

Proton pump inhibitors in gastroesophageal reflux disease: a custom-tailored therapeutic regimen

Proton pump inhibitors in gastroesophageal reflux disease: a custom-tailored therapeutic regimen

The Gastric H,K ATPase as a Drug Target

Gastric H,K-ATPase as a Drug Target

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