{"id":773,"date":"2012-06-01T00:00:03","date_gmt":"2012-06-01T07:00:03","guid":{"rendered":"http:\/\/rhochistj.org\/RCP_TEST\/?p=773"},"modified":"2014-02-07T11:15:09","modified_gmt":"2014-02-07T18:15:09","slug":"proton-pump-inhibitor-use-complications","status":"publish","type":"post","link":"https:\/\/rhochistj.org\/RhoChiPost\/proton-pump-inhibitor-use-complications\/","title":{"rendered":"Proton Pump Inhibitor Use and Complications"},"content":{"rendered":"

By: Lauren Kaveski, Pharm.D. Candidate c\/o 2013<\/span><\/p>\n

–<\/p>\n

We see proton pump inhibitors (PPIs) used in many medication regimens, but it is unknown whether the majority of patients receive these medications for appropriate durations or indications.\u00a0 For all labeled indications, other than Zollinger-Ellison Syndrome (a rare condition characterized by damaging gastrin hypersecretion and subsequent hydrochloric acid eviction from gastric parietal cells), the length of prescription PPI use should not exceed eight successive weeks.1<\/sup>\u00a0 This class of medications is readily accessible over the counter (OTC) with a projected usage of 14 days.1<\/sup>\u00a0 Extended PPI consumption is indicated for patients taking certain medications that augment the risk of a gastrointestinal bleed, such as long-term oral steroids, non-steroidal anti-inflammatory drugs (NSAIDs), and clopidrogel (Plavix\u00ae<\/sup>).1<\/sup><\/p>\n

Using PPIs for prophylaxis against ulceration of the gastrointestinal track remains an off-labeled indication, and it is unknown whether there is a better class of medications for this indication.\u00a0 The PPIs available in the United States are rabeprazole (Aciphex\u00ae<\/sup>), dexlansoprazole (Dexilant\u00ae<\/sup>), esomeprazole (Nexium\u00ae<\/sup>), lansoprazole (Prevacid\u00ae<\/sup>), omeprazole (Prilosec\u00ae<\/sup>), pantoprazole (Protonix\u00ae<\/sup>), esomeprazole \/ naproxen (Vimovo\u00ae<\/sup>), and omeprazole \/ sodium bicarbonate (Zegerid\u00ae<\/sup>).\u00a0 Omeprazole, omeprazole \/ sodium bicarbonate, lansoprazole, and pantoprazole are now available as generics, and each of these, except pantoprazole, are available as OTCs.1,2<\/sup><\/p>\n

Reports from MedWatch\u00a9<\/sup> motivated a number of investigators to conduct epidemiological studies, including but not limited to prospective and retrospective cohorts, case-control trials, medical chart reviews, and statistical data analyses on larger studies such as the Women\u2019s Health Initiative.\u00a0 There was conflicting evidence regarding the magnitude and existence of these associations.2<\/sup>\u00a0 Although these studies were individually weak (as they could not evaluate causality; hence, only associations), their quantity has demanded clinical attention.2<\/sup><\/p>\n

Enclosed within the eighth edition of DiPiro\u2019s, there is a chilling collection of adverse drug events\u00a0 associated with PPIs.3<\/sup>\u00a0 Data reveals that PPIs diminish the absorption of certain nutrients, such as iron, calcium, and cyanocobalamin (vitamin B12), and thus amplify osteoporotic pathogenesis and fracture risk.3<\/sup>\u00a0 This class of medications may also cause an overgrowth of bacteria, increasing the risk of enteric infections and community-acquired pneumonia.3<\/sup>\u00a0 Moreover, Clostridium <\/i>difficile<\/i> (C. diff.)<\/i> infections may increase due to the more alkaline gastrointestinal milieu.3<\/sup>\u00a0 Regardless of these issues, the message currently conveyed to readers is that long-term PPI use is \u201crelatively safe.\u201d3<\/sup><\/p>\n

Furthermore, in the subject area of bone fracture risk, studies are in disagreement.\u00a0 The proposed pathophysiology of enhanced fracture risk is a hindrance in the proton\/potassium ATPasein osteoclasts and\/or thwarting in calcium absorption.3<\/sup>\u00a0 However, calcium absorption is profoundly reliant on other variables, such as the presence of vitamin D, the calcium salt ingested, and the particular individual.3 <\/sup>\u00a0Fracture risk is a more recent concern, as there is apparent association between hip, wrist, forearm, and spinal fractures and PPI use.4<\/sup>\u00a0 Alas, the data is diverse and at odds.<\/p>\n

One sizeable epidemiological study unearthed that PPI ingestion correlated with a 25% increase in total fracture risk and a 47% increase in spinal fracture risk in post-menopausal women.4<\/sup>\u00a0 We need to remain mindful that these are not absolute risks; instead, they are odds-ratios that estimate relative risk.\u00a0 Relative risk conveys more reliability than the odds-ratio measurement, particularly if the incidence of the event is more than 10%.\u00a0 This particular study did not provide data to calculate the incidences of spine, wrist, or overall fractures; thus, it was not possible to computer the absolute risk.4<\/sup>\u00a0 The discrepancy existing between the absolute risk of PPI users and nonusers was not quantifiable; so, it is not feasible to relay the clinical significance of this finding to the public.\u00a0 For some reason, we have an incidence of hip fracture, but the null hypothesis remains true for this variable: there was no statistical difference between the two groups.4<\/sup>\u00a0 Moreover, a noteworthy amount of confounding variables existed within the study (e.g.<\/i> dissimilar baseline characteristics among groups), which may explain the elevated risk that was obtained.4<\/sup><\/p>\n

Despite the lack of strength of epidemiological and observational studies, the FDA is proactive.\u00a0 It added the risk of increased hip, wrist, forearm, and spinal fractures to the prescription PPI labeling.\u00a0 OTC PPIs do not have this warning, as they are for short-term use.\u00a0 Since there is only an association between PPIs and fractures with long-term PPI use, the FDA declared that short-term PPI use probably does not increase the risk of fractures.4<\/sup><\/p>\n

Fracture risk is greatest in postmenopausal women over 50 years of age who have not already had a fracture.4<\/sup>\u00a0 Data also yields an association between PPI use and fractures in elder males; but the data on this area remains conflicting and inconsistent at best.\u00a0 Moreover, there is no firm correlation between bone mineral density and PPI use.4<\/sup>\u00a0 Thus, patients should not stop taking their indicated PPIs, and should maintain regular evaluation from their physician every few months to govern whether the PPI is still required.\u00a0 As with any medication, patients should receive the lowest effective doses and durations.<\/p>\n

Cases of hypomagnesemia emerged in patients taking PPIs after three months of use.3<\/sup>\u00a0 However, the vast majority of those who suffered this side effect took PPIs for at least a year.3<\/sup>\u00a0 Hypomagnesemia may occur due to shrunken gastrointestinal absorption of magnesium, secondary to a less acidic atmosphere.3<\/sup>\u00a0 If a patient takes medications that deplete magnesium, such as thiazide diuretics, he or she has an augmented risk.3<\/sup>\u00a0 It is crucial to ensure that this side effect does not happen in digoxin users, as digoxin toxicity interconnects inversely to serum magnesium levels.3<\/sup>\u00a0 Because the myocardium needs magnesium to effectively contract, altered levels prompt life-threatening arrhythmias, in addition to palpitations, tremor, seizures, and muscle cramps and spasms.3<\/sup><\/p>\n

Physicians should acquire baseline magnesium levels and periodically monitor levels in patients who may be candidates for extensive PPIs use or who take other medications that call for magnesium level examining.\u00a0 If hypomagnesemia occurs, it may be irreversible, even with magnesium supplementation.3<\/sup>\u00a0 Magnesium levels typically normalize in patients within a week of discontinuation of the causative PPI.3<\/sup>\u00a0 Upon removal of the PPI, the patient can receive a histamine-2-receptor-antagonist (H2RA) to manage the rebound hypergastrinemia, as well as to replace the PPI if needed and if effective for the particular patient.3<\/sup>\u00a0 Quick administration of intravenous magnesium to correct the situation is appropriate if hypomagnesemia becomes symptomatic or serum magnesium dwindles to less than one milliequivalent per liter.3<\/sup>\u00a0 The FDA found no increased risk of occurrence of gastric \/ colon cancers or unwanted cardiovascular events, especially with omeprazole and esomeprazole, which was a public concern in the past.3<\/sup><\/p>\n

PPIs also increase the risk of infections.\u00a0 This holds true for both short and long-term use.\u00a0 This phenomenon is likely due to the PPIs\u2019 ability to diminish the body\u2019s natural acidic secretions that normally act as a barrier of defense against a plethora of microorganisms.\u00a0 In other words, PPIs, as well as histamine-2 receptor antagonists (H2-blockers) to a slighter degree, make the gastrointestinal system, a more hospitable and welcoming place for microorganisms; this allows a change in flora to occur.\u00a0 PPI users are at increased risk for succumbing to gram-negative induced nosocomial pneumonia.\u00a0 Those at highest risk have undergone intubation and used PPIs.3<\/sup><\/p>\n

Upon evaluation of 25 of the references used in the article \u201cNew warnings that PPIs (e.g. <\/i>omeprazole) might increase the risk of Clostridium difficile-associated diarrhea\u201d that appeared in Pharmacist\u2019s letter in March 2012, 17 epidemiological studies and one meta-analysis discovered a positive association or correlation \u2013 they found PPI use to be a risk factor for C. diff. <\/i>infection.2<\/sup>\u00a0 Three observational studies discovered no statistical difference in the risk for C. diff. <\/i>for the variable of PPI or acid suppression therapy use.2<\/sup>\u00a0 Three studies did not mention PPI use as a risk factor for acquisition of this gram positive, anaerobic, spore-forming bacillus.2<\/sup><\/p>\n

Risk factors commonly associated with C. diff. <\/i>infection include2<\/sup><\/p>\n