Therapeutic Benefits of PPIs
Dr. Horn is professor of pharmacy at the University of Washington School of Pharmacy and associate director ofpharmacy services at the University of Washington Medical Center, Seattle, Washington.
Gastroesophageal reflux disease(GERD) is a widespread, chronicdisease that has been estimatedto cause heartburn symptoms atleast monthly in over 40% of the USpopulation and weekly in up to 20%.1,2GERD is most often a result of refluxedstomach contents irritating the liningof the esophagus producing symptomssuch as heartburn, regurgitation,and cough. A number of risk factorshave been associated with heartburn,including lifestyle (eg, smoking, obesity,recumbency after eating), diet (eg,fatty foods, citrus juices, carbonatedbeverages), drugs (eg, narcotics, anticholinergicagents, estrogens), anddisease states (eg, motility disorders,hiatal hernia).
The goals of treatment for GERDinclude the clinical marker of maintainingpH >4, symptom relief, thehealing of esophageal erosions, andthe prevention of their recurrence.The mitigation of GERD and relief ofheartburn correlates with the controlof gastric acid secretion, accountingfor the recognition of proton pumpinhibitors (PPIs) as the drugs of choicefor the treatment of GERD.3,4 Antacidsare useful for the temporary reliefof heartburn, but provide no efficacyfor healing erosive esophagitis.H2-receptor antagonists (H2RAs)are effective for both symptom reliefand healing but have lower healingand higher recurrence rates than PPIsdue to their lower potency of gastricacid suppression.5 Additionally, studieshave confirmed that the long-termuse of the H2RAs may be limited bythe development of tachyphylaxis, ortolerance, which can occur with H2RAtreatment in as brief as 1 week.6
PPIs are prodrugs that are absorbedin the small intestine, carried to thegastric parietal cell, exposed to gastricacid in the secretory canaliculus of theparietal cell, and converted to an activesulfenamide. The sulfenamide covalentlybinds to active proton pumps,the final common pathway for theproduction of gastric acid, effectivelysuppressing their secretion of acid.7Because the PPIs are weak bases,exposure to stomach acid will greatlyreduce their absorption. Therefore,most PPIs are protected from stomachacid by a pH-sensitive entericcoating that prevents dissolution untilthe more neutral pH of the smallintestine is encountered. This delayedrelease(DR) formulation slows thetime of peak PPI plasma concentrationto about 1.5 to 3.5 hours after dosingand contributes to the delayed onsetof acid suppression observed with allDR PPIs.8 Because of this extendedtime to peak plasma concentration,DR PPIs should be dosed 30 to 60 minutesbefore a meal to maximize meal-stimulated parietal cell acid secretionneeded to activate the prodrug andprovide active pumps to bind with thesulfenamide.
Immediate-release omeprazole (IR OME)formulations (suspension and capsule)use sodium bicarbonate to protect theOME from gastric acid, thus eliminatingthe need for enteric coating (Table).9 IROME is absorbed more quickly thanDR OME, with IR OME peak plasmaconcentration occurring about 30 minutesafter administration. In addition,the sodium bicarbonate may activateparietal cells, which would renderthem susceptible to OME inhibition.10The more rapid absorption of IR OMEcontributed to nearly twice as high apeak plasma OME concentration as DROME; however, the total area underthe plasma concentration.time curvewas not different.11 It is important tonote that the combination of antacidswith DR PPIs OME,12 rabeprazole,13 andlansoprazole14 did not increase theirpeak plasma concentrations or time topeak concentration.
IR OME (Zegerid capsule) was comparedrecently with DR lansoprazolecapsules and DR pantoprazole tabletsin a crossover study of patients withGERD.15 Each PPI was administered 1hour before breakfast for 7 days. Thepercentage of time that the intragastricpH was above 4 during a 24-hourperiod after 7 days of dosing was significantlygreater 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-hourgastric pH was higher with IR OME(4.62) than lansoprazole or pantoprazole,3.89 and 2.42, respectively. Themean time to reach a pH >4 after theseventh dose was significantly shorterfor IR OME (20 minutes) than the DRPPIs (65-70 minutes). IR OME demonstrateda faster and greater reductionin gastric pH than the comparator DRPPIs. Although no disease endpointswere measured in this trial, no differencesin clinical adverse eventswere noted between products. Thepotential for IR OME to produce bettersymptom relief in patients with GERDawaits further study.
The Role of Immediate-Release Omeprazole
One of the advantages of IR OME is thedosing flexibility it offers to patients.One of the available dosage forms isdesigned to be suitable for patientswho have difficulty swallowing soliddosage forms. Additionally, IR OMEeliminates the requirement of takinga PPI before eating to maximize itsefficacy. The presence of antacid inthe formulation may serve to activateproton pumps and render them susceptibleto the plasma concentrationsof OME achieved within 30 minutes ofadministration of IR OME. The antacidalso provides an immediate buffer forstomach acid while the PPI starts towork. It should be noted that the 20-and 40-mg dosages of IR OME containthe same quantity of antacid. Thus, 2doses of the 20-mg formulation arenot equivalent to a single 40-mg dose.9The 40-mg dose provides twice theOME dose but the same amount ofantacid as the 20-mg size.
Many patients with GERD sufferfrom nocturnal symptoms. Nocturnalreflux affects sleep quality and daytimefunctioning and has been associatedwith more severe GERD, includingesophageal injury, esophageal stricture,and adenocarcinoma.16 When IROME 40 mg at bedtime was comparedwith DR pantoprazole 40 mg beforedinner, the median percentage of time(2200-0600 hours) with the gastricpH >4 was 54.7% and 26.5%, respectively.10 Median pH over the 8-hournocturnal period was 4.7 and 2.0 forIR OME and DR pantoprazole, respectively.Although the effect of reducingnocturnal acid reflux on symptomswas not evaluated in this study, IROME taken at bedtime would appearto be an excellent option for GERDpatients who need acid control duringthe night.
The removal of the enteric coatingand use of antacids to protect OME as itpasses through the stomach has provento be an elegant modification thatenhances pH control. By eliminatingthe enteric coating, IR OME is more rapidlyabsorbed and suppresses gastricacid secretion faster than DR OME andother DR PPIs and to a greater extentthan lansoprazole and pantoprazole.Additionally, due to the unique formulationof IR OME, DR OME products orformulations.Prilosec, Prilosec OTC,and generic OME.are not therapeuticallyequivalent. There are no AB-ratedgeneric equivalents to Zegerid accordingto the FDA Orange Book.17
Although additional studies are neededto define any formulation-dependentdifferences in symptom relief, patientswill benefit from the availability of aneasy-to-swallow formulation and theremoval of the requirement to take thePPI before meals.
Components of IR Omeprazole Formulations
IR Omeprazole (Zegerid) formulation
Sodium bicarbonate (mg)
IR = immediate release.
- The Gallup Organization. A Gallup Organization national survey: heartburn across America. Princeton, NJ: The Gallup Organization Inc; 1988.
- 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.
- Huang JQ, Hunt RH. pH, healing rate and symptom relief in acid-related diseases. Yale J Biol Med. 1996;69(2):159-174.
- Dekel R, Morse C, Fass R. The role of proton pump inhibitors in gastro-oesophageal reflux disease. Drugs. 2004;64(3):277-295.
- 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.
- Fackler WK, Ours TM, Vaezi MF, Richter JE. Long-term effect of H2RA therapy on nocturnal gastric acid breakthrough. Gastroenterology. 2002;122:625-632.
- Robinson M, Horn J. Clinical pharmacology of proton pump inhibitors: what the practising physician needs to know. Drugs. 2003;63(24):2739-2754.
- Barone JA, Horn JR. Comparative pharmacology of proton pump inhibitors. Manag Care. 2001;10(10 Suppl):11-16.
- Zegerid product information. Santarus, Inc., San Diego, January 2008.
- 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.
- 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).
- 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.
- 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.
- 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.
- 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.
- 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.
- FDA Web site. Electronic Orange Book. www.fda.gov/cder/obannual.pdf. Accessed November 3, 2008.