Vol. IV, No. IV
July/August 2001
Mandy Leonard
Pharm.D.,BCPS
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Pharmacotherapy
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Esomeprazole (Nexium™):
A New Proton Pump Inhibitor
Introduction: In 1989, the FDA approved the first proton pump inhibitor (PPI)
in the United States, omeprazole (Prilosec™). Lansoprazole
(Prevacid®) was the second FDA-approved PPI in 1995, followed
by rabeprazole (Aciphex™) in 1999 and pantoprazole (Protonix®)
in 2000. Esomeprazole (Nexium™) received FDA-approval
in 2001 and is the S-isomer of omeprazole.
Indications:
Esomeprazole is FDA-approved for the treatment of symptomatic
gastroesophageal reflux disease (GERD), short-term treatment
of erosive esophagitis, and maintenance of erosive esophagitis
healing. It is also approved for use with antibiotics for
the treatment of Helicobacter pylori-associated duodenal
ulcers.
See Table 1 for FDA-approved indications of the PPIs.
Clinical Pharmacology: Esomeprazole works by binding irreversibly
to the H+/K+ ATPase in the proton pump. Because the proton
pump is the final pathway for secretion of hydrochloric acid
by the parietal cells in the stomach, its inhibition dramatically
decreases the secretion of hydrochloric acid into the stomach
and alters gastric pH. This is the same mechanism of action
as omeprazole and the other PPIs.
Pharmacokinetics: (See Table 2) Esomeprazole is the
S-isomer of omeprazole. It must be administered using an enteric-coated
formulation, which delays release of the drug to the alkaline portion
of the gastrointestinal tract. Peak plasma concentrations occur 1.56 to
2.3 hours after oral administration on an empty stomach. Esomeprazole
is eliminated from the body by hepatic metabolism to inactive metabolites.
Hepatic metabolism is performed by the cytochrome P-450 system, specifically
the isoenzymes CYP2C19 (73%) and CYP3A4 (27%). Less than 1% of esomeprazole
is excreted unchanged in the urine, with 80% excreted renally and the
remainder excreted in the feces. The elimination half-life of esomeprazole
following single-dose oral administration is 0.85 hours. The half-life
increases to 1.2 to 1.5 hours after 5 days of oral administration. The
volume of distribution of esomeprazole is 16 to 18 L. Alterations in renal
function have no effect on esomeprazole's pharmacokinetics, while patients
with liver cirrhosis will have a small delay in the time-to-peak plasma
concentration (2 vs 1.56 hours). The geometric mean AUC is increased by
76%, and the half-life is increased by 29%. Mild-to-moderate hepatic dysfunction
has no effect on the pharmacokinetics of esomeprazole. Severe hepatic
dysfunction (Child-Pugh Class C) can increase the AUC and half-life of
esomeprazole.
Adverse Reactions: The adverse events associated with esomeprazole
therapy are generally similar to those seen with the placebo
and omeprazole therapy. This is similar to the previously
available PPIs. The most common adverse events reported in
the clinical trials were diarrhea, abdominal pain, flatulence,
gastritis, nausea, and headache.
Drug-Drug Interactions: Drug interactions
reported with omeprazole have included prolonged elimination
of diazepam, warfarin, and phenytoin. Isolated reports of
changes in elimination have been reported with cyclosporine,
disulfiram, and other benzodiazepines. No drug-drug interactions
were found between esomeprazole and phenytoin, R-warfarin,
quinidine, amoxicillin, oral contraceptives, and clarithromycin.
Esomeprazole may interfere with the elimination of other drugs
metabolized by CYP2C19. Coadministration of esomeprazole and
diazepam results in a 45% reduction in diazepam clearance
and increased plasma diazepam levels. Changes in gastric pH
can affect the bioavailability of some medications. Examples
of medications where the bioavailability of the medication
may be decreased with profound and long-lasting inhibition
of gastric acid secretion are ketoconazole and iron salts.
Dosage and Administration: (See table 4) The recommended dose of esomeprazole is 20 mg
or 40 mg once daily for 4 to 8 weeks for the treatment of
erosive esophagitis, 20 mg once daily for maintenance of healed
erosive esophagitis (studies lasted up to 6 months), 20 mg
once daily for symptomatic GERD for 4 weeks, and as part of
a 10-day triple drug regimen for eradication of H. pylori
infections (the esomeprazole will be given as a single dose).
The regimen recommended for the eradication of H. pylori infection is esomeprazole 40 mg once daily, amoxicillin
1000 mg twice daily, and clarithromycin 500 mg twice daily
for 10 days. The capsule should be swallowed whole 1 hour
before eating. If the patient has difficulty swallowing the
capsule, it can be opened and mixed with applesauce and taken
immediately. The applesauce should not be hot and should be
soft enough to be swallowed without chewing. The pellet should
not be chewed or crushed. It may also be mixed with tap water,
orange juice, apple juice, or yogurt.
Click here to see a cost comparison of various PPIs.
References Available Upon Request
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