By Shimwoo Lee
Case: A 31-year-old man with poorly controlled type 2 diabetes was hospitalized for community-acquired pneumonia. His home medications included esomeprazole. When asked why he was receiving this medication, the patient said it was first started during his prior hospitalization for “ulcer prevention” eight months ago and that he had continued to take it since. He denied any history of upper gastrointestinal symptoms. Esomeprazole was tapered off during this admission. When being discharged after successful treatment of his pneumonia, he was told he no longer needed to take esomeprazole.
Proton pump inhibitors (PPIs) are one of the most widely used medications in the US. Last year, esomeprazole was ranked as one of the top three best-selling drugs in the nation, with 17.8 million prescriptions . PPIs are the most potent inhibitors of gastric secretion and are used to treat common upper gastrointestinal disorders, such as gastroesophageal reflux disease (GERD) and peptic ulcer disease. The effectiveness of PPIs and their perceived low toxicity profile have led to their popularity and even inappropriate overutilization in the medical setting, as exemplified by the patient case above. However, PPI use can have potentially serious medical consequences, including an increased risk of infections, malabsorption, and adverse drug-drug interactions.
Physicians use empiric PPI therapy to diagnose GERD, one of the most common gastrointestinal diseases. If symptoms improve with empiric therapy, PPIs are then continued, often indefinitely, though it may be possible to step down to acid suppression with H-2 blockers such as ranitidine. PPIs work by irreversibly inhibiting the parietal cell H+K+ATPase, a pump that actively secretes protons into the gastric lumen in exchange for potassium ions. Because PPIs take several days to cut down maximal acid output, short-term use of a PPI does not provide optimal acid inhibition . Upon discontinuation of the drug, patients can experience rebound acid hypersecretion due to hypergastrinemia, leading to worsening of GERD symptoms. These are reasons that many physicians simply keep patients on daily PPIs indefinitely. Currently, there are no evidence-based guidelines for discontinuing PPIs.
Prolonged PPI use can have serious infectious risks. Reduced acid production due to PPIs compromises the sterility of the gastric lumen, thus making it easier for pathogens to colonize the upper gastrointestinal tract and subsequently alter the colonic microbiome . The best-documented enteric infection linked to PPI use is Clostridium difficile, which is the leading cause of gastroenteritis-associated death in the US . In 2012, a meta-analysis of 42 studies linked PPI use with a significantly increased risk of both incident and recurrent C difficile infection (odds ratio 1.7) . Through a similar mechanism of decreased gastric sterility, PPIs predispose patients to other bacterial gastroenteritides, as well as to both community-acquired and nosocomial pneumonia (as, perhaps, in our patient above). A meta-analysis of 31 studies in 2011 found that patients taking PPIs were at increased risk for pneumonia (odds ratio 1.27) .
PPI use also has been implicated in gut malabsorption. In 2011, the FDA issued a safety warning regarding the risk of hypomagnesemia in patients who have been on PPIs for more than a year . PPIs promote the loss of magnesium, which is essential for nucleic acid synthesis, by disrupting active transport molecules in the gut that actively absorb magnesium . Hypomagnesemia is associated with a host of conditions, including hypertension and type 2 diabetes. Furthermore, PPI-induced hypochlorhydria can reduce calcium absorption and thus decrease bone density. The Nurses’ Health Study in 2012 demonstrated that the risk of hip fracture was 36 percent higher among postmenopausal women who regularly used PPIs for at least two years compared with nonusers .
Another reason for caution when prescribing PPIs is their potential to cause deleterious drug interactions (uncommonly). PPIs are metabolized via hepatic cytochrome P450 enzymes, CYP2C19 being the predominant isoenzyme . The use of PPIs can interfere with many other drugs sharing the same hepatic metabolic pathway, especially in individuals with CYP2C19-inactivating polymorphisms. For instance, patients on warfarin can have a 10 percent decrease in prothrombin time with concomitant use of omeprazole, and the same PPI can also lead to increased half-life of diazepam by 130 percent . Furthermore, due to studies linking omeprazole use to decreased activation of clopidogrel, the FDA issued an alert in 2009 regarding this potential drug interaction raising concern for adverse cardiovascular events; however, the clinical significance of such interaction remain controversial .
Given the possible dangers of using PPIs, the widespread practice of physicians keeping patients on prolonged PPI therapy is concerning. While currently we lack an evidence-based approach for discontinuing PPIs, the general guideline is that patients with GERD or dyspepsia deserve a consideration for a PPI taper after being asymptomatic for three to six months. In order to prevent rebound acid secretion when attempting to stop PPIs, it may be necessarily to temporarily overlap use with an H2 blocker, which when stopped does not result in acid rebound. Unfortunately, physicians frequently over-prescribe PPIs in the first place and fail to follow up their patients with a goal toward stopping unnecessary therapy . A 2010 study conducted in a Veterans’ Administration ambulatory care center showed that, of 946 patients receiving PPI therapy, 36 percent had no documented appropriate indication for initiating such therapy, and 42 percent lacked re-evaluation of their upper-GI symptoms, thus precluding any potential for step-down therapy .
Overutilization of PPIs occurs in the inpatient setting as well. In the intensive care unit (ICU), PPIs are indicated specifically for stress ulcer prophylaxis in select patients with high risk of GI bleeding, including those with coagulopathies, traumatic brain injury, and severe burns, or on long-term mechanical ventilation . However, no such indications exist in non-ICU settings. Yet, a study of 1769 non-ICU patients found that 22 percent received PPIs for stress ulcer prophylaxis, and over half of these patients were subsequently discharged home on PPIs inappropriately . The majority of physicians who prescribe PPIs in non-ICU settings appear to do so out of fear of upper GI bleeding and associated legal repercussions . However, such hospital practice not only incurs unnecessary costs but also can lead to serious harm since PPIs can further add to the already high rates of hospital-acquired C difficile infections and pneumonia.
Even if physicians were to stop over-prescribing PPIs, this would not eliminate the problem of PPI overuse. Thanks to the FDA approval of over-the-counter omeprazole (Prilosec-OTC) in 2010, more individuals have access to PPIs. Advertised as “on-demand” relief medication for people with frequent heartburn, Prilosec-OTC has a label warning against its use for more than 14 days. What is troubling with this message is that it may promote chronic on-and-off usage, which is not optimal, given that PPIs take several days to take maximal effect and can cause rebound acid reflux when stopped abruptly. Hence, over-the-counter PPIs may provide only suboptimal relief of symptoms while exposing patients to adverse side effects all the same.
We need more judicious usage of PPIs in the face of their ever-rising popularity. Their widespread use certainly attests to their effectiveness, but more care must be taken to minimize their overuse. Physicians have a big role as stewards of guiding proper use of PPIs, even Prilosec-OTC, by educating patients about the adverse effects of PPIs and keeping close track of both their prescription and over-the-counter medication lists. It is crucial for physicians to check proper indications for PPIs before prescribing them and regularly reassess patients’ symptoms for possible step-down therapy. Just as important is their role in counseling patients on lifestyle changes that can improve reflux symptoms–avoiding acidic foods, quitting smoking, and losing weight–to decrease or even eliminate the need for PPIs.
Shimwoo Lee is a 3rd year medical student at NYU School of Medicine
Peer Reviewed by Michael Poles, MD Associate Professor of Medicine, Division of Gastroenterology
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