Review
Proton pump inhibitors in GORD: An overview of their pharmacology, efficacy and safety

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Abstract

Gastric acid secretion is a complex phenomenon under nervous and hormonal influence. The stimulation of proton pump (H+, K+-ATPase) in the parietal cell represents the final step of acid secretion and this knowledge has led to the development of a class of drugs, the proton pump inhibitors (PPIs), which are targeted at blocking this enzyme. Chemically, all the available PPIs consist of a benzimidazole ring and a pyridine ring, but vary in the specific side ring substitution. As a class, they are the most potent inhibitors of gastric acid secretion available. Although there are differences among PPIs concerning their pharmacokinetics, pharmacodynamics, influence by food and antacids as well as potential for drug interactions, it is not always evident whether these often subtle differences are clinically relevant. A careful evaluation of the available studies reveals that rabeprazole and esomeprazole achieve more rapid acid inhibition than other PPIs. Also, the effect of rabeprazole is less dependent upon genetic make-up than all other PPIs, giving rise to less inter-subject variability and leading to a more predictable effect. Esomeprazole, by inhibiting its own catabolism, makes all patients slow metabolizers, but could expose them to potential drug interactions. PPIs are the mainstay of medical treatment of gastro-oesophageal reflux disease (GORD), in that they are able to provide 80–85% healing rate of oesophageal lesions, including ulcers, and to reduce the incidence of complications like strictures as well as dysplasia and adenocarcinoma in Barrett's oesophagus (BO). Also relief of symptoms can be achieved in about 80% of cases, even though this benefit is reduced by a factor of approximately 20% in patients with non-erosive reflux disease (NERD). Their effect on Barrett's oesophagus and the extra-oesophageal manifestations of GORD is much less consistent. In general, the tolerability profile of PPIs is good in both short- and long-term clinical trials. This safety profile is similar across the various PPIs used in clinical practice and is extended to children and pregnant women, where they do not present any major teratogenic risk.

Section snippets

Regulation of acid secretion

Gastric acid secretion is under nervous and hormonal influence [1]. This physiologic process is controlled by a number of redundant second messenger pathways activated as a result of the binding of gastrin, acetylcholine, histamine, and prostaglandins to the specific receptors on the basolateral surface of parietal cells. The stimulatory effect of acetylcholine and gastrin is mediated by an increase in cytosolic calcium, whereas that of histamine is mediated by activation of adenylate cyclase

Chemistry and pharmacology of PPIs

Chemically, all the available PPIs [8], [9] consist of a benzimidazole ring and a pyridine ring, but vary in the specific side ring substitution (Fig. 2). They are all weak protonatable pyridines, with a pKa of about 4 for omeprazole and lansoprazole, about 3.9 for pantoprazole, and about 5.0 for rabeprazole. As a result, once drugs have reached the gastric mucosa after systemic absorption, they accumulate specifically and selectively in the secretory canaliculus, the highly acidic space of the

Why are PPIs better antisecretory agents than H2-RAs?

H2-RAs have a relatively short duration of action and, depending on the individual agent and whether the patient is in a fed or fasting state, suppress acid for approximately 4–8 h [14] Consequently, multiple daily doses of these agents are likely to be required. Furthermore, H2-RAs produce incomplete inhibition of post-prandial gastric acid secretion. Overall, these agents inhibit acid secretion by up to 70% over a 24-h period [14], [15].

A further shortcoming is that tolerance to standard H2

Are currently available PPIs all the same?

Although there are differences among PPIs concerning their pharmacokinetics, pharmacodynamics, influence by food and antacids as well as potential for drug interactions [8], [38] it is not always evident whether these often subtle differences are clinically relevant. Several comprehensive analyses of the available clinical trials concluded that – when used at equivalent doses in the treatment of various acid-related disorders – all the available agents are similarly effective [8], [39], [40].

Therapy of gastro-oesophageal reflux disease

According to the recent Montreal definition [52], gastro-oesophageal reflux disease is a chronic condition, which develops when the reflux of stomach contents causes troublesome and recurrent symptoms, which could be typical (i.e. oesophageal) and atypical (i.e. extra-oesophageal), and/or complications. Possible complications include oesophagitis, ulcer, stricture and Barrett's oesophagus.

The aims of treatment of GORD include [53]:

  • Relief of symptoms and improvement of Quality of Life (QoL).

Short- and long-term safety of proton pump inhibitors

PPIs represent a very effective class of drugs, widely prescribed in all age populations, often to patients with co-morbid conditions (and therefore polymedicated) and, in some instances, for prolonged periods of time. All these factors may challenge their safety profile. However, the tolerability of PPIs in both short- and long-term use has been remarkably good. This safety profile is similar across the various PPIs used in clinical practice. The most common adverse events are represented by

Conclusions

Since their introduction into clinical practice almost two decades ago, PPIs have revolutionized the medical treatment of GORD. The marked progress that has been achieved in symptom resolution and oesophageal mucosal healing has made PPIs the first choice treatment not only for reflux disease but also for other acid-related diseases. Although PPIs are very effective drugs they are still far from the ideal antisecretory compound and display a number of shortcomings mainly due to their intrinsic

Authors’ declaration of personal interests

The authors have received consulting and/or lecture fees from pharmaceutical companies and other organizations. The authors have received research support from charities and government sources at various times. No author has any direct stock holding in any pharmaceutical company.

Acknowledgements

This work was carried out thanks to an unrestricted educational grant from Janssen-Cilag Italy, who supported the meetings amongst the authors. The Company had no role in design, planning or execution of the review, or in writing the manuscript. The terms of the financial support from Janssen-Cilag included freedom for the authors to reach their own conclusions, and an absolute right to publish the results of their work, irrespective of any conclusions reached. Janssen-Cilag did not have the

References (249)

  • P.O. Katz et al.

    Histamine receptor antagonists, proton pump inhibitors and their combination in the treatment of gastro-oesophageal reflux disease

    Best Pract Res Clin Gastroenterol

    (2001)
  • K.E.L. McColl et al.

    Proton pump inhibitors—differences emerge in the hepatic metabolism

    Dig Liver Dis

    (2002)
  • M. Tonini et al.

    Clinical pharmacology and safety profile of esomeprazole, the first enantiomerically pure proton pump inhibitor

    Dig Liver Dis

    (2001)
  • F. Pace et al.

    The lessons learned from randomized clinical trials of GERD

    Dig Liver Dis

    (2007)
  • N. Chiba et al.

    Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease: a meta-analysis

    Gastroenterology

    (1997)
  • I.M. Gralnek et al.

    Esomeprazole versus other proton pump inhibitors in erosive esophagistis: a meta-analysis of randomized clinical trials

    Clin Gastroenterol Hepatol

    (2006)
  • J.E. Richter et al.

    Efficacy and safety of esomeprazole compared with omeprazole in GERD patients with erosive esophagitis: a randomized controlled trial

    Am J Gastroenterol

    (2001)
  • P. Miner et al.

    Rabeprazole in nonerosive gastroesophageal reflux disease: a randomized placebo-controlled trial

    Am J Gastroenterol

    (2002)
  • E.M. Quigley

    Functional dyspepsia (FD) and non-erosive reflux disease (NERD): overlapping or discrete entities?

    Best Pract Res Clin Gastroenterol

    (2004)
  • B.B. Dean et al.

    Effectiveness of proton pump inhibitors in nonerosive reflux disease

    Clin Gastroenterol Hepatol

    (2004)
  • M. Frazzoni et al.

    Pathophysiological characteristics of the various forms of gastro-oesophageal reflux disease. Spectrum disease or distinct phenotypic presentations?

    Dig Liver Dis

    (2006)
  • J.P. Galmiche et al.

    Functional esophageal disorders

    Gastroenterology

    (2006)
  • R.A. Davidson

    Does it work or not? Clinical vs statistical significance

    Chest

    (1994)
  • A. Caos et al.

    Rabeprazole for the prevention of pathologic and symptomatic relapse of erosive or ulcerative gastroesophageal reflux disease. Rabeprazole Study Group

    Am J Gastroenterol

    (2000)
  • S.J. Hersey et al.

    Gastric acid secretion

    Physiol Rev

    (1995)
  • E. Lindstrom et al.

    Control of gastric acid secretion: the gastrin–ECL cell-parietal cell axis

    Comp Biochem Physiol A Mol Integr Physiol

    (2001)
  • Shin JM, Munson K, Vagin O, Sachs G. The gastric H+, K+-ATPase: structure, function, and inhibition. Pflugers Arch; in...
  • W.Y. Chey et al.

    Neural control of the release and action of secretin

    J Physiol Pharmacol

    (2003)
  • L. Olbe et al.

    A proton-pump inhibitor expedition: the case histories of omeprazole and esomeprazole

    Nat Rev Drug Discov

    (2003)
  • C.A.M. Stedman et al.

    Review article: comparison of the pharmacokinetics, acid suppression and efficacy of proton pump inhibitors

    Aliment Pharmacol Ther

    (2000)
  • G. Sachs

    Proton pump inhibitors and acid-related diseases

    Pharmacotherapy

    (1997)
  • W. Kromer

    Relative efficacies of gastric proton-pump inhibitors on a milligram basis: desired and undesired SH reactions. Impact of chirality

    Scand J Gastroenterol

    (2001)
  • G. Sachs et al.

    The pharmacology of the gastric acid pump: the H+, K+-ATPase

    Annu Rev Pharmacol Toxicol

    (1995)
  • J.G. Hatlebakk et al.

    Proton pump inhibitors: better acid suppression when taken before a meal than without a meal

    Aliment Pharmacol Ther

    (2000)
  • D.G. Colin-Jones

    The role and limitations of H2-receptor antagonists in the treatment of gastro-oesophageal reflux disease

    Aliment Pharmacol Ther

    (1995)
  • C. Scarpignato et al.

    Traitment médical du RGO par les antagonistes des récepteurs H2 de l’histamine

    Gastroenterol Clin Biol

    (1999)
  • C.H. Wilder-Smith et al.

    Tolerance during dosing with H2-receptor antagonists. An overview

    Scand J Gastroenterol

    (1992)
  • K. Furuta et al.

    Tolerance to H2 receptor antagonist correlates well with the decline in efficacy against gastroesophageal reflux in patients with gastroesophageal reflux disease

    J Gastroenterol Hepatol

    (2006)
  • A.K. Sandvik et al.

    Review article: the pharmacological inhibition of gastric acid secretion: tolerance and rebound

    Aliment Pharmacol Ther

    (1997)
  • A. Rackoff et al.

    Histamine-2 receptor antagonists at night improve gastroesophageal reflux disease symptoms for patients on proton pump inhibitor therapy

    Dis Esophagus

    (2005)
  • H.A. Redstone et al.

    H2-receptor antagonists in the treatment of functional (nonulcer) dyspepsia: a meta-analysis of randomized controlled clinical trials

    Aliment Pharmacol Ther

    (2000)
  • J. Zacny et al.

    Systematic review: the efficacy of intermittent and on-demand therapy with histamine H2-receptor antagonists or proton pump inhibitors for gastro-oesophageal reflux disease patients

    Aliment Pharmacol Ther

    (2005)
  • D. Earnest et al.

    Managing heartburn at the ‘base’ of the GERD ‘iceberg’: effervescent ranitidine 150 mg b.d. provides faster and better heartburn relief than antacids

    Aliment Pharmacol Ther

    (2000)
  • M. Robinson et al.

    Synergy between low-dose ranitidine and antacid in decreasing gastric and oesophageal acidity and relieving meal-induced heartburn

    Aliment Pharmacol Ther

    (2001)
  • S. Xue et al.

    Bedtime H2 blockers improve nocturnal gastric acid control in GERD patients on proton pump inhibitors

    Aliment Pharmacol Ther

    (2001)
  • L.B. Cross et al.

    Combination drug therapy for gastroesophageal reflux disease

    Ann Pharmacother

    (2002)
  • T. Pan et al.

    Additional bedtime H2-receptor antagonist for the control of nocturnal gastric acid breakthrough

    Cochrane Database Syst Rev

    (2004)
  • N. Vakil et al.

    The effect of over-the-counter ranitidine 75 mg on night-time heartburn in patients with erosive oesophagitis on daily proton pump inhibitor maintenance therapy

    Aliment Pharmacol Ther

    (2006)
  • W.C. Orr

    Night-time gastro-oesophageal reflux disease: prevalence, hazards, and management

    Eur J Gastroenterol Hepatol

    (2005)
  • R. Tutuian et al.

    Nocturnal acid breakthrough: pH, drugs and bugs

    Eur J Gastroenterol Hepatol

    (2004)
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