By: Tamara Yunusova, Senior Staff Editor

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Proton Pump Inhibitors (PPIs) are acid-reducing agents that have multiple uses in the treatment and prophylaxis of conditions such as peptic ulcer diseases, H. Pylori infection, Zollinger-Ellison syndrome, GERD, and NSAID gastroduodenal ulcers. Their versatility in treating a wide range of conditions, unparalleled efficacy over their Histamine-2-receptor antagonist (H2RA) predecessors, and limited side-effect profile places them as the 9th largest class in prescription volume in the U.S., with worldwide sales of approximately 13.6 billion in 2009.^{1, 2}   However, their success has been confronted by doubt as recent studies that question the safety of long term PPI use point to a spectrum of potential health consequences ranging from malabsorption to infections (such as Clostridium difficile and community-acquired pneumonia [CAP]). These studies have raised concerns over health conditions associated with long term use of PPIs, galvanizing FDA alerts and label changes.

PPIs are lipophilic weak bases that are protonated to the activated sulphenamide form upon entry into parietal cells of the gastrointestinal (GI) tract.³ The activated form binds covalently to and inhibits the hydrogen-potassium triphosphate pump, thereby irreversibly inhibiting acid secretion.³ There are six drugs that belong to the PPI class, of which two, omeprazole (Prilosec^®) and lansoprazole (Prevacid^®), are available as over the counter medications.

In March 2011, the FDA issued a warning about low serum magnesium levels associated with long term PPI use. Hypomagnesemia is an adverse drug reaction that has been observed in patients on long term PPI use, with approximately 1% of reported cases.¹ Symptoms of hypomagnesemia include tetany, seizures, arrhythmias, and hypotension and develop with a mean onset time of 5.5 years after the initiation of PPI therapy.^1,3 Patients with this condition require hospitalization, and in 25% of cases, hypomagnesemia persists after the administration of magnesium supplements.¹ Magnesium levels are only restored after discontinuation of the PPI.¹ Furthermore, in a few notable cases, once magnesium levels were reinstated and patients were reintroduced to PPIs, symptoms of hypomagnesemia reoccured.¹ Thus, the recurrent hypomagnesemia that occurs when a patient is rechallenged with a PPI supports the idea of PPI-induced hypomagnesemia.

The FDA recommends that healthcare providers periodically monitor serum magnesium levels of patients on long term PPI therapy as well as those who may be taking any additional medications that are known to cause hypomagnesemia.¹ For patients who exhibit clinically significant hypomagnesemia, discontinuation of PPI therapy, magnesium supplementation, and alternative treatment with H2RAs are suggested courses of action.¹ Findings from other research studies have indicated that subsequent treatment with H2RAs prevents the reoccurrence of hypomagnesemia.²

In addition to magnesium, disturbances in calcium electrolyte levels are also associated with long term PPI therapy. Numerous studies have suggested that calcium absorption is dependent upon the acidic environment of the GI tract.¹ Therefore, a reduction in the acidity prompted by PPIs and other acid-reducing agents can lead to a decrease in calcium absorption. Bone fractures, one of the health consequences of long term PPI use, result from the domino effect of decreased GI acidity: the reduction in calcium absorption leads to decreased osteoblastic activity resulting in lower bone mineral density, thus increasing the risk of bone fractures.¹ Findings from the Canadian Multicentre Osteoporosis Study reveal that the use of PPIs is associated with lower bone density particularly at the hip and femoral neck.¹

While many studies associate long term PPI use with an increased risk of fractures, they fail to take multiple variables into account.¹ For instance, common risk factors for bone fractures observed in patients who take PPIs include: sedentary lifestyle and concomitant use of certain medications such as thiazide diuretics and corticosteroids (the former, being associated with depleting calcium levels).¹ Other variables include the dose (patients taking a higher dose of PPI are more likely to get fractures than those taking a lower dose) and duration of therapy (patients who take PPIs for more than a year are at a higher risk).¹ In regards to the causal link between long term PPI use and an increased risk of bone fractures, experimental results are inconclusive: in order to confirm this relationship, there is a need for further research studies that investigate the relationship in the absence of confounding variables. In 2010, the FDA issued a product label warning about the increased risk of bone fractures.¹ The warning however, was restricted to OTC PPIs in March 2011.¹

The inconclusive nature of current research is echoed by FDA and American College of Gastroenterology (ACG) policy recommendations. According to the ACG, osteoporosis is not a contraindication to PPI therapy unless another risk factor for hip fractures exists.¹ In 2013, ACG issued guidelines stating that there is inadequate evidence to require routine bone mineral density testing, calcium supplementation, and other routine precautions throughout the duration of PPI therapy.⁴ On the contrary, Health Canada issued an alert in April 2013 encouraging healthcare providers to closely monitor patients with existing risk factors for osteoporosis and stated that patients should receive PPI therapy at the lowest effective dose.¹ The FDA has issued similar recommendations.¹

In addition to interfering with the absorption of certain minerals, long term PPI use can increase susceptibility to certain infections, notably, community-acquired pneumonia (CAP) and Clostridium difficile infections. The results of a recent meta-analysis of 9 studies involving a total of 120,863 patients are surprising. While the findings show no association between CAP and PPI use that exceeds 180 days, a strong association was observed between CAP and PPI use for less than 30 days (OR, 1.65; 95% CI, 1.00-1.21).⁵ In this way, the results point to short term PPI use as a potential risk factor of CAP rather than long term use. In addition, a strong association was also observed between CAP and high dose PPI (OR, 1.50; 95% Cl, 1.33-1.68).⁵

Initially, the idea that gastric acid protects against Clostridium difficile colonization of the GI tract was dismissed in the face of the pathogen’s means of transmission via acid-resistant spores.² It was soon revisited however, when several research studies showed a higher risk of infection in patients who use PPIs. According to the results of a 2005 retrospective study, patients taking PPIs had a 2.9-fold increase in the risk of acquiring C. difficile compared to those who were not on a PPI.⁶ In addition, patients on concomitant therapy of a PPI and C. difficile treatment were 42% more likely to experience recurrent infection after completing therapy.⁶ While the pathogenesis remains poorly understood, it is believed that lower gastric acid levels facilitate the conversion of the spore to the vegetative form thereby allowing the pathogen to thrive in the lumen of the GI tract.²

Studies have also shown that PPIs, which are metabolized by the cytochrome P450 pathway, specifically by CYP2C19 and CYP3A4 enzymes, alter the pharmacodynamics of clopidogrel (Plavix^®). As a prodrug, clopidogrel requires transformation into its active metabolite form, a process that is also mediated by CYP2C19 and CYP3A4 enzymes.² Thus, it has been thought that competition at CYP2C19 can reduce the activity of the drug. This pharmacodynamic interaction was confirmed by in vitro studies which showed a reduced antiplatelet effect and increased platelet activity.² In January 2009, the FDA advised against concomitant use of clopidogrel and all PPIs.² Shortly after, the recommendation was revised to warn only against omeprazole, esomeprazole, and cimetidine as potent CYP2C19 inhibitors. This modification was made on the basis of several retrospective database studies, which indicated that higher rates of stent thrombosis, myocardial infarction, and death were observed in patients taking clopidogrel with a PPI than in those on clopidogrel alone.²

While PPIs are efficacious in treating a variety of conditions, they are accessible as OTC self-treatment for long term use, which can render patients more susceptible to harmful health consequences in the absence of any monitoring or physician intervention. In the face of limited and conflicting research studies, the results of current studies serve as an introductory caveat to long term PPI therapy. More research remains to be conducted in order to disarm the underlying details of pathogenesis of long term PPI-induced malabsorption and infection.

SOURCES:

1. Culpepper BL, Galdo JA, O’Neill LW. Long-term consequences of chronic proton pump inhibitor use. U.S. Pharmacist. 2013;38(12):38-42. http://www.uspharmacist.com/content/d/feature/c/45678/
2. Johnson DA, Oldfield EC. Reported side effects and complications of long-term proton pump inhibitor use. Clinical Gastroenterology and Hepatology. 2013;11(5):458-464. http://www.medscape.com/viewarticle/804146_2
3. Hughes JD, Lee YP, Luk CP, Parsons R. Proton pump inhibitor-associated hypomagnesemia: what do FDA data tell us? Annals of Pharmacotherapy. 2013;47(6):773-80. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3782221/
4. Kahrilas PJ, Shaheen NJ, Vaezi MF, et al. American Gastroenterological Association Institute technical review on the management of gastroesophageal reflux disease. Gastroenterology.2008;135:1392-1413. http://www.uspharmacist.com/content/d/feature/c/45678/
5. Giuliano C, Wilhelm SM, Kale-Pradhan PB. Are proton pump inhibitors associated with the development of community acquired pneumonia? A meta-analysis. Expert Rev Clin Pharmacol 2012;5:337–344
6. Dial S, Delaney JA, Barkun AN, Suissa S. Use of gastric acid-suppressive agents and the risk of community-acquired Clotridium difficile-associated disease. JAMA. 2005;294:2989-2995. http://www.uspharmacist.com/content/d/feature/c/45678/