**4. Proton pump inhibitors (PPIs)**

PPIs, currently available on the market, include omeprazole (Prilosec®), esomeprazole (Nexium®), lansoprazole (Prevacid®), dexlansoprazole (Dexilant®), pantoprazole (Protonix®), and rabeprazole (Aciphex®). PPIs are available both over-the-counter or via a prescription and are widely used to manage GERD, treatment/prevention of PUD, dyspepsia, pyrosis, *H. pylori* eradication, NSAID-induced ulcers, and erosive esophagitis [22].

PPIs irreversibly bind to the (H+, K+)-ATPase enzyme in the stomach's parietal cells, preventing gastric acid (H+) release [23]. PPIs are prodrugs converted to the active form (sulphenamide) of the drug via protonation by hydrogen ions in the gastric acid [24]. Dexlansoprazole (Dexilant®), the R-enantiomer of lansoprazole, is available as a unique dual delayed-release formulation. Dexlansoprazole is currently the only dual delayed-release formulation of a PPI commercially available in the United States [25]. Dexlansoprazole capsules contain two sets of enteric-coated granules designed to disintegrate at different pH levels [25]. The first set of granules begins to disintegrate in the proximal small intestine and the second set disintegrates at a higher pH further down the intestinal tract [25].

PPIs are the recommended first-line agents for pharmacological management of GERD. An 8-week course of therapy is recommended to provide symptomatic relief and allows healing of erosive esophagitis [4]. All PPIs are considered clinically equivalent; therefore, any agent is acceptable as a first-line option [4]. Once a day, dosing before the first meal of the day is recommended initially for most PPIs [25]. Administering traditional delayed-release PPIs 30–60 minutes prior to meals is preferred in order to obtain optimal pH control. Administration of PPIs before meals allow the prodrug to be converted to the active sulphenamide form via gastric acid [26]. In contrast, newer formulations such as Dexilant® do not have to be administered regarding meals, allowing for dosing flexibility [4]. If a patient only has a partial response to PPI therapy, it is recommended to either change the timing of the dose or switch to a different PPI [4]. If neither of these changes is effective, further options include increasing the PPI from once to twice daily, primarily if the patient reports night-time symptoms or sleep disturbances [4]. Alternatively, a trial of dexlansoprazole can be considered due to its unique release mechanism, which may help reduce breakthrough symptoms [25]. Maintenance therapy beyond the initial 8 weeks can be considered if the patient continues to be symptomatic after completion of therapy or has complications such as Barrett's esophagus or erosive esophagitis [4]. The lowest effective dose possible should always be used to avoid complications and long-term side effects [4].

Typical side-effects include headache, diarrhea, nausea, vomiting, and abdominal pain. PPIs' potentially more severe side effects include hypomagnesemia, B12 deficiency, increased risk of osteoporosis-related fractures, and *C. difficile* infections. PPIs should not be used long-term unless instructed by the patient's provider to minimize the risk of the severe side effects mentioned above. Other potential risks include reduced nutrient absorption, dementia, and an increased risk of pneumonia [27].

The reduction of gastric acid due to PPI use may result in decreased absorption of vitamin B12 (cyanocobalamin), iron, and calcium salts [28]. It is recommended for patients to be monitored for pernicious anemia while on PPI therapy [28].

As mentioned above, PPI therapy use can potentially increase the risk of developing a *C. difficile* infection. Therefore, it should be used cautiously in high-risk patients for *C. difficile* [4]. Additionally, increasing evidence suggests a link between acid-suppression therapy and community- and hospital-acquired pneumonia [27]. Short-term PPI usage may increase the risk of community-acquired pneumonia compared to long-term users [4]. Several theories have been proposed to rationalize this association discussed previously. Initiating a PPI after the first case of pneumonia is associated with an increased risk of recurrent pneumonia. The risk seems to be elevated during the first 30 days of PPI use [27, 29].

Another potential side-effect of long-term PPI use is osteoporosis [4]. It is not recommended to discontinue a PPI in patients diagnosed with osteoporosis [4]. Additionally, concern for hip fractures and osteoporosis should not affect the decision to initiate PPIs for long-term use as long as other risk factors for osteoporosis are not present [4]. Patients treated with bisphosphonates such as alendronate should consider using H2RA for GERD as PPIs can potentially increase the risk of fracture for patients with osteoporosis by 38% [30]. While, all PPIs have similar safety profiles if a patient does experience a side effect with a particular PPI, switching to another PPI can potentially reduce adverse drug reactions [4].

Similar to H2RAs, drug interactions, while taking a PPI, can occur due to increasing the pH of the stomach [15]. Medications that require an acidic environment for absorption include itraconazole, ketoconazole, ampicillin, cephalosporins, sulfonylureas, dasatinib, iron salts, gefitinib, enteric-coated budesonide, and cyanocobalamin [31]. PPIs with specific antiretroviral agents such as atazanavir, delavirdine, and nelfinavir can decrease their bioavailability. Therefore, the coadministration of PPIs with these medications should be avoided [32].


## **Table 3.**

*PPI dose, frequency, and duration of use recommended for GERD [34–39].*

In 2009, the FDA issued warnings regarding concomitant PPI therapy and clopidogrel use. Clopidogrel is a prodrug activated to its active metabolite through the CYP 450 mechanism [4, 33]. All PPIs apart from dexlansoprazole have been found to exert some degree of CYP2C19 inhibition. Furthermore, all PPIs, including dexlansoprazole, are CYP2C19 substrates [33]. For a patient taking clopidogrel, PPIs can potentially reduce their antiplatelet effects due to CYP2C19 inhibition [4, 33]. Consider the use of a PPI with minimal or no impact on CYP2C19, such as rabeprazole, pantoprazole, lansoprazole, or dexlansoprazole if a PPI is necessary for a patient receiving clopidogrel as these did not result in a clinically significant reduction in exposure to the active metabolite of clopidogrel or clopidogrel-induced platelet inhibition [4, 33]. The use of omeprazole and esomeprazole significantly reduced the antiplatelet activity of clopidogrel when administered concomitantly or 12 hours apart [4, 33]. Pantoprazole is the preferred PPI in the hospital setting to minimize drug interactions as it is a weak CYP2C19 inhibitor (**Table 3**) [4, 33].
