Therapeutic Benefits of PPIs

John R. Horn, PharmD, FCCP

Published Online: Monday, December 1, 2008

---

Dr. Horn is professor of pharmacy at the University of Washington School of Pharmacy and associate director of pharmacy services at the University of Washington Medical Center, Seattle, Washington.

---

Gastroesophageal reflux disease (GERD) is a widespread, chronic disease that has been estimated to cause heartburn symptoms at least monthly in over 40% of the US population and weekly in up to 20%.^1,2 GERD is most often a result of refluxed stomach contents irritating the lining of the esophagus producing symptoms such as heartburn, regurgitation, and cough. A number of risk factors have been associated with heartburn, including lifestyle (eg, smoking, obesity, recumbency after eating), diet (eg, fatty foods, citrus juices, carbonated beverages), drugs (eg, narcotics, anticholinergic agents, estrogens), and disease states (eg, motility disorders, hiatal hernia).

The goals of treatment for GERD include the clinical marker of maintaining pH >4, symptom relief, the healing of esophageal erosions, and the prevention of their recurrence. The mitigation of GERD and relief of heartburn correlates with the control of gastric acid secretion, accounting for the recognition of proton pump inhibitors (PPIs) as the drugs of choice for the treatment of GERD.^3,4 Antacids are useful for the temporary relief of heartburn, but provide no efficacy for healing erosive esophagitis. H₂-receptor antagonists (H₂RAs) are effective for both symptom relief and healing but have lower healing and higher recurrence rates than PPIs due to their lower potency of gastric acid suppression.⁵ Additionally, studies have confirmed that the long-term use of the H₂RAs may be limited by the development of tachyphylaxis, or tolerance, which can occur with H₂RA treatment in as brief as 1 week.⁶

PPIs are prodrugs that are absorbed in the small intestine, carried to the gastric parietal cell, exposed to gastric acid in the secretory canaliculus of the parietal cell, and converted to an active sulfenamide. The sulfenamide covalently binds to active proton pumps, the final common pathway for the production of gastric acid, effectively suppressing their secretion of acid.⁷ Because the PPIs are weak bases, exposure to stomach acid will greatly reduce their absorption. Therefore, most PPIs are protected from stomach acid by a pH-sensitive enteric coating that prevents dissolution until the more neutral pH of the small intestine is encountered. This delayedrelease (DR) formulation slows the time of peak PPI plasma concentration to about 1.5 to 3.5 hours after dosing and contributes to the delayed onset of acid suppression observed with all DR PPIs.⁸ Because of this extended time to peak plasma concentration, DR PPIs should be dosed 30 to 60 minutes before a meal to maximize meal-stimulated parietal cell acid secretion needed to activate the prodrug and provide active pumps to bind with the sulfenamide.

Immediate-Release Omeprazole

Immediate-release omeprazole (IR OME) formulations (suspension and capsule) use sodium bicarbonate to protect the OME from gastric acid, thus eliminating the need for enteric coating (Table).⁹ IR OME is absorbed more quickly than DR OME, with IR OME peak plasma concentration occurring about 30 minutes after administration. In addition, the sodium bicarbonate may activate parietal cells, which would render them susceptible to OME inhibition.¹⁰ The more rapid absorption of IR OME contributed to nearly twice as high a peak plasma OME concentration as DR OME; however, the total area under the plasma concentration.time curve was not different.¹¹ It is important to note that the combination of antacids with DR PPIs OME,¹² rabeprazole,¹³ and lansoprazole¹⁴ did not increase their peak plasma concentrations or time to peak concentration.

IR OME (Zegerid capsule) was compared recently with DR lansoprazole capsules and DR pantoprazole tablets in a crossover study of patients with GERD.¹⁵ Each PPI was administered 1 hour before breakfast for 7 days. The percentage of time that the intragastric pH was above 4 during a 24-hour period after 7 days of dosing was significantly greater with IR OME (59.7%, 14.3 hours) than following lansoprazole (48.8%, 11.7 hours) or pantoprazole (41.9%, 10 hours). The median 24-hour gastric pH was higher with IR OME (4.62) than lansoprazole or pantoprazole, 3.89 and 2.42, respectively. The mean time to reach a pH >4 after the seventh dose was significantly shorter for IR OME (20 minutes) than the DR PPIs (65-70 minutes). IR OME demonstrated a faster and greater reduction in gastric pH than the comparator DR PPIs. Although no disease endpoints were measured in this trial, no differences in clinical adverse events were noted between products. The potential for IR OME to produce better symptom relief in patients with GERD awaits further study.

The Role of Immediate-Release Omeprazole

One of the advantages of IR OME is the dosing flexibility it offers to patients. One of the available dosage forms is designed to be suitable for patients who have difficulty swallowing solid dosage forms. Additionally, IR OME eliminates the requirement of taking a PPI before eating to maximize its efficacy. The presence of antacid in the formulation may serve to activate proton pumps and render them susceptible to the plasma concentrations of OME achieved within 30 minutes of administration of IR OME. The antacid also provides an immediate buffer for stomach acid while the PPI starts to work. It should be noted that the 20- and 40-mg dosages of IR OME contain the same quantity of antacid. Thus, 2 doses of the 20-mg formulation are not equivalent to a single 40-mg dose.⁹ The 40-mg dose provides twice the OME dose but the same amount of antacid as the 20-mg size.

Many patients with GERD suffer from nocturnal symptoms. Nocturnal reflux affects sleep quality and daytime functioning and has been associated with more severe GERD, including esophageal injury, esophageal stricture, and adenocarcinoma.¹⁶ When IR OME 40 mg at bedtime was compared with DR pantoprazole 40 mg before dinner, the median percentage of time (2200-0600 hours) with the gastric pH >4 was 54.7% and 26.5%, respectively. 10 Median pH over the 8-hour nocturnal period was 4.7 and 2.0 for IR OME and DR pantoprazole, respectively. Although the effect of reducing nocturnal acid reflux on symptoms was not evaluated in this study, IR OME taken at bedtime would appear to be an excellent option for GERD patients who need acid control during the night.

The removal of the enteric coating and use of antacids to protect OME as it passes through the stomach has proven to be an elegant modification that enhances pH control. By eliminating the enteric coating, IR OME is more rapidly absorbed and suppresses gastric acid secretion faster than DR OME and other DR PPIs and to a greater extent than lansoprazole and pantoprazole. Additionally, due to the unique formulation of IR OME, DR OME products or formulations.Prilosec, Prilosec OTC, and generic OME.are not therapeutically equivalent. There are no AB-rated generic equivalents to Zegerid according to the FDA Orange Book.¹⁷

Although additional studies are needed to define any formulation-dependent differences in symptom relief, patients will benefit from the availability of an easy-to-swallow formulation and the removal of the requirement to take the PPI before meals.

Table

Components of IR Omeprazole Formulations IR Omeprazole (Zegerid) formulation Omeprazole (mg) Sodium bicarbonate (mg) Oral Suspension 20 1680 40 1680 Capsule 20 1100 40 1100 IR = immediate release.

References

1. The Gallup Organization. A Gallup Organization national survey: heartburn across America. Princeton, NJ: The Gallup Organization Inc; 1988.
2. Locke GR, Talley NJ, Fett SL, Zinsmeister AR, Melton LJ. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmstead county, Minnesota. Gastroenterology. 1997;112(5):1448-1456.
3. Huang JQ, Hunt RH. pH, healing rate and symptom relief in acid-related diseases. Yale J Biol Med. 1996;69(2):159-174.
4. Dekel R, Morse C, Fass R. The role of proton pump inhibitors in gastro-oesophageal reflux disease. Drugs. 2004;64(3):277-295.
5. Sandmark S, Carlsson R, Fausa O, Lundell L. Omeprazole or ranitidine in the treatment of reflux esophagitis. Results of a double-blind, randomized, Scandinavian multicenter study. Scand J Gasroenterol. 1988;23(5):625-632.
6. Fackler WK, Ours TM, Vaezi MF, Richter JE. Long-term effect of H2RA therapy on nocturnal gastric acid breakthrough. Gastroenterology. 2002;122:625-632.
7. Robinson M, Horn J. Clinical pharmacology of proton pump inhibitors: what the practising physician needs to know. Drugs. 2003;63(24):2739-2754.
8. Barone JA, Horn JR. Comparative pharmacology of proton pump inhibitors. Manag Care. 2001;10(10 Suppl):11-16.
9. Zegerid product information. Santarus, Inc., San Diego, January 2008.
10. Castell D, Bagin R, Goldlust B, Major J, Hepburn B. Comparison of the effects of immediate-release omeprazole powder for oral suspension and pantoprazole delayed-release tablets on nocturnal acid breakthrough in patients with symptomatic gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2005;21(12):1467-1474.
11. Hepburn B, Goldlust B. Comparative effects of an omeprazole antacid complex-immediate release (OAC-IR) and omeprazole delayed-release (OME-DR) on omeprazole pharmacokinetics and gastric pH in healthy subjects. Gastroenterology. 2003;124:A228(Abstract).
12. Tuynman HA, Festen HP, Rohss K, Meuwissen SG. Lack of effect of antacids on plasma concentrations of omeprazole given as enteric-coated granules. Br J Clin Pharmacol. 1987;24(6):833-835.
13. Yasuda S, Higashi S, Murakami M, Tomono Y, Kawaguchi M. Antacids have no influence on the pharmacokinetics of rabeprazole, a new proton pump inhibitor, in healthy volunteers. Int J Clin Pharmacol Ther. 1999;37(5):249-253.
14. Delhotal-Landes B, Cournot A, Vermerie N, Dellatolas F, Benoit M, Flouvat B. The effect of food and antacids on lansoprazole absorption and disposition. Eur J Drug Metab Pharmacokinet. 1991;3:315-320.
15. Howden CW, Ballard DE, Koch FK, et al. Control of 24-hour intragastric acidity with morning dosing of immediate-release and delayed-release proton pump inhibitors in patients with GERD. J Clin Gastroenterol. In Press.
16. Katz PO, Anderson C, Khoury R, Castell DO. Gastro-oesophageal reflux associated with nocturnal gastric acid breakthrough on proton pump inhibitors. Aliment Pharmacol Ther. 1998;12(12):1231-1234.
17. FDA Web site. Electronic Orange Book. www.fda.gov/cder/obannual.pdf. Accessed November 3, 2008.