Beating Back GERD with PPIs

This article is brought to you by Santarus Inc., makers of Zegerid

Nearly 15 million Americanssuffer daily from symptomsrelated to gastroesophagealreflux disease (GERD), andnearly 38 million people experiencesymptoms at least weekly.1-3 Asedentary lifestyle contributes tothe prevalence of the disease. Patientswith GERD frequently areoverweight, eat large high-fat meals,and drink caffeinated beverages?all of which increase the dilation ofthe lower esophageal sphincter andthe subsequent reflux of acid intothe lower esophagus (LE).4

Complications of acid reflux in theLE include varying degrees of erosiveesophagitis (EE), stricture, bleeding,and anemia and may lead to Barrett'sesophagus.5 Barrett's esophagus isthought to be a precursor to adenocarcinomaof the esophagus. Theseverity of EE often is classified byusing the Los Angeles (LA) gradingsystem, in which Grade A is mild diseaseand Grade D is severe diseasecomplicated by ulcerations, significantinflammation, and in some casesstricture.2

Proton pump inhibitors (PPIs) arethe most efficacious agents used inthe treatment of EE.4 For mild-to-moderatedisease (LA Grades A andB), all PPIs should result in greaterthan 90% healing rates. With moresevere grades of EE, 70% and 80%healing rates are reported. Despitethe effective suppression of acid byPPIs, only about 70% of patients experiencecomplete pain relief, and40% to 70% of patients suffering fromnocturnal GERD report sleep disturbancesat least once per week.1,2,6


The PPIs are substituted benzimidazolesthat covalently bind to thehydrogen-potassium adenosine triphosphatase(H+/K+-ATPase) enzyme?thereby inhibiting the finalstep in gastric acid secretion in adose-dependent manner.7,8 Whenexposed to acid in the canaliculus ofa parietal cell, the PPI is convertedto the active sulfonamide moiety,which binds to the various cysteineresidue sites within the H+/K+-ATPase proton pump, inhibiting theenzyme and acid secretion.8 BecausePPIs block this final step, theyare more potent than histaminereceptor antagonists, which blockonly 1 pathway in acid secretion.

PPIs are acid-labile, in that exposureto acid prior to entry into theparietal cell will activate the moleculeand cause binding to any H+/K+-ATPase. Thus, most commerciallymarketed PPI capsules and tablets?omeprazole (Prilosec), esomeprazole(Nexium), rabeprazole (Aciphex), lansoprazole(Prevacid), pantoprazole(Protonix)?have an enteric coating toprotect them from acid degradationby gastric acid. All of these productsare termed delayed-release PPIs (DRPPIs).8

Immediate-release omeprazole/sodium bicarbonate (IR-OME; Zegerid)contains the antacid sodium bicarbonateto prevent omeprazole fromdegradation by gastric acid, makingan enteric coating unnecessary.9This drug is supplied to pharmacistsas 20-and 40-mg capsules and as apowder for oral suspension in unitdosepackets. IR-OME is indicatedfor the short-term treatment ofactive duodenal ulcer or benign gastriculcer; for symptomatic GERD; forthe treatment and maintenance ofhealing therapy for EE; and for thereduction of risk of upper gastrointestinalbleeding in critically illpatients (IR-OME 40 mg/sodiumbicarbonate powder for oral suspension).9,10

A pharmacokinetic study comparingdelayed-release omeprazole(DR-OME) capsules with IR-OMEsuspension demonstrated the timeto mean peak plasma levels of IROMEto be ~30 minutes on day 1,compared with 1.74 hours and 2.34hours for DR-OME 20 and 40 mg,respectively.11,12 Extemporaneouslycompounded omeprazole in bicarbonate,generally referred to assimplified omeprazole suspension,should not be regarded as equivalentto IR-OME, because pharmacokinetic studies of this suspensionhave shown that it is similar to DROMEcapsules.12,13 There are notherapeutic equivalents for IR-OME,and, because of its unique absorptioncharacteristics, IR-OME is notAB-rated, compared with DR-OMEcapsules or OTC omeprazole.14

Dosing and Administration

Depending on the indication, IROMEis administered as 20 or 40 mgas a single dose daily. Titration tohigher doses generally is not necessaryin most patients. The AmericanCollege of Gastroenterology recommendsthat PPIs be administered 30minutes to 1 hour prior to a meal foroptimal gastric acid suppression.Both the IR-OME capsule and thesuspension should be administeredon an empty stomach at least 1hour before a meal for optimal acidsuppression.9,15

In an open-label, randomized,crossover trial of 36 patients withnocturnal GERD symptoms, IR-OME40 mg dosed once daily at bedtimeproduced a significantly highermedian gastric pH, achieved agreater percentage of time withgastric pH >4, and decreased theproportion of patients with nocturnalacid breakthrough (NAB), comparedwith pantoprazole 40 mgdosed once daily before dinner.16 Aprimary end point in clinical studiesis NAB (defined as gastric pH <4 formore than 1 hour during the nighttime).A study of 54 patients withnocturnal GERD symptoms comparedIR-OME 40 mg, esomeprazole40 mg, and lansoprazole 30 mg, alladministered on an empty stomach5 hours after dinner.17 Bedtime IROMEproduced a more rapid andsustained control of nighttime gastricpH and NAB, compared withboth esomeprazole and lansoprazole.Bedtime administration of IROMEmay be an effective strategy inpatients with NAB. Esomeprazoleand lansoprazole, however, shouldbe administered prior to a meal asinstructed in their respective prescribinginformation.18,19

Side Effects and Interactions

All PPIs generally are well-tolerated,with the most frequently reportedadverse events being headache,diarrhea, and abdominal pain.15Atrophic gastritis has been notedoccasionally in gastric corpus biopsiesfrom patients treated over along term with omeprazole. Reactionto the sodium bicarbonate containedin IR-OME, including metabolic alkalosis,is possible in some patients.9

IR-OME powder for oral suspensioncontains 460 mg of sodium perdose in the form of sodium bicarbonate(1680 mg/20 mEq), and IROMEcapsules contain 300 mg ofsodium per dose in the form of sodiumbicarbonate (1100 mg/13 mEq).This quantity should be taken intoconsideration for patients on sodium-restricted diets.

PPI dosing generally does notrequire adjustment for renal impairment.8 Omeprazole dose adjustmentshould be considered, however,in patients with hepatic insufficiencyand in Asians.9,20 Asians havea decreased ability to metabolizeomeprazole and have demonstrateda 4-fold increase in the area underthe curve, compared with Caucasians.20 Omeprazole has a Category Cpregnancy rating. Omeprazole affectsliver oxidation and may delaythe clearance and enhance thepharmacodynamic actions of drugseliminated by this route. These drugsmay include diazepam, phenytoin,and warfarin.9,21 Patients should bemonitored if these products areadministered with omeprazole.

Clinical Outlook

IR-OME powder for oral suspensionforms a homogeneous suspensionthat is FDA-approved for administrationthrough naso-or orogastrictubes. Extemporaneouslycompounded PPI-bicarbonate productshave limited shelf life and mayclog tubes when administered.Crushing tablets is not recommended,and removal of the contents ofcapsules and delivering the drugthrough a tube may cause clogging.8,18,22-24 IR-OME suspension alsois an alternative for patients whohave difficulties swallowing soliddosage forms, such as capsules andtablets.

Patients with nocturnal GERDoften report symptoms despite theonce-daily administration of a PPI.Alternatives to reduce symptomsinclude twice-daily dosing andadministration prior to the eveningmeal rather than before breakfast.15The unique formulation of IR-OMEand its ability to rapidly suppressgastric acid appear to be effective incontrolling nocturnal gastric acidity.IR-OME dosing once daily at bedtimeis more effective in controllingNAB than preprandial pantoprazoleeither once or twice daily or esomeprazoleand lansoprazole administeredorally at bedtime.

Dr. Olsen is professor and chair of the department of pharmacy practice at the University of Nebraska MedicalCenter, Omaha.


1. Farup C, Kleinman L, Sloan S, et al. The impact of nocturnal symptoms associatedwith gastroesophageal reflux disease on health-related quality of life. Arch Intern Med.2001;161:45-52.

2. Dent J, El-Serag HB, Wallander MA, Johansson S. Epidemiology of gastrooesophagealreflux disease: a systemic review. Gut. 2005;54:710-717.

3. Shaker R, Castell DO, Schoenfeld PS, Spechler SJ. Nighttime heartburn is an underappreciatedclinical problem that impacts sleep and daytime function: results of a Gallupsurvey conducted on behalf of the American Gastroenterological Association. Am JGastroenterol. 2003;98:1487-1493.

4. Howden CW, Chey WD. Gastroesophageal reflux disease. J Fam Pract. 2003; 52:240-247.

5. Sharma P, McQuaid K, Dent J, et al. A critical review of the diagnosis andmanagement of Barrett's esophagus: the AGA Chicago workshop. Gastroenterology.2004;127:310-330.

6. Castell D, Kahrilas P, Richter J, et al. Esomeprazole (40 mg) compared withlansoprazole (30 mg) in the treatment of erosive esophagitis. Am J Gastroenterol. 2002;97:575-583.

7. Richardson P, Hawkey CJ, Stack WA. Proton pump inhibitors: pharmacology andrationale for use in gastrointestinal disorders. Drugs. 1998;56:307-335.

8. Devlin JW, Welage LS, Olsen KM. Proton pump inhibitor formulary considerations inthe acutely ill: Pt 1: Pharmacology, pharmacodyanmic, and available formulations. AnnPharmacother. 2005; 39:1667-1677.

9. Prescribing Information. Zegerid (omeprazole/sodium bicarbonate) Powder for OralSuspension. San Diego, Calif: Santarus Inc. Revised February 2006.

10. Conrad S, Gabrielli A, Margolis B, et al. Randomized double-blind comparison ofimmediate-release omeprazole oral suspension versus intravenous cimetidine for theprevention of upper gastrointestinal bleeding in critically ill patients. Crit CareMed. 2005;33:760-765.

11. Castell D. Review of immediate-release omeprazole for the treatment of gastric acidrelateddisorders. Expert Opin Pharmacother. 2005;6(14):2501-2510.

12. Data on file.

13. Phillips JO, Olsen KM, Rebuck JA, Rangnekar NJ, Miedema BW, Metzler MH. Arandomized, pharmacokinetic and pharmacodynamic, cross-over study of duodenal orjejunal administration compared to nasogastric administration of omeprazole suspensionin patients at risk for stress ulcers. Am J Gastroenterol. 2001;96:367-372.

14. FDA. Electronic Orange Book, November 2005 (updated monthly). Available Accessed November 2006.

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

16. Castell D, Bagin R, Goldlust B, Major J, Hepburn B. Comparison of the effects ofimmediate-release omeprazole powder for oral suspension and pantoprazole delayedreleasetablets on nocturnal acid breakthrough in patients with symptomaticgastroesophageal reflux disease. Aliment Pharmacol Ther. 2005;21:1467-1474.

17. Katz PO, Koch FK, Ballard ED, et al. Comparison of the effects immediate-releaseomeprazole oral suspension, delayed-release lansoprazole capsules and delayed-releaseesomeprazole capsules on nocturnal gastric acidity after bedtime dosing in patients withnight-time GERD symptoms. Aliment Pharmacol Ther. 2007; 25:197-205.

18. Furuta T, Ohashi K, Kosuge K, et al. CYP2C19 genotype status and effect ofomeprazole on intragastric pH in humans. Clin Pharmacol Ther. 1999;65:552-561.

19. Prescribing Information. Prevacid. Lake Forest, Ill: TAP Pharmaceuticals Inc.Revised September 2006.

20. Prescribing Information. Nexium (esomeprazole magnesium). Wilmington, Del:Astra-Zeneca LP. Revised September 2006.

21. Devlin JW, Welage LS, Olsen KM. Proton pump inhibitor formulary considerationsin the acutely ill: Pt 2: Clinical efficacy, safety, and economics. Ann Pharmacother.2005;39:1844-1851.

22. Olsen KM, Bergman KL, Kaufman SS, Rebuck JA, Collier DS. Omeprazolepharmacodynamics and gastric acid suppression in critically ill pediatric transplantpatients. Ped Crit Care Med. 2001;2:232-237.

23. Kaufman SS, Lyden ER, Brown CR, et al. Omeprazole therapy in pediatric patientsafter liver and intestinal transplantation. J Pediatr Gastronenterol Nutr. 2002;34:194-198.

24. Welage LS, Berardi R. Evaluation of omeprazole, lansoprazole, pantoprazole andrabeprazole in the treatment of acid-related disorders. J Am Pharm Assoc (Wash). 2000;40:52-62.

25. DiGiacinto JL, Olsen, KM, Bergman KL, Hoie EB. Stability of suspensionformulations of lansoprazole and omeprazole in amber-colored plastic syringes. AnnPharmacother. 2000;34:600-606.

26. Phillips JO, Metzler MH, Olsen K. The stability of simplified lansoprazolesuspension (SLS) [abstract]. Gastroenterology. 1999;116A:G0382.

27. Devlin JW, Bakshi A, Bungay K, Olsen KM. An in vitro comparison of differentproviders to deliver four proton pump inhibitor products through a feeding tube. AlimentPharmacol Ther. 2006; 24:1603-1611.