Considerations for Proton Pump Inhibitor Utilization

Dr. Copeland is a clinical pharmacist specialist at Parkwest Medical Center in Knoxville, Tennessee.

Proton pump inhibitors (PPIs) have been the mainstay of acid-suppression therapy since their introduction in the late 1980s. Results of 33 randomized trials show that symptomatic relief can be expected in 83% of PPI-treated patients, and esophagitis was healed in 78% of PPI-treated patients.¹ PPIs inhibit the final step of gastric acid secretion and should be taken prior to the first meal of the day for maximal effect. In patients with severe nocturnal reflux, it may be advisable to try taking the medication prior to the evening meal. Patients should be counseled that PPIs have a long onset of action, and they may not experience the full effect immediately. Once-daily dosing of PPIs results in maximum reduction of acid output at 5 days. During that time, it is reasonable to use OTC agents to supplement therapy as needed until the full effect of the PPI is seen.²

Appropriate Prescribing and Utilization

PPIs are widely prescribed due to their efficacy and relative lack of serious side effects. Studies have noted that many patients are started on PPI therapy for inappropriate reasons.3 When this occurs in the hospital setting, it is likely the medication will be continued in the outpa-tient setting regardless of clinical indication.4 Keep in mind that these studies do not take into account the utilization of OTC PPIs for non-approved indications. Currently, the only approved indication for omeprazole OTC is the treatment of heartburn for 14 days followed by discontinuation of the medication. This may be repeated for a total of 3 courses over a 12-month period. While not indicated, some patients choose to use OTC PPI therapy for long-term management of gastroesophageal reflux disease (GERD), once a diagnosis has been made, as a cost-saving measure. This is acceptable, provided that the patient is under the care of a physician for this disease process. Overall, care should be exercised that PPIs are prescribed only for patients with clear indications.

Duration of Therapy

Once it is properly identified, optimal treatment of GERD should be continued for a minimum of 8 weeks. If the patient maintains response, a trial off of the medications should be considered. If symptoms recur within 3 months, as is common, continuous therapy should be restarted. If the symptoms return more than 3 months after stopping treatment, they can generally be controlled with short-term, acute therapies.1

Potential Problems Associated with Long-Term Use of PPIs

When long-term omeprazole use was originally reviewed, a major concern was the incidence of hypergastrinemia with a potential increase in frequency of gastric carcinoid tumors. Subsequent studies did not demonstrate this risk in humans.5 An increased rate of atrophic gastritis has been seen in conjunction with omeprazole, which could theoretically lead to an increased incidence of gastric cancer in the presence of Helicobacter pylori.6 Because of this and other research, current guidelines support the identification and eradication of H pylori in patients with long-term PPI use for treatment of GERD.5

Dial et al evaluated the risk of developing community-acquired Clostridium difficile during the utilization of various medications in 2 population-based case-control trials. They noted antibiotics present the highest risk of the medications assessed; however, exposure to a PPI within the previous 90 days resulted in an increased risk for the development of C difficile.7,8

In a nested case control, the risk of hip fracture was found to be significantly increased among patients aged 50 or older who were taking PPIs for more than 1 year, especially at higher doses (defined as 1.75 times per day or more).9 Another study documented an increased risk of vertebral fracture in postmenopausal women who took omeprazole.10 Targownik et al echoed these findings, noting that 5 years of continu-ous therapy with a PPI increased the risk of hip fracture. All types of osteoporotic fractures were increased after 7 years.11 An acceptable in-tervention is to recommend use of calcium supplementation. If the patient chooses to use the least expensive option, calcium carbonate, the medication should be taken with a meal, preferably breakfast, to enhance absorption.

Vitamin B12 absorption has been shown to be decreased in the presence of chronic PPI use. It is reasonable to periodically assess patients who are receiving chronic PPI therapy for B12 deficiency.12 Malabsorption of other nutrients, specifically iron, has not been definitively es-tablished.

Very few studies have been conducted in patients who have received PPI therapy for more than 10 years, making it difficult to assess the overall impact of these concerns.

PPIs and Drug Interactions

In general, PPIs are metabolized via the cytochrome P450 (CYP450) enzyme system. Specifically, omeprazole and esomeprazole are predomi-nantly me--tabolized by CYP2C19, leading to several potential drug interactions. For example, omeprazole was recently reported to reduce the antiplatelet effect of clopidogrel.13 Given the prevalence of clopidogrel use, the impact of this is currently under review by the FDA.14 Rabeprazole is metabolized by CYP3A4 in addition to CYP2C19; however, there are few documented reports of drug interactions. Lanso--prazole is metabolized principally by CYP3A4. Finally, pantoprazole is primarily metabolized by CYP2C19, followed rapidly by sulfate conjugation. This results in the lowest potential for P450 enzyme interactions.

Enteric formulations are designed to pass through the normally acidic environment of the stomach and dissolve upon reaching the higher pH of the intestinal tract. With an elevated pH in the stomach, these medications will exhibit increased bioavailability. Citalopram, escitalo-pram, and digoxin exhibit increased absorption as well. Antifungals will generally demonstrate a decrease in absorption with elevated gas-tric pH. Antiretrovirals may exhibit either increased or decreased absorption depending on the agent used.

Adjunctive Therapy

Although PPIs demonstrate clinical efficacy in acid suppression, many pa--tients experience breakthrough symp--toms, most commonly at night. A survey of 2680 patients on chronic PPI therapy reported between 29% and 53% experienced breakthrough heartburn often more than twice a week.15 These events translate into a high degree of dissatisfaction, as indicated by polling that reflected only 58% of patients on PPIs reported a high level of satisfaction with therapy.16

To address the unmet need, large numbers of patients on PPI therapy have been identified who supplement their therapy with OTC medi-cations,15-17 and often do not tell their doctor.17 This practice presents opportunities for pharmacists to help counsel and educate patients on appropriate adjunctive therapies.

Antacids

Antacids are the least expensive and most readily available form of OTC acid control. Antacids result in almost immediate control of symp-toms, have a long history of use, and most patients are comfortable using them. Different forms of antacids include calcium salts, aluminum salts, and magnesium salts in a variety of formulations. Calcium-containing products have the benefit of supplementing calcium intake. The primary disadvantage of antacids is a relatively short duration of action. Adverse events are rare, but patients should be aware of possible accumulation of magnesium and/or aluminum with renal insufficiency, depending on the product chosen.

H2-Receptor Antagonists

H2-receptor antagonists (H2RAs) have been proven to decrease gastric acid production. All 4 H2RAs approved in the United States are available OTC in generic form and have an onset of action of less than 30 minutes after administration. They have a much longer duration of action compared with antacids; however, they are more expensive. Cimetidine and ranitidine are considered to be safe in pregnancy, which is often associated with symptoms such as heartburn. H2RAs have been demonstrated to be less effective than PPIs for both symptomatic relief and healing of esophagitis.1,2 Drug-drug interactions have been well documented with cimetidine via the P450 system. The other H2RAs are generally weak inhibitors and substrates with less potential for interactions. Ad--verse effects are generally mild.

Combination Products

Famotidine, calcium carbonate, and magnesium hydroxide are available as single-dose, OTC products (Tums Dual Action, Pepcid Complete). This combination provides the patient with both the effectiveness and duration of famotidine in addition to the rapid onset of the antacids, which can be beneficial for control of breakthrough symptoms at night.

Summary and Recommendations

PPIs are the cornerstone of therapy for conditions requiring long-term acid suppression. When a PPI is chosen, the patient should be coun-seled on the delayed onset of action. During this time, an additional OTC adjunctive therapy may be considered for immediate control. In addition, if breakthrough symptoms are experienced later, an H2RA or antacid/H2RA combination product may be added to therapy. For less severe symptoms, patients may be controlled with on-demand therapy using antacids, H2RAs, or a combination antacid/H2RA product.

Additional PPIs are likely to be available OTC within the next 24 months. During this transition, the pharmacist will be asked more questions from patients seeking to utilize these agents. Pharmacists should be aware of their proper place in therapy, potential complications associated with their use, and available alternatives to help their patients identify appropriate and effective therapy.

1. American Gastroenterological Association Institute Technical Review on the Management of Gastroesophageal Reflux Disease. Gastroenterology. 2008;135:1392-1413.

2. DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol. 2005;100:190-200.

3. Pham CQD, Regal RE, Bostwick TR, Knauf KS. Acid suppressive therapy use on inpatient internal medicine service. Ann Pharmacother. 2006;40:1261-1266.

4. Grant K, Al-Adhami N, Tordoff J, et al. Continuation of proton pump inhibitors from hospital to community. Pharm World Sci. 2006;28:189-193.

5. Jensen RT. Consequences of long-term proton pump blockade: insights from studies of patients with gastrinomas. Basic Clin Pharmacol Toxicol. 2006;98:4-19.

6. Lundell L, Miettinen P, Myyrvold HE, et al. Lack of effect of acid suppression therapy on gastric atrophy. Gastroenterology. 1999;117:319-326.

7. Dial S, Delaney JAC, Barkun A, Suissa S. Use of gastric acid-suppressive agents and the risk of community acquired Clostridium difficile associated disease. JAMA. 2005;294:2989-2995.

8. Dial S, Delaney JAC, Schneider V, Suissa S. Proton pump inhibitor use and risk of community-acquired Clostridium difficile-associated disease defined by prescription for oral vancomycin therapy. CMAJ. 2006;175:745-748.

9. Yang Y, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006;296:2947-2953.

10. Roux C, Briot K, Gossec L, et al. Increase in vertebral fracture risk in postmenopausal women using omeprazole. Calcif Tissue Int. 2008;84:13-19.

11. Targownik LE, Lix LM, Metge CJ, et al. Use of proton pump inhibitors and risk of osteoporosis related fractures. CMAJ. 2008;179:319-326.

12. Marcuard SP, Albernaz L, Khazanie PG. Omeprazole therapy causes malabsorption of cyanocobalamin. Ann Intern Med. 1994;120:211-215.

13. Gilard M, Arnaud B, Cornily JC, 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;51:256-260.

14. US Food and Drug Administration, Center for Drug Evaluation and Research. Early communication about an ongoing safety review of clopidogrel bisulfate. http://www.fda.gov/Cder/drug/early_comm/clopidogrel_bisulfate.htm. Accessed March 2009.

15. Jacobson BC, et al. Who is using chronic acid suppression therapy and why? Am J Gastroenterol. 2003;98(1):51-58.

16. Fass R, Sifrim D. Management of heartburn not responding to proton pump inhibitors. Gut. 2009;58:295-309.

17. Jones R, et al. Does the treatment of gastroesophageal reflux disease (GERD) meet patients’ needs? A survey based study. Cur Med Res Opin. 2006;22(4):657-662.