Gastroenterology

Gastroenterology

Volume 139, Issue 4, October 2010, Pages 1115-1127
Gastroenterology

Reviews in Basic and Clinical Gastroenterology and Hepatology
Safety of Proton Pump Inhibitor Exposure

https://doi.org/10.1053/j.gastro.2010.08.023Get rights and content

Proton pump (H+/K+–adenosine triphosphatase) inhibitors (PPIs) are widely used to treat patients with acid-related disorders because they are generally perceived to be safe and effective. However, as with any pharmacologic agent, they have the potential for side effects. Many studies have examined the side effects of long-term or short-term PPI exposure. We review the mechanism of action of PPIs, focusing on recently released products that might have greater risks of adverse effects than older products because of increased potency and/or duration of action. We summarize the data available on the putative adverse effects of PPI therapy and propose guidelines for clinicians who prescribe these agents to limit the potential for adverse outcomes in users of these effective therapeutic agents.

Section snippets

Mechanism of Action of Proton Pump Inhibitor Therapy

PPIs are prodrugs; they require activation by parietal cells in the presence of gastric acid, which leads to formation of an active sulfenamide moiety. This moiety binds irreversibly to the hydrogen potassium ATPase on the secretory canaliculus of actively secreting parietal cells, which inhibits the ability of cells to produce hydrochloric acid.2, 4, 16, 17, 18 The prodrug is systemically absorbed or delivered directly into the bloodstream, resulting in a relatively short half-life in serum;

Vitamin B12

Gastric acidity is important for the absorption of vitamin B12.39, 40 Most dietary vitamin B12 is tightly bound to protein; it is released in the stomach by gastric acid and pepsin and binds to salivary R proteins and subsequently to intrinsic factors.41 This complex remains intact until the terminal ileum, where vitamin B12 is absorbed. PPI-induced hypochlorhydria could induce malabsorption of vitamin B12 by interfering with the acid-activated proteolytic digestion of dietary protein-bound

Balancing the Risk and Benefit of PPI Therapy

PPIs have revolutionized the management of acid-related diseases. They improve outcomes in patients with peptic ulcer disease, gastroesophageal reflux, hypersecretory conditions, and nonsteroidal anti-inflammatory drug gastropathy. Although these drugs have been linked with a number of potential adverse effects, almost all the existing data in this regard are based on observational studies that are susceptible to bias and confounding. It is important to remember that all drugs carry risks and

References (152)

  • M.B. O'Connell et al.

    Effects of proton pump inhibitors on calcium carbonate absorption in women: a randomized crossover trial

    Am J Med

    (2005)
  • R.P. Heaney

    Factors influencing the measurement of bioavailability, taking calcium as a model

    J Nutr

    (2001)
  • M.L. Kochman et al.

    Post-translation processing of gastrin in neoplastic human colonic tissues

    Biochem Biophys Res Commun

    (1992)
  • C.M. Thorburn et al.

    Gastrin and colorectal cancer: a prospective study

    Gastroenterology

    (1998)
  • Y.X. Yang et al.

    Chronic proton pump inhibitor therapy and the risk of colorectal cancer

    Gastroenterology

    (2007)
  • D.J. Robertson et al.

    Proton pump inhibitor use and risk of colorectal cancer: a population-based, case-control study

    Gastroenterology

    (2007)
  • E.C. Klinkenberg-Knol et al.

    Long-term omeprazole treatment in resistant gastroesophageal reflux disease: efficacy, safety, and influence on gastric mucosa

    Gastroenterology

    (2000)
  • D.M. Nguyen et al.

    Medication usage and the risk of neoplasia in patients with Barrett's esophagus

    Clin Gastroenterol Hepatol

    (2009)
  • X.-Q. Li et al.

    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)
  • M. Gilard et al.

    Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study

    J Am Coll Cardiol

    (2008)
  • M.L. O'Donoghue et al.

    Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials

    Lancet

    (2009)
  • D. Metz

    Proton pump inhibitor therapy: safety issues

  • S. Shi et al.

    Proton pump inhibitors: an update of their clinical use and pharmacokinetics

    Eur J Clin Pharmacol

    (2008)
  • D.C. Metz et al.

    On-demand therapy for gastroesophageal reflux disease

    Am J Gastroenterol

    (2007)
  • T.B. Nealis et al.

    Is there a dark side to long-term proton pump inhibitor therapy?

    Am J Ther

    (2008)
  • A.S. Raghunath et al.

    Review article: the long-term use of proton-pump inhibitors

    Aliment Pharmacol Ther

    (2005)
  • R.T. Jensen

    Consequences of long-term proton pump blockade: insights from studies of patients with gastrinomas

    Basic Clin Pharmacol Toxicol

    (2006)
  • J.P. Galmiche et al.

    Tenatoprazole, a novel proton pump inhibitor with a prolonged plasma half-life: effects on intragastric pH and comparison with esomeprazole in healthy volunteers

    Aliment Pharmacol Ther

    (2004)
  • R.H. Hunt

    Review article: the unmet needs in delayed-release proton-pump inhibitor therapy in 2005

    Aliment Pharmacol Ther

    (2005)
  • R.H. Hunt et al.

    Effect on intragastric pH of a PPI with a prolonged plasma half-life: comparison between tenatoprazole and esomeprazole on the duration of acid suppression in healthy male volunteers

    Am J Gastroenterol

    (2005)
  • R.H. Hunt et al.

    Predictable prolonged suppression of gastric acidity with a novel proton pump inhibitor, AGN 201904-Z

    Aliment Pharmacol Ther

    (2008)
  • P.O. Katz et al.

    Review article: acid-related disease—what are the unmet clinical needs?

    Aliment Pharmacol Ther

    (2006)
  • D.C. Metz et al.

    Review article: dual delayed release formulation of dexlansoprazole MR, a novel approach to overcome the limitations of conventional single release proton pump inhibitor therapy

    Aliment Pharmacol Ther

    (2009)
  • D.A. Peura et al.

    Safety profile of dexlansoprazole MR, a proton pump inhibitor with a novel dual delayed release formulation: global clinical trial experience

    Aliment Pharmacol Ther

    (2009)
  • C. Scarpignato et al.

    Review article: the opportunities and benefits of extended acid suppression

    Aliment Pharmacol Ther

    (2006)
  • J.M. Shin et al.

    Pharmacology of proton pump inhibitors

    Curr Gastroenterol Rep

    (2008)
  • G. Sachs et al.

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

    Annu Rev Pharmacol Toxicol

    (1995)
  • G. Sachs et al.

    Review article: the clinical pharmacology of proton pump inhibitors

    Aliment Pharmacol Ther

    (2006)
  • C.W. Howden et al.

    Dose-response evaluation of the antisecretory effect of continuous infusion intravenous lansoprazole regimens over 48 h

    Aliment Pharmacol Ther

    (2006)
  • T.O.G. Kovacs et al.

    Intravenous and oral lansoprazole are equivalent in suppressing stimulated acid output in patient volunteers with erosive oesophagitis

    Aliment Pharmacol Ther

    (2004)
  • R.D. Lee et al.

    Clinical trial: the effect and timing of food on the pharmacokinetics and pharmacodynamics of dexlansoprazole MR, a novel dual delayed release formulation of a proton pump inhibitor—evidence for dosing flexibility

    Aliment Pharmacol Ther

    (2009)
  • D.C. Metz et al.

    Greater immediate gastric acid suppression with lansoprazole 30 mg administered as a 2-minute intravenous bolus injection versus a 30-minute infusion

    Pharmacotherapy

    (2008)
  • D.C. Metz et al.

    Comparison of the effects of intravenously and orally administered esomeprazole on acid output in patients with symptoms of gastro-oesophageal reflux disease

    Aliment Pharmacol Ther

    (2005)
  • K. Rzeszutek et al.

    Proton pump inhibitors control osteoclastic resorption of calcium phosphate implants and stimulate increased local reparative bone growth

    J Craniofac Surg

    (2003)
  • J. Tuukkanen et al.

    Omeprazole, a specific inhibitor of H+-K+-ATPase, inhibits bone resorption in vitro

    Calcif Tissue Int

    (1986)
  • N.G.M. Hunfeld et al.

    Systematic review: rebound acid hypersecretion after therapy with proton pump inhibitors

    Aliment Pharmacol Ther

    (2007)
  • E.J. Kuipers et al.

    Atrophic gastritis and Helicobacter pylori infection in patients with reflux esophagitis treated with omeprazole or fundoplication

    N Engl J Med

    (1996)
  • J.W. Freston et al.

    The clinical safety of long-term lansoprazole for the maintenance of healed erosive oesophagitis

    Aliment Pharmacol Ther

    (2009)
  • R. Lamberts et al.

    Effects of very long (up to 10 years) proton pump blockade on human gastric mucosa

    Digestion

    (2001)
  • R. Fass et al.

    Systematic review: proton-pump inhibitor failure in gastro-oesophageal reflux disease—where next?

    Aliment Pharmacol Ther

    (2005)
  • Cited by (187)

    • Drug interactions with micronutrient metabolism

      2022, Cahiers de Nutrition et de Dietetique
    • Proton pump inhibitor therapy and risk of knee replacement surgery: a general population-based cohort study

      2022, Osteoarthritis and Cartilage
      Citation Excerpt :

      As a result, PPIs are currently among the most commonly used medications for patients with OA. The prescription of PPIs has been rising in recent years, particularly among older adults10–12. While PPIs have been generally perceived to be safe and effective, an increasing concern has been raised on its potential adverse effect of hypomagnesemia10,11,13,14.

    View all citing articles on Scopus

    Conflicts of interest The authors disclose the following: Dr Metz is a consultant and receives honoraria and/or grant support from AstraZeneca, Takeda, Novartis Consumer, and Xenoport. Dr Yang discloses no conflicts.

    View full text