The Choice of Proton Pump Inhibitor: Does it matter?
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C Basic & Clinical Pharmacology & Toxicology 2004, 94, 106–111.
Printed in Denmark . All rights reserved
Copyright C
ISSN 1742-7835
MiniReview
The Choice of Proton Pump Inhibitor: Does it matter?
Per M. Hellström1 and Sigurd Vitols2
Units of Gastroenterology and Hepatology, and 2Clinical Pharmacology, Department of Medicine,
1
Karolinska Hospital, Stockholm, Sweden
(Received September 22, 2003; Accepted January 13, 2004)
Abstract: Proton pump inhibitors are used at different dosages for the treatment of acid-related gastrointestinal disorders,
such as gastro-oesophageal reflux and peptic ulcer disease. Comparisons of four different proton pump inhibitors: lansop-
razole, omeprazole, pantoprazole, and rabeprazole show that they all have similar potency and efficacy. Rabeprazole,
however, displays a slightly more rapid onset of acid inhibition than the others; the clinical advantage of this seems
limited. The S-isomer of omeprazole, esomeprazole, exhibits a somewhat higher potency than the other proton pump
inhibitors. Reports supporting a clinical advantage of this property are not convincing. To conclude, all inhibitors seem
comparable as regards inhibition of gastric acid secretion.
In 1988 the first proton pump inhibitor, omeprazole was scanned reviewed scientific articles from the PubMed li-
launched. Since then the use of these inhibitors has in- brary of officially recognized medical journals.
creased steadily and we can now choose between several
inhibitors of different molecular structures. The patent pro-
The drug target: The enzyme Hπ,Kπ-ATPase
tection of omeprazole expired in 2003 and we are already
seeing a number of generics on the market. The indications Proton pump inhibitors are substituted benzimidazoles with
for proton pump inhibitors have been broadened through alkaline properties, which act as precursors of thiophilic
the discovery of Helicobacter pylori as the infectious agent sulphenamides. The transformation is pH-dependent and
causing peptic ulcer disease. Today eradication of the bac- occurs within the parietal cell. The sulphenamide is cova-
terium is the mainstay of treatment. Due to the high preva- lently bound to hydrogen sulphide residues of the Hπ,Kπ-
lence of gastro-oesophageal reflux disease in the population ATPase molecule on the luminal side of the canaliculi in the
this is now the most important indication for treatment parietal cell (fig. 1). This binding takes place at a high velo-
with a proton pump inhibitor. city at pH 1 (Sachs et al. 1995). The inhibitory effect of
The first proton pump inhibitor was omeprazole and the omeprazole on the Hπ,Kπ-ATPase is similar for the S- and
latest proton pump inhibitor is esomeprazole (S-omeprazo- R-isomers. Both isomers are activated in a pH-dependent
le). Omeprazole is a racemate of two optical forms, the R- fashion and transformed to a cyclic sulphenamide, which
isomer and the S-isomer. The isomers are metabolized in effect is independent of its optical form (Erlandsson et al.
the liver along two separate metabolic pathways; the S-iso- 1990). The higher the pKa of the precursor, the more rapid
mer having a less efficient metabolism resulting in higher is the conversion from inactive to active molecule: the sul-
plasma levels in vivo. Nonetheless (and illogically) the rec- phenamide.
ommended dose of the S-isomer is 40 mg daily; the recom- The mechanism of action is similar for all proton pump
mended daily dose of omeprazole is 20 mg (Thitiphuree & inhibitors. They bind to a common distinct site on the a-
Talley 2000). The question to be raised is: Do the various subunit of the proton pump, namely cysteine 813 on the
proton pump inhibitors differ in potency and pharmaco- luminal loop between transmembrane domains 5 and 6.
logical characteristics, and if so, are these differences of Pantoprazole also binds to the adjacent cysteine 822, and
clinical importance? And, finally, what dosage would be ap- omeprazole to cysteine 892. Lansoprazole and rabeprazole
propriate for treatment of acid-related disorders in the clin- bind to additional sites at cysteine 892 and cysteine 321
ical setting? In order to answer these questions we have (Besancon et al. 1997).
All proton pump inhibitors form active sulphenamides at
a similar rate at pH 1. Hence, their maximal antisecretory
capacity and potency in vivo are similar provided that the
Author for correspondence: Per M. Hellström, Unit of Gastro-
enterology and Hepatology, Department of Medicine, Karolinska
pharmacokinetic properties of the molecules are compar-
Hospital, SE-171 76 Stockholm, Sweden (fax π46 8 51772058, able. The antisecretory capacity of omeprazole is similar to
e-mail Per.Hellstrom/medks.ki.se). that of pantoprazole in animal experiments (Kromer et al.MiniReview CHOICE OF PROTON PUMP INHIBITOR FOR ACID INHIBITION 107
Antisecretory potency in man
The intra- and inter-experiment variability in acid inhibi-
tory effect of the various proton pump inhibitors is con-
siderable. Thus, results from different studies have to be
examined and evaluated with caution. It seems that even a
double dosage of proton pump inhibitors will not always
lead to statistically significant differences in acid inhibition.
Fig. 1. Schematic drawing of the molecular structure of the enzyme
Such data support the view that the proton pump inhibitors
Hπ,Kπ-ATPase. The enzyme consists of 1034 amino acid residues
localized to two subunits. Upon secretion of Hπ-ions one phos- are utilized within the upper shallow range of the dose-re-
phate group is transferred from ATP in the cytoplasm to aspartic sponse curve, where an increased dosage only leads to a
acid in the active centre of the enzyme, which leads to the formation marginally increased effect.
of a phosphorous intermediate. This intermediate releases Hπ-ions Studies in vitro exhibit a similar acid inhibitory effect of
at the luminal side of the enzyme. The catalytic a-subunit, driving
the exchange between Hπ- and Kπ-ions, is a large protein with 10 omeprazole, lansoprazole, pantoprazole and rabeprazole
domains crossing the cell membrane. The proton pump inhibitors (Bastaki et al. 2000). Dose-response studies comparing
(PPIs) bind to the part of the enzyme that is located on the outer, omeprazole, lansoprazole and pantoprazole in man have
luminal membrane of the canaliculi, and inhibits phosphorylation shown a similar pH-raising effect of the drugs on a milli-
and exchange of Hπ- and Kπ-ions. The b-subunit crosses the cell
gram basis (Ashida et al. 1995; Langtry & Wilde 1997). This
membrane only at one point. The extracellular domain of the b-
subunit is heavily glucosylated adjacent to the a-subunit. The func- has been confirmed by investigations in animals (Kromer et
tion of the b-subunit is yet to be defined. al. 1990). Lansoprazole and omeprazole also produce a
similar increment of intragastric pH (Yasuda et al. 1994),
albeit with a somewhat more rapid onset of action for lan-
1990). Although pantoprazole (pKa 3.96) and rabeprazole soprazole (Brummer et al. 1997). Comparisons between 40
(pKa 4.9) differ greatly in terms of pKa, and activation rate, mg omeprazole daily and 40 mg pantoprazole daily show
they induce the same degree of gastric acid inhibition with similar increments of intragastric pH during 24 hr (Hannan
similar ID50-values, which also holds true for lansoprazole et al. 1992). Omeprazole and pantoprazole, both at doses
(pKa 4.01), as well as omeprazole and esomeprazole (pKa of 20 and 40 mg, also lead to comparable results for the
3.97) (Kromer et al. 1998) (fig. 2). The activation of proton healing of gastroesophageal reflux disease (Plein et al.
pump inhibitors is considered to have a doubling-time of 1998), as well as duodenal and gastric peptic ulcers (Kromer
1–5 min., which should be compared to a half-life in the et al. 1999) (fig. 3). In accordance with this observation,
circulation of about 60 min. (Yasuda et al. 1994). The po- studies of omeprazole and rabeprazole, both at 20 mg dos-
tency of anyone of these drugs depends on the amount of age, reveal similar clinical effects for healing of gastro-
free precursor, plasma AUC (‘‘area under curve’’), and the oesophageal reflux disease (Dekkers et al. 1999), duodenal
activation time at pH 1. Since all proton pump inhibitors and gastric ulcers (Müller et al. 1992). Thus, data speak for
are available in plasma for binding to the Hπ,Kπ-ATPase a similar potency of the proton pump inhibitors.
for a considerably longer time span than needed for inhi- Studies of the pharmacokinetics of esomeprazole and
bition of the enzyme, minor differences in time lag for the omeprazole at a dose of 20 mg (five days treatment) show
activation of the proton pump inhibitors in an acidic milieu higher plasma concentrations of esomeprazole (almost
are therefore negligible. twice greater AUC) than of omeprazole (Lind et al. 2000).
At a dose of 40 mg, esomeprazole causes considerably
higher plasma concentrations (about 5 times greater AUC)
than with 20 mg omeprazole (Lind et al. 2000). With 20
mg, esomeprazole maintains intragastric pH⬎4 for more
Fig. 2. Intravenous dosage of proton pump inhibitors to achieve Fig. 3. Duration of intragastric pH⬎4 during 24 hr in subjects
half-maximal inhibition (ID50; average∫95% confidence interval) of treated with omeprazole and pantoprazole, both at 40 mg daily
pentagastrin-stimulated acid secretion in the chronic gastric fistula doses in comparable studies, study A (Koop et al. 1994) and study
rat. One mmol of each drug equals 0.37 mg lansoprazole; 0.35 mg B (Brunner et al. 1997). The results illustrate the variability in re-
omeprazole; 0.38 mg pantoprazole; 0.36 mg rabeprazole (Kromer sults between different studies. Comparisons between different
et al. 1990). studies should therefore be made with caution (Kromer et al. 1999).108 PER M. HELLSTRÖM AND SIGURD VITOLS MiniReview
than 12 hr in 54% of individuals compared to 44% for ome- There are reports of comparative studies of different pro-
prazole. At 40 mg, the corresponding value for esomeprazo- ton pump inhibitors revealing a strong effect of some agents
le is 92%. Accordingly, intragastric pH⬎4 is maintained for already at a low dose, suggesting a high potency. We found
16 hr in 24%, 14% and 54% of the individuals, respectively two studies where a significantly better effect was seen with
(Lind et al. 2000). This difference in acid inhibition is mir- rabeprazole than with omeprazole at 20 mg daily. In one
rored by differences in intragastric pH. Esomeprazole at a of these studies, the 24 hr intragastric pH was measured
daily dose of 40 mg generates an intragastric pH of 4.9 (on (Williams et al. 1998), revealing a more rapid pH increment
the average), while 20 mg generates pH 4.1, which should with rabeprazole than with omeprazole during an 8-day
be compared to pH 3.6 after omeprazole 20 mg (Lind et al. treatment of healthy individuals. In another study of gastric
2000). Esomeprazole 40 mg daily has been found to be ulcer (Dekkers et al. 1998), 20 mg rabeprazole was found
more effective in raising intragastric pH than lansoprazole to be more effective than 20 mg omeprazole as regards
30 mg, pantoprazole 40 mg or rabeprazole 20 mg, as well symptom relief, but equally effective as regards ulcer heal-
as omeprazole at doses of 20 and 40 mg (Röhss et al. 2000a) ing. The published findings have to be evaluated against the
(fig. 4). The conclusion of these findings is that, for any variability of the effects of the proton pump inhibitors; so
given proton pump inhibitor an increased AUC will cause far, true differences concerning their effectiveness or useful-
a greater acid inhibition. It remains to show that such dif- ness have not been disclosed. We have found two studies
ferences in acid inhibition are of clinical importance. that claim a stronger effect of a lower dose of a specific
proton pump inhibitor in relation to a higher dose of an-
other (Florent & Forestier 1997). One of these studies did
Dose-response relationships
not demonstrate any difference between lansoprazole 30 mg
Basically, the acid inhibitory effect of proton pump inhibi- daily and pantoprazole 40 mg as regards endoscopic or
tors displays rectilinear dose-response relationships up to a symptomatic remission in gastro-oesophageal reflux disease
near-maximal effect. Doses currently used in clinical prac- (Florent & Forestier 1997), whereas the results of the other
tice seem to induce acid inhibition in the 60–90% range, study indicate that treatment with lansoprazole 30 mg gives
which means that the values often fall on the rectilinear part a better result than treatment with pantoprazole 40 mg in
of the dose-response curve. In studies of gastro-oesophageal the maintenance treatment of reflux oesophagitis (Jaspersen
reflux disease, lansoprazole displays increased healing rates et al. 1998).
when the dose is increased from 15 to 30 mg daily but with Several clinical studies have shown esomeprazole 40 mg
no further improvement at 60 mg (Earnest et al. 1998). In to be marginally more effective than omeprazole 20 mg in
the same way, pantoprazole shows increased healing rates the treatment of gastro-oesophageal reflux disease and ero-
with doses from 10 to 40 mg. The dose-response relation- sive oesophagitis. Studies on erosive oesophagitis during an
ships that are applicable for omeprazole and pantoprazole 8-week period demonstrated that esomeprazole at doses of
in the treatment of gastro-oesophageal reflux disease and 20 and 40 mg gave healing rates of 89.9% and 94.1%, re-
duodenal, as well as gastric peptic ulcer disease have been spectively, compared to omeprazole 20 mg with a healing
analyzed by Kromer et al. (1999), who showed higher heal- rate of 86.9% (Kahrilas et al. 2000). Moreover, esomeprazo-
ing rates with 40 than with 20 mg. Since a clear relationship le 40 mg gave better symptom relief and more complete
between acid inhibition and healing of duodenal ulcer dis- healing of oesophagitis than lansoprazole 30 mg (Castell et
ease exists, as shown by Savarino et al. (1994), it is reason- al. 2002). Other studies, however, show that pantoprazole
able to assume that the healing of duodenal ulcers reflects 40 mg causes the same oesophageal pH-increment (Simon
the inhibition of acid secretion. et al. 2001) and symptom relief as esomeprazole 40 mg in
the treatment of moderate to severe oesophagitis (Scholten
et al. 2002). In patients with gastro-oesophageal reflux dis-
ease esomeprazole at doses of 40 mg or 20 mg gives a simi-
lar symptom relief during 4–8 weeks of treatment (Nexium
(package insert), Wilmington 2001).
Optimal dosage of proton pump inhibitors in acute and
maintenance treatment of acid-related disorders
Many studies of gastro-oesophageal reflux disease demon-
strate that treatment with 40 mg omeprazole gives a better
healing rate than 20 mg. Compared to omeprazole 20 mg,
esomeprazole 40 mg causes about 15% higher healing rates
in gastro-oesophageal reflux disease (Kahrilas et al. 2000).
Fig. 4. Duration of intragastric pH⬎4 during 24 hr in 114 patients
Dose-dependent healing rates in gastro-oesophageal reflux
under treatment with esomeprazole or omeprazole, both at 40 mg disease also seem valid for pantoprazole as shown in studies
daily, on the fifth day of treatment (Röhss et al. 2000b). of 10, 20 and 40 mg daily (Bochenek et al. 1998). Lansopra-MiniReview CHOICE OF PROTON PUMP INHIBITOR FOR ACID INHIBITION 109
tenance treatment with a sustained healing of 93.2% during
a 6-month period (Johnson et al. 2001). Data from studies
of pantoprazole show similar results with 20 and 40 mg
(Plein et al. 1998). Taken together, 20 mg daily seems to be
an adequate dose of esomeprazole, omeprazole and panto-
prazole, while a 15-mg dose of lansoprazole seems to be
sufficient in the maintenance treatment of gastro-oeso-
phageal reflux disease.
Conclusion
Proton pump inhibitors are used in various standard dos-
ages for inhibition of acid secretion in acute and mainten-
ance treatment of acid-related disorders. Comparisons be-
tween different proton pump inhibitors show that the four
compounds lansoprazole, omeprazole, pantoprazole and
Fig. 5. Different proton pump inhibitors compared with omeprazo- rabeprazole have a similar anti-secretory potency on a milli-
le 20 mg daily. Odds ratio with 95% confidence interval for healing gram basis. Rabeprazole seems to produce a slightly more
of gastro-oesophageal reflux disease with various proton pump in- rapid onset of acid inhibition than the others. Esomeprazo-
hibitors. Comparison with omeprazole 20 mg daily (odds ratio 1.0),
8-week treatment period (Corinaldesi et al. 1995; Mossner et al. le displays a somewhat greater acid inhibitory potency than
1995; Castell et al. 1996; Mee & Rowley 1996; Mulder et al. 1996; other proton pump inhibitors. The clinical gain of these
Bochenek et al. 1998; Dekkers et al. 1999; Delchier et al. 2000). The findings seems marginal and studies demonstrating clinical
healing ratio shows the relative difference in healing rates between importance are lacking. The inhibition of Hπ,Kπ-ATPase
omeprazole and other proton pump inhibitors, where 1.0 represents
with a daily dosage of 40 mg of the proton pump inhibitors
an equal treatment result with 95% confidence interval.
falls in the top range of the dose-response curve, which
means that differences in acid inhibitory effect between the
different inhibitors tend to be minor and difficult to estab-
lish.
zole displays comparative dose-response relationships as re- From available data the dosage 30–40 mg of proton
gards efficiency of 15 and 30 mg (Earnest et al. 1998). To pump inhibitors appears to be optimal for the treatment of
summarize, available data indicate that the optimal dosage active ulcer disease as well as moderate to severe gastro-
of any proton pump inhibitor for the treatment of gastro- oesophageal reflux disease. For the eradication of Helicob-
oesophageal reflux disease is 30–40 mg daily (fig. 5). acter pylori a two-dose regimen of proton pump inhibitor
In the treatment of peptic ulcer disease it seems that the in combination with antibiotics is required. In mild sympto-
optimal dosage for prompt symptom relief and increased matic gastro-oesophageal reflux disease, or in maintenance
healing rate is 40 mg daily with omeprazole as well as treatment after the healing of erosive oesophagitis 15–20 mg
pantoprazole. Lansoprazole has not been investigated at daily seems sufficient. These ‘‘standard dosages’’ of proton
this dosage, but a dosage of 60 mg seems more effective pump inhibitors accord with current knowledge as regards
than lower dosages as judged from studies of intragastric potency and efficacy of the different proton pump inhibi-
24-hr pH measurements (Seensalu et al. 1995). In other tors, and do not solely mirror the relative potency of the
words, the pharmacodynamic profile of lansoprazole does drugs on a milligram basis. The conclusion would be that
not seem to differ from those of other proton pump inhibi- all proton pump inhibitors display similar potency.
tors. Rabeprazole 20 mg inhibits acid secretion as effec- In a global perspective patented proton pump inhibitors
tively as omeprazole 20 mg, both as regards peptic ulcer are now competing with generics. A consequence of the
and reflux disease (Dekkers et al. 1999). A specific feature competition for market shares will be reduced pricing.
of rabeprazole seems to be that the onset of acid inhibition From a clinical point of view the most important goal must
occurs more rapidly than with omeprazole and can be be to establish criteria for the selection of the proper drug
noted already on the first day of treatment (Williams & and the appropriate dose. In the clinical setting, all proton
Pounder 1999). This effect may reflect the high pKa of ra- pump inhibitors have a similar potency and the same in-
beprazole. herent capacity to inhibit acid secretion. The clinician has
In terms of maintenance treatment of gastro-oesophageal to decide what degree of acid inhibition he aims for in the
reflux disease, 15 mg lansoprazole, alternatively 20 mg ome- individual patient, based on his knowledge of the nature
prazole or pantoprazole, is considered sufficient, even and severity of the disease. The desired result will be ob-
though there are studies showing that a dose of 10 mg may tained with any one of the proton pump inhibitors after
be as effective (Laursen et al. 1995). As regards esomeprazo- selecting the proper dosage of the drug to be used in that
le it seems that a daily dose of 20 mg gives a reliable main- particular patient.110 PER M. HELLSTRÖM AND SIGURD VITOLS MiniReview
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