Antiulcer Drugs 1
Antiulcer Drugs
This article discusses drugs used in acid-related diseases of the gastrointestinal tract.
Wolfgang Kromer, Byk Gulden, Konstanz, Federal Republic of Germany
Stefan Postius, Byk Gulden, Konstanz, Federal Republic of Germany
Uwe Krüger, Byk Gulden, Konstanz, Federal Republic of Germany
1. Introduction . . . . . . . . . . . . . . .
2. Pathophysiology and Therapeutic
Concepts . . . . . . . . . . . . . . . . . .
3. Drugs . . . . . . . . . . . . . . . . . . . .
3.1. Proton Pump Inhibitors . . . . . . . .
3.2. H2 -Receptor Antagonists . . . . . . .
3.3. Antacids . . . . . . . . . . . . . . . . . .
3.4. Miscellaneous Drugs . . . . . . . . . .
3.4.1. Prostaglandin Derivates . . . . . . . . .
3.4.2. Prokinetic Drugs . . . . . . . . . . . . .
1. Introduction
Acid-related diseases of the upper gastrointesti-
nal tract (GI-tract) comprise all the diseases of
the esophagus, stomach, and duodenum that can
be beneficially affected by neutralizing gastric
acid or by inhibiting its secretion. These dis-
eases include gastroesophageal reflux disease
(GERD) [1], gastritis [2], gastric and duodenal
ulcers (GU and DU [3]), drug-induced ulcers [4],
Zollinger – Ellison syndrome [5], and stress ul-
cers [6]. However, “acid related” does not mean
that all these diseases are causally related to acid
hypersecretion. They may in fact go along with
normal or even subnormal acid secretion. The
complex pathophysiology is based on an imbal-
ance between aggressive and defensive factors
and will be discussed in Chapter 2.
Acid-related disorders of the GI-tract still
constitute a major national-economical issue in
western countries. The “crude lifetime ulcer
prevalence” has been estimated in the United
States to be between 8 and 30 % [7]. This prin-
cipal notion also applies to Germany where,
in 1995, 239 × 106 daily doses of antiulcer
drugs [H2 -receptor antagonists (H2 -RAs), pro-
ton pump inhibitors (PPIs), etc.] were prescribed
[8]. Three major risk factors for peptic ulcers and
related disorders have been identified by Ku-
rata and Nogawa [9]: infection by Helicobac-

c 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
10.1002/14356007.a02 321
1 3.4.3. Antimuscarinic Drugs . . . . . . . . . . 12
3.4.4. Sucralfate . . . . . . . . . . . . . . . . . . 12
1 3.4.5. Bismuth Compounds . . . . . . . . . . 13
2 4. Prospect for Future Developments . 14
2 4.1. Reversibly Binding Acid Pump An-
5 tagonists . . . . . . . . . . . . . . . . . . 14
8 4.2. Drugs Directed Against Helicobacter
10 pylori . . . . . . . . . . . . . . . . . . . . 14
10 5. Relative Drug Assessment . . . . . . 15
11 6. References . . . . . . . . . . . . . . . . . 15
ter pylori (H.p.), use of nonsteroidal antiinflam-
matory drugs (NSAIDs) such as diclofenac, and
cigarette smoking. H.p. infection is predomi-
nantly acquired in childhood, but the incidence
of infections during childhood was considered
to have decreased over the past decades be-
ing in line with a cohort phenomenon [10],
[11]. Thus, as far as peptic ulcers caused by
H.p. infection are concerned, their prevalence
was expected to decrease in the future because
transmission should become less likely under
improved hygienic conditions in industrialized
countries [12]. On the other hand, Hornemann
et al. [13] found an age-dependent increase in the
prevalence of H.p. infection in healthy German
children between birth and 17 years of age ad-
mitted to hospital for minor surgical procedures
in 1983 and 1984. Consequently, these authors
questioned a hygiene-related cohort effect and
interpreted their data as possibly pointing to an
oral-oral route of infection as opposed to a fecal-
oral route.
2. Pathophysiology and Therapeutic
Concepts
Although the dictum “no acid – no ulcer” [14] is
still valid in the majority of peptic ulcer cases,
2 Antiulcer Drugs
nowadays much more is known about their com-
plex etiology and pathophysiology [15]. In fact,
gastric acid and pepsin are the most important
aggressive factors acting in concert with toxic
factors of H.p. or with either NSAIDs, stress
or smoking, but they are physiologically coun-
terbalanced by defensive factors such as mucus
and bicarbonate, epithelial cell lining and re-
pair mechanisms, and mucosal blood flow [15],
[16]. Consequently, although inhibition of acid
secretion will be therapeutically effective even
in cases with normal acid secretion, eradication
of H.p. by antibiotics or improvement of mu-
cosal defense, for example, by sucralfate and
antacids, will either eliminate H.p. as the cause
of the disease, or shift the balance in favor of
defensive factors. Bismuth compounds do a lit-
tle of both. Prostaglandin (PG) derivatives help
preventing NSAID-induced ulcers by “gastro-
protective” (misleadingly also called “cytopro-
tective”) mechanisms but heal peptic ulcers only
when given in antisecretory doses [17], [18]. Ul-
cer pain may be triggered by exposure of the
inflamed mucosa to gastric acid [19] and will
therefore be alleviated by antisecretory or acid-
neutralizing drugs, apart from their healing ef-
fect.
The most effective target of acid-inhibitory
drugs is the H+ /K+ -ATPase (acid pump; pro-
ton pump) of the parietal cell’s apical mem-
brane [20]. PPIs (pantoprazole, omeprazole, lan-
soprazole, see Section 3.1) block the final step
in acid production (Fig. 1) and therefore dis-
play a higher antisecretory efficacy and clin-
ical reliability than H2 -RAs (see Section 3.2)
or, even more so, M1 -antimuscarinics. H2 -
RAs block receptors for histamine located up-
stream on the basolateral membrane of the
parietal cell (H2 -receptor), M1 -antimuscarinics
block receptors for actetylcholine on either
the histamine-liberating ECL-cell or intramural
neurons (M1 -receptors). Consequently, both of
these leave other pathways of acid stimulation
unaffected. The only antimuscarinic antiulcer
drug still in use is pirenzepine (see Section 3.4.3)
which seems outdated due to its comparatively
low efficacy combined with unwanted effects.
Antacids (see Section 3.3), PG derivatives (see
Section 3.4.1), sucralfate (see Section 3.4.4) and
bismuth compounds (see Section 3.4.5) display
complex actions partially related to acid, mu-
cosal defensive mechanisms, and H.p. (see Sec-
tion 4.2). Figure 1 provides an overview. Finally,
the prokinetic drugs cisapride, metoclopramide,
and domperidone facilitate propulsive motil-
ity of the GI-tract thus enhancing oral to abo-
ral movement of contents to prevent duodeno-
gastric reflux of bile acids or gastro-esophageal
reflux of gastric acid (see Section 3.4.2).
3. Drugs
This section lays special emphasis on proton
pump inhibitors as these drugs represent the lat-
est development in the antisecretory therapy of
peptic ulcer disease, succeeding H2 -receptor an-
tagonists. In general, information on chemical
and pharmaceutical drug properties, synonyms,
trade names, dosages etc. beyond the informa-
tion given below may be obtained from [22–26].
In the following sections, the chemical names of
individual drugs are indicated according to the
WHO nomenclature.
3.1. Proton Pump Inhibitors
Chemically, proton pump inhibitors (PPIs) con-
sist of a substituted benzimidazole moiety linked
by an essential sulfinylmethyl group to a sub-
stituted pyridine ring [20], [27]. They are acid-
labile prodrugs that have first to be activated by
acid in order to gain pharmacological activity but
will subsequently be degraded to inactive prod-
ucts (see below). They are therefore adminis-
tered as enteric-coated formulations (which pro-
tects the prodrug from acid in the gastric lumen),
become absorbed from the intestine and pene-
trate into the acid compartment of the gastric
parietal cell from the blood. The pH in the order
of 1 present inside the canaliculus of a secreting
parietal cell [20] causes protonation of the pyri-
dine nitrogen (pK a about 4) and thereby drug
accumulation by a factor of more than 1000 rel-
ative to the blood. This protonation goes along
with a complex, intramolecular rearrangement
of the prodrug structure to form a thiophilic
cyclic sulfenamide. The latter is a highly reac-
tive compound and would be further degraded
to inactive products (see above) if it were not
generated in the vicinity of the extracytoplas-
mic portion of the proton pump where it imme-
diately and covalently reacts with thiol groups of
 Antiulcer Drugs 3

Figure 1. Simplified and incomplete illustration of the interplay between various aggressive and defensive gastric mucosal
factors, their physiological regulation, and the different drug targets in peptic ulcer therapy.
ACh = acetylcholine; ECL = enterochromaffine-like; G = gastrin receptor; Hist = histamine; H2 = histamine H2 -receptor;
M1 = muscarinic M1 -receptor; N = nicotinic receptor; NSAIDs = nonsteroidal antiinflammatory drugs; PG = prostaglandin
receptor.
X indicates inhibition of the respective target.
After Brunton [21], slightly modified.

the proton pump. The result is a mixed disulfide
of the active drug and the enzyme protein [28],
[29]. The disulfide structure arrests the catalytic
cycle of the proton pump [20] and thus inhibits
acid secretion. Although this constitutes an irre-
versible mode of inhibition in a chemical sense,
acid inhibition by PPIs is biologically reversible
due to the turnover of both the proton pump (t 1/2
approx. 72 or 54 h for the rat proton pump or its
alpha subunit; [30], [31]) and the parietal cell
(turnover time in the rat ca. 164 d [32]).
It has been estimated that about one-third of
the parietal cell mass is in its resting state even
during meal stimulation [33] and therefore not
available for inhibition by PPIs [34]. These rest-
ing cells are liable to endogenous stimulation af-
ter the drug has been eliminated from blood cir-
culation and thus mainly determine the recovery
of acid secretion following a first drug admin-
istration. It also follows that PPIs achieve their
steady state effect only over about 3 days of daily
administration, and any co-administration of re-
ceptor antagonists (be it H2 - or M1 -blockers)
with PPIs is contraindicated. In fact, the latter
would lose instead of gain efficacy because re-
ceptor blockade would prevent a certain percent-
age of parietal cells from being stimulated for
acid secretion thus kept in a resting state not al-
lowing for PPI activation.
Cyclic sulfenamides generated by acid from
the inactive prodrugs (for review, see [27]) are
specific SH-reagents which can modify any thiol
group and should therefore be prevented from
unwanted reactions at any targets apart from the
parietal cell’s proton pump in order to avoid
side effects as much as possible. Thus, the main
aspect governing selection of candidate com-
pounds during drug development was their pH-
dependent activation profile. As discussed in de-
tail by Kromer et al. [37], PPIs should be acid-
activated as fast as possible at low pH values
of about 1 in order to potently inhibit the pari-
4 Antiulcer Drugs
etal cell’s proton pump. However, they should
be activated as slowly as possible at pH values
well above 3 to avoid unwanted SH-reactions
in moderately acidic tissue compartments like
lysosomes and other acidic vesicles. “Fast” and
“slow” activation is always meant relative to
the serum elimination half-life t 1/2 . For exam-
ple, omeprazole is as quickly activated at pH
5 (where activation is unwanted) as it is elim-
inated from serum (t 1/2 approx. 1 h), whereas
the PPI pantoprazole is eliminated from blood
by a factor of about 3 faster than it is activated
at pH values in the order of 5 [37]. For lanso-
prazole and rabeprazole, see [35], [36]. All of
these drugs are acid-activated at pH 1 with ac-
tivation half-lifes in the order of a few minutes
compared to their serum elimination half-lifes
of about 1 hour. They all display therefore sim-
ilar antisecretory potencies and efficacies [38–
44] which solely depend on the activation rate
within the acid space of the parietal cell. For the
same reason, 20 mg omeprazole achieved lower
healing rates than 40 mg of either omeprazole
or pantoprazole in a number of studies [45–51].
This data does not conflict at all with the failure
of other studies [52], [53] to statistically distin-
guish 40 mg pantoprazole from 20 mg omepra-
zole since the two doses represent the upper
part of the dose – response relationship. Conse-
quently, they are separated by only a small (but
clinically relevant) difference in healing rates
confounded by comparatively large variations
between different patient samples. It has there-
fore been judged from a medical rather than a
statistical point of view that 20 mg omeprazole
daily being underdosed and 40 mg daily of both
omeprazole and pantoprazole being the correct
and desirable dose for acute ulcer healing [54],
[55]. Figure 2 demonstrates the congruence be-
tween animal data, human pharmacology data,
and selected clinical data (see above) and shows
the equipotency and equiefficacy of pantopra-
zole compared to omeprazole on a milligram
basis.
A further goal pursued during selection of
PPIs was to minimize potential interactions with
cytochrome P450 in order to avoid unwanted
drug interactions in the liver. Following phase
I oxidation in the endoplasmic reticulum of
the liver cell, pantoprazole undergoes cytosolic
phase II sulfate conjugation which is indepen-
dent of cytochrome P450 and not subject to drug
interactions [57]. By contrast, phase II conjuga-
tion is lacking in case of omeprazole, which in
addition has an about seven-fold higher affin-
ity to human cytochrome P450 than pantopra-
zole [58]. The two differences, i.e., lower affin-
ity to cytochrome P450 and phase II conjugation
of pantoprazole as opposed to omeprazole ex-
plain well that pantoprazole did not display any
metabolic drug interactions in man [59], [60],
whereas omeprazole did in a number of studies
[61–70], for review, see [71].
Another goal considered during PPI selection
and development was to obtain linear pharma-
cokinetics both with respect to dose increments
and repeated dosing over time. This goal has
been achieved with pantoprazole [72–74] but not
with omeprazole [75].
All of the differences in the aforementioned
drug properties depend on the different sub-
stitution patterns of the two ring systems of
the PPIs (Table 1). Regarding the pH-selectivity
in the PPI’s chemical activation (see above),
“the difluoromethoxy group present in panto-
prazole slows reaction at neutral pH by elec-
tron withdrawal, which decreases the pK a of
the benzimidazole N and reduces its protona-
tion at all but highly acidic pH values” [20].
The higher lipophilicity of omeprazole explains
its higher volume of distribution (i.e., a higher
percentage shifted from serum into tissues)
and, consequently, its somewhat lower maxi-
mum serum concentration (C max ) and area un-
der the serum concentration – time curve (AUC)
(→ Pharmaceutical Dosage Forms, Chap. 1. on
bioavailability) compared to the same dose of
pantoprazole [37], [76]. The biological implica-
tions of these differences have been discussed
in [37]. The individual PPIs will be presented
below in alphabetical order.
Table 1. Chemical structures of four proton pump inhibitors
Lansoprazole
Omeprazole

Pantoprazole
Pariprazole/Rabeprazole/E3810
Lansoprazole [103577-45-3], 2-[[[3-
methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]-
methyl]sulfinyl]benzimidazole (WHO),
C16 H14 F3 N3 O2 S, M r 369.37 [77], available
as capsules containing either 15 or 30 mg (free
acid) of the racemic mixture (chiral center at the
asymmetric sulfinyl group). Both the (+)- and
(−)-enantiomers of lansoprazole are converted
to the optically inactive cyclic sulfenamide and
are therefore of the same antisecretory potency
in vitro [78].
Trade names: Agopton (Takeda) and in ad-
dition various licensed products under different
trade names (see [23]).
Omeprazole [73590-58-6], 5-methoxy-2-
[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]-
sufinyl]benzimidazole (WHO), C17 H19 N3 O3 S,
M r 345.42 [52], available as capsules contain-
ing either 10, 20, or 40 mg and as a lyophylisate
for i.v. infusion containing 40 mg of the racemic
mixture (40 mg being equivalent to 42.6 mg of
the sodium salt). The omeprazole enantiomers
can be separated but both of them display about
the same antisecretory potency in vitro [79],
[80].
Trade names: The racemic mixture is pro-
duced by Astra/Hässle under trade names Antra
and Losec, and is in addition distributed by
various licensees under different trade names
(see [23]).
Omeprazole was the first PPI in clinical use
and has therefore attained the largest drug safety
data base. Omeprazole has a remarkable safety
profile with most adverse events in the range of
that of placebo treatment [81–83]. Challenges
had been hypergastrinemia (also seen with the
other PPIs) with subsequent induction of carci-
noids in rats chronically exposed to high toxico-
Antiulcer Drugs 5
logical doses [84], gastric bacterial overgrowth
due to anacidity [85], impaired absorption of
vitamin B12 and iron [86], induction of cy-
tochrome P450 IA2 which both generates and
detoxifies mutagens [87], [88]; suspected geno-
toxicity [89], and very rare events not conclu-
sively related to omeprazole treatment (impaired
vision and hearing, inflammatory and immuno-
logic events like fever, vasculitis and colitis).
All of these issues have been reviewed by ex-
perts and considered to be of either no rele-
vance or even unrelated to omeprazole treat-
ment [86], [90–96]. The aforementioned adverse
events published as case reports seem to be ex-
tremely rare relative to the large number of treat-
ment courses with omeprazole of well above
100 million. Some of these adverse effects, how-
ever, disappeared upon cessation of omepra-
zole therapy and reappeared upon rechallenge
suggesting a causal relationship. These include
cases of myopathy [97], neuromyositis [98], ery-
thema nodosum [99], arthralgia [100], pityriasis
rosea-like skin eruption [101], hemolytic anemia
[102], interstitial nephritis [103], [104], CNS-
symptoms [105], [106], and acute gout [107].
Pantoprazole [102625-70-7], 5-(difluoro-
methoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]-
sulfinyl]benzimidazole (WHO), sodium salt
C16 H15 F2 N3 NaO4 S, M r 405.38, [27], [53],
[56], [108–111]. Figure 3 shows the synthe-
sis of the sodium salt, Figure 4 its chemical
activation. Pantoprazole is available as enteric
coated tablets containing 45.1 mg of the sodium
salt sesquihydrate equivalent to 40 mg of the
racemic mixture of the free anhydrous acid,
and as a lyophylisate for i.v. infusion. The (+)-
and (−)-enantiomers do not differ in their anti-
secretory potencies in animals. An oral 20 mg
formulation for GERD/maintenance therapy has
been approved recently.
Trade names: Pantozol (Byk Gulden) and
others; various licensed products under differ-
ent trade names (see [23]).
3.2. H2 -Receptor Antagonists
H2 -receptor antagonists (H2 -RAs) are structural
analogues of histamine that – at least those in
clinical use – competitively and surmountably
6 Antiulcer Drugs

Figure 2. Congruence between animal data, human pharmacology data and clinical data with respect to equipotency and
equiefficacy of two gastric proton pump inhibitors.A) Inhibition of gastric acid secretion in various animal models: Inhibitory
doses, ID50 values (µmol/kg; 1 µmol = 0.35 mg of omeprazole or 0.38 mg of pantoprazole, free acid). HPD = Heidenhain
pouch dog, FR = acute fistula rat, GSR = Ghosh-Schild rat, 2-DG = 2-deoxy-d-glucose. The routes of administration refer to
test drugs, not secretagogues (impromidine, penta. = pentagastrin, bethan. = bethanechol). For further information, see [56].B)
24 h-pH-metry in healthy volunteers (time of intragastric pH > 4). All doses 40 mg orally, daily over 7 d Left pair of columns:
Koop et al. [40]. Right pair of columns: Brunner et al. [44]. The comparison between the two studies shows that, although PPIs
may vary in their efficacy depending on the random sample, omeprazole and pantoprazole proved equipotent when compared
intraindividually.C) Healing rates in gastroesophageal reflux disease (GERD), duodenal ulcer (DU), and gastric ulcer (GU) in
a comparison between daily oral doses of either 20 or 40 mg omeprazole or 40 mg pantoprazole. Selected studies that show a
clear cut advantage of the 40 mg dose. From left to right: Hetzel et al. [45]; Laursen et al. [46]; Bate et al. [47]; Lauritsen
et al. [48]; Walan et al. [49]; Valenzuela et al. [50]; Witzel et al. [51]. The specifications “all” and “> 1 cm” below the
sixth group of columns [50] refer to the ulcers evaluated. p-Values are indicated at the bottom of columns compared to each
other. All of the differences between the two doses shown in the figure are statistically significant irrespective of the particular
drug involved. It is important to note that the failure of other studies (not shown here; see [50] and [53]) to demonstrate any
significant difference between the healing rates upon 40 mg pantoprazole compared to 20 mg omeprazole does not conflict
with the aforementioned superiority of the 40 mg dosage. In fact, 40 mg of either drug represent a ceiling dose separated by
a comparatively small difference from the healing rate upon 20 mg. Thus, both of the two doses are localized in the upper
portion of the dose response curve. Because of the large interindividual variation seen in clinical studies, the difference will
be statistically significant in one, but statistically insignificant in another study.
 Antiulcer Drugs 7

block the H2 -receptors located on the basolat-

eral membrane of the parietal cell. Histamine is
the major secretagogue in humans [33], [112].
An imidazole ring as part of the structure was
originally regarded essential for specific H2 -
antagonism but this was refuted by the newer
H2 -RAs (see [113]). They show a similarly fa-
vorable safety profile as the PPIs [114] but face
the problem of about 10 % resistant peptic ulcers
[115] and loss of effectiveness by about 50 %
over a 4-week treatment course (tolerance devel-
opment [116]). Potential reasons have been dis-
cussed in [117], [33]. Table 2 shows the chemical
structures of the H2 -RAs. In contrast to cime-
tidine (imidazole ring), the newer compounds
contain thiazole (famotidine and nizatidine), fu-
ran (ranitidine) or piperidine and benzene (rox-
atidine) ring systems. This helps to avoid un-
wanted cytochrome P450, i.e., metabolic drug
interactions [118]. The individual drugs are dis-
cussed in the following in alphabetical order.

Table 2. Chemical structures of H2 -receptor antagonists. Note the

different ring systems. The imidazole ring is mainly responsible for
metabolic drug interactions [118].

Cimetidine

Famotidine

Figure 3. Synthesis of pantoprazole sodium as an example

of PPIs [108]
Nizatidine

Cimetidine [51481-61-9], 1-cyano-2-

methyl-3-[2-[[(5-methylimidazol-4-yl)methyl]-
thio]ethyl]guanidine (WHO) [119],
C10 H16 N6 S, M r 252.34, mp 141 – 143 ◦ C, sol-
Ranitidine
ubility in water at 37 ◦ C 1.14 wt % increased by
dilute HCl, pK a -values 6.8 and 7.1. Cimetidine
is a crystalline powder with bitter taste and char-
acteristic odor. Citmetidine was the first of the
Roxatidine H2 -RAs and revolutionized peptic ulcer therapy
when introduced in the 1970s [120].
Trade names: Tagamet (SmithKline
Beecham) and numerous others (see [23]).
8 Antiulcer Drugs
Figure 4. The chemical activation pathway of substituted
benzimidazoles exemplified by pantoprazole (according to
[27])E = enzyme
Famotidine [76824-35-6], [1-amino-3-
[[[2-[(diaminomethylene)-amino]-4-thiazolyl]-
methyl]thio]propylidene]-sulfamide (WHO)
[121], C8 H15 N7 O2 S3 , M r 337.43, mp
163 – 164 ◦ C, solubility in water at 20 ◦ C
0.1 wt %.
Trade names: Pepdul (Merck Sharp &
Dohme) and numerous others (see [23]).
Nizatidine [76963-41-2], N-[2-[[[2-[(di-
methylamino)methyl]4-thiazolyl]methyl]-
thio]ethyl]N’-methyl-2-nitro-1,1-ethenediamine
(WHO) [122], C12 H21 N5 O2 S2 , M r 331.45, mp
130 – 132 ◦ C, solubility in water 0.1 – 0.33 wt %,
pK a -values 2.1 and 6.8.
Trade names: Nizax (Lilly) and others
(see [23]).
Ranitidine [66357-35-5], N-[2-[[5-[(di-
methylamino)-methyl]furfuryl]thio]ethyl]N’-
methyl-2-nitro-1,1-ethenediamine (WHO)
[123], C13 H22 N4 O3 S, M r 314.41, mp
69 – 70 ◦ C, freely soluble in water. Ranitidine
was the second H2 -receptor antagonist intro-
duced in the early 1980s. It further optimized
peptic ulcer therapy by minimizing unwanted
interactions with androgen receptors and cy-
tochrome P450 (see above). It has a higher
affinity and, hence, greater potency compared to
cimetidine which, however, is important only in
the context of the relative drug safety margins.
Trade names: Zantic (Glaxo) and numerous
others (see [23]). Ranitidine is also available as
Raniditine bismuth citrate used in H.p.-positive
ulcer patients (see Section 3.4.5).
Roxatidine [78273-80-0], N-[3-[(α-
piperidino-m-tolyl)oxy]-propyl]glycolamide
(WHO) [124], C17 H26 N2 O3 , M r 306.41, mp
59 – 60 ◦ C.
Trade name: Roxit (Albert-Roussel).
3.3. Antacids
Starting with naturally occurring carbonates
centuries ago and later followed by potash com-
bined with bismuth more than one century ago,
antacids have since been developed and widely
used over decades (see [125]). They are better
than placebos and as effective as cimetidine in
DU healing but less effective in GU healing
[125]. Available both as liquids and tablets, they
are nowadays usually taken 1 h after each meal
and at bedtime in a total daily dose equivalent
to about 400 mmol neutralizing capacity. This
should be sufficient for all patients while min-
imizing adverse effects (see below). Such regi-
mens elevate intragastric pH above 3.5 for about
2 h. Water-insoluble, aluminum – magnesium-
containing antacids (like magaldrate) leave the
stomach more slowly with the solid meal por-
tion and are therefore longer acting. In ad-
dition to acid neutralization, these aluminum-
containing antacids enhance the production
of mucosal prostaglandins and possibly SH-
containing compounds to protect the mucosa
from injury (“gastroprotection”) [125]. In ther-
apy and prevention of mild GERD, acid neu-
tralization, subsequent partial pepsin inactiva-
tion, and binding of bile acids and lysolecithin
may act in concert (see [125]). Antacids display
a favorable cost : benefit ratio in mild diseases.

More severe cases of acid related disorders re-
quire PPIs (see Section 3.1).
Although antacids did not display any ter-
atogenic effects in animals and may therefore
be used in pregnancy- and delivery-associated
GERD (see [125]), they can interfere with iron
absorption and may facilitate metabolic alcalo-
sis and fluid overload. The latter effects depend
on their bicarbonate and sodium ion content
which is considered obsolete. In general, low
sodium products should be preferred. Particulate
antacids may also cause pneumonia upon aspi-
ration and have been substituted for prevention
of reflux complications largely by antisecreta-
gogues. Nonulcer dyspepsia (NUD) and prophy-
laxis of NSAID-induced ulcers (see misoprostol,
Section 3.4.1) are no recommended indications
for antacids. Apart from the aforementioned ad-
verse effects, aluminum-containing antacids can
bind tetracyclines and many other drugs and
thus prevent their absorption [21]. Aluminum-
containing antacids may also complex phos-
phate (to cause osteomalacia in the worst case)
and constipate the patient. The latter effect is
counterbalanced by magnesium [21] contained
in combination formulations such as magal-
drate (see [126]), because magnesium salts in
the intestine increase GI motility and cause os-
motic diarrhea [127]. HCl converts insoluble
aluminum oxide and hydroxide into more read-
ily soluble and absorbable aluminum chloride.
However, the causal relationship between alu-
minum intake with antacids and Alzheimer’s
disease is unlikely, while chronic intake of high
doses may cause CNS toxicity in patients with
renal insufficiency [128], [129].
Antacids containing carbonate, namely
NaHCO3 or CaCO3 , produce CO2 with HCl
and cause therefore gastric flatulence, belching
and acid reflux. Na+ may cause problems in hy-
pertensive patients, Ca2+ adversely stimulates
gastrin and HCl secretion (“acid rebound”).
Those salts of carbonic acid are considered ob-
solete even in antacid mixtures although they
are still used to some extent. Modern alterna-
tives are the poorly soluble bases magnesium
and aluminum hydroxide. If the two are incor-
porated together into one tridimensional lattice
as represented by magaldrate (see below), they
behave as a monosubstance buffering the pH
between about 3 and 5 [130].
Antiulcer Drugs 9
For tabulated overviews of antacids, see [21],
[131], [132]. The indicated in vitro neutraliza-
tion capacities do not necessarily reflect the rel-
ative therapeutic efficacies which are also af-
fected by pH-dependent dissolution, viscosity,
gastroprotective effects, etc. (see magaldrate).
Antacid formulations may contain many addi-
tives such as simethicone (carminative contained
in Riopan; see [131]); these are not considered
here. Only the major antacid components which
influence gastric acidity will be discussed below
in alphabetical order.
Aluminum hydroxide [21645-51-2],
Al(OH)3 , M r 77.99, insoluble in water, solu-
ble in dilute mineral acids and alkali hydroxides
(4 % suspension in water), white, amorphous
powder. For other relevant properties and pro-
duction, see → Aluminum Oxide, Chap. 1.1.
Available as Al(OH)3 ·nH2 O (algedrate) and
algedrate hexitol complex. Depending on gastric
acidity, stepwise buffering proceeds according
to
Al(OH)3 + 3 HCl
Al(OH)2 Cl + H2 O + 2 HCl

Al(OH)Cl2 + 2 H2 O + HCl
AlCl3 + 3 H2 O
Pure Al(OH)3 ·nH2 O is not very stable, it ages
at room temperature upon loss of water (forma-
tion of aluminum oxide) and neutralizing capac-
ity. Aluminum hydroxide is preferably used as
a combination preparation with magnesium hy-
droxide to counterbalance gut motility effects.
This mixture also displays increased stability.
Generated from aluminum hydroxide and gas-
tric acid, aluminum chloride binds phosphate as
insoluble AlPO4 which is then excreted with
feces. Aluminum hydroxide is therefore also
used at mealtime in patients on dialysis to re-
duce phosphate intake. Magnesium containing
antacids (see below) are contraindicated in this
condition to avoid dangerous hypermagnesemia
[132].
Trade names: Actal and numerous others
(see [23]).
Aluminum phosphate [7784-30-7],
AlPO4 , M r 121.95, white powder, insoluble in
water, soluble in concentrated mineral acids, pH
5.5 – 6.5 (4 % suspension in water). Available as
AlPO4 gel or AlPO4 ·2 H2 O. For other relevant
properties and production, see → Phosphoric
Acid and Phosphates, Chap. 3.3.6.
10 Antiulcer Drugs
Trade names: Phosphalugel (Boehringer In-
gelheim) and others (see [23]).
Magnesium hydroxide [1309-42-8],
Mg(OH)2 , M r 58.32, amorphous powder, vir-
tually insoluble in water (pH 9.5 – 10.5), solu-
ble in dilute acids. For other relevant properties
and production, see → Magnesium Compounds,
Chap. 4. Available in combination preparations
with aluminum hydroxide and under numerous
trade names (see [23]). The equation for neu-
tralization is
Mg(OH)2 + 2 HCl
MgCl2 + 2 H2 O
For potential side effects, see general discussion
of antacids.
Magaldrate (hydroxymagnesium alumi- anced, opposing actions of aluminum and mag-
nate) [74978-16-8], Al5 Mg10 (OH)31 (SO4 )2 ·nH2 O, nesium on gut motility [21].
insoluble in water, white, odorless crystalline
powder, soluble in dilute mineral acids. Mag-
aldrate [133] favorably combines the strongly
basic properties of magnesium located in the
crystal core with the less basic properties of alu- 3.4.1. Prostaglandin Derivates
minum ions surrounding the former in a layered
lattice (Fig. 5). The magaldrate layered lattice
consists of recurrent stacks of octahedral ba-
sic layers with an excess of positive charges
[Al5 Mg10 (OH)30 ]5+ on the outer gel surface
[134], [135]. These charges electrostatically in-
teract with negative charges of the gastric mucus
layer to favorably increase the antacid’s reten-
tion time in the stomach [136].
Trade names: Riopan (Byk Gulden) and nu-
merous others (see [23]).
In these brucite-like layers, about one third of tifacient and are contraindicated during preg-
the HO – Mg – OH units are substituted by pos-
itively charged HO – Al+ – OH units, counter-
balanced by SO2− −
4 and OH anions in the aque-
ous interlayer [137–139]. Compared to antacids
composed of mixed hydroxides of aluminum
and magnesium, magaldrate has a low aluminum
content per milliliter and releases less aluminum
because it rebinds aluminum ions in exchange
for the more basic magnesium ions provided by
an excess of antacid [140], [141]. A further ad-
vantage of the layered lattice is that its inner
surface is not accessible to aluminum-binding
proteins that otherwise reduce the buffering
capacity of aluminum-containing conventional
antacids [142]. In fact, although the in vitro acid- ter. Misoprostol is approved for prophylaxis of
neutralizing capacity of magaldrate is similar to
that of other antacids, its in vivo neutralizing ca-
pacity in humans is significantly higher [142]
due to the exclusion of proteins [133]. How-
ever, magaldrate forms a gel with a large inner
surface confining water spaces readily accessi-
ble to HCl. The alternation of magnesium and
aluminum hydroxides within the layered lattice
prevents losses of buffering capacity by aging.
Magaldrate thereby shows prolonged acid neu-
tralization up to the optimum of pH 4 [133]. In
contrast, an aging phenomenon is found in alu-
minum hydroxide gels which is due to transition
of aluminum hydroxide to aluminum oxide upon
loss of water.
The magaldrate gel binds cholic acids like an
anion exchanger, and it binds lysolecithin and
pepsin on its outer surface [143]. It provides bal-
3.4. Miscellaneous Drugs
(→ Prostaglandins)
Prostaglandin (PG) derivatives exert gastropro-
tective effects at subantisecretory doses [144]
but have the disadvantage of frequent side ef-
fects (mostly diarrhea and cramps) when ad-
ministered at higher, antisecretory doses [128].
Only the latter accelerate healing of GU and DU.
Prostaglandins seem to be somewhat inferior to
H2 -receptor antagonists [145], particularly with
respect to pain relief. Prostaglandins are abor-
nancy and lactation. Low doses of PG deriva-
tives have proved valuable in the prophylaxis of
NSAID-induced peptic ulcers [21], [132]. Apart
from the PG-E1 derivative misoprostol (see be-
low), other PG-E1 (rioprostil) and PG-E2 deriva-
tives (arboprostil, enprostil, trimoprostil) had
been under study [21], [146].
Misoprostol [59122-46-2], 15-deoxy-
16-hydroxy-16-methyl-PG-E1 , (±)-Methyl-
(1R,2R,3R)-3-hydroxy-2-[(E)-(4RS)-4-
hydroxy-4-methyl-1-octenyl]-5-oxocyclopen-
taneheptanoate (WHO) [147], C22 H38 O5 , M r
382.54, light yellow oil, slightly soluble in wa-

Figure 5. Schematic drawing of the layered lattice of magaldrate, a special example of an antacid (according to [134])
NSAID-induced ulcers and the treatment of DU
and GU regardless of the limitations mentioned
above.
Trade names: Cytotec (Heumann) and others
(see [23]).
3.4.2. Prokinetic Drugs
Reflux esophagitis (GERD) is caused by reflux
of gastric acid and therefore treated not only by
PPIs and antacids but also by prokinetic drugs
which facilitate oral to aboral clearing of the
esophagus and emptying of the stomach [148].
Prokinetic drugs do so by alternately decreasing
the frequency of intermittent lower esophageal
sphincter relaxations, and increasing the ampli-
tude and frequency of esophageal as well as gas-
tric peristaltic contractions. Two pharmacologi-
cal principles are used: (1) blockade of periph-
eral dopamine D2 -receptors by domperidone or
metoclopramide which may lead to disinhibi-
tion of motility (although its mediation by D2 -
receptor blockade is controversial), and (2) ac-
tivation of peripheral 5-HT4 -receptors by either
metoclopramide or cisapride. The latter inter-
action triggers the release of acetylcholine that
subsequently stimulates motor neurons [149],
[150]. Side effects relate primarily to either
blockade of dopamine receptors (extrapyrami-
dal motor and prolaktin effects as well as diar-
rhea; [151]) or release of acetylcholine (cramps,
Antiulcer Drugs 11
diarrhea; [152]). Domperidone has the advan-
tage over metoclopramide of not significantly
entering the central nervous system (CNS), thus
avoiding central side effects. Although cisapride
concentrations in rat brain can reach one-third
to half of the plasma concentration, it does
not block dopamine receptors and is therefore
devoid of extrapyramidal motor and prolaktin
effects [152]. Drug interactions by prokinetic
drugs have been reviewed in [153].
Cisapride [81098-60-4], cis-4-amino-5-
chloro-N-[1-[3-(p-fluorophenoxy)-propyl]-3-
methoxy-4-piperidyl]-o-anisamide (WHO)
[152], C23 H29 ClFN3 O4 , M r 465.95, available
as monohydrate, mp 109.8 ◦ C is, like metoclo-
pramide, a substituted benzamide.
Trade names: Propulsin (Janssen) and others
(see [23]).
Domperidone [57808-66-9], 5-chloro-1-
[1-[3-(2-oxo-1-benzimidazolinyl)propyl]-4-
piperidyl]-2-benzimidazolinone (WHO) [154],
12 Antiulcer Drugs
C22 H24 ClN5 O2 , M r 425.92, mp 242.5 ◦ C, avail-
able as maleate (M r 544.06).
Trade names: Motilium (Byk Gulden) and
others (see [23]).
Metoclopramide [364-62-5], 4-ami-
no-5-chloro-N-[2-(diethylamino)-ethyl]-o-
anisamide (WHO) [155], C14 H22 ClN3 O2 , M r
299.81, mp 146.5 – 148 ◦ C, solubility in wa-
ter at 25 ◦ C 0.02 wt %, pK a -values 7.3 and
9.0. Metoclopramide is available as hydrochlo-
ride monohydrate (M r 354.28) as a 10 % aque-
ous solution of pH 4.5 – 6.0.
Trade names: Gastrosil (Heumann) and many
others (see [23]).
3.4.3. Antimuscarinic Drugs
The only antimuscarinic drug still used in
peptic ulcer disease is pirenzepine which has
limited selectivity for M1 -muscarinic recep-
tors present on both intramural neurons and
paracrine, histamine-releasing cells (i.e., ECL-
cells) of the gastric mucosa [156], [157].
Pirenzepine [28797-61-7], 5,11-dihydro-
11-[(4-methyl-1-piperazinyl)acetyl]-6H-
pyrido[2,3-b][1,4]benzodiazepin-6-one (WHO)
[158], C19 H21 N5 O2 , M r 351.42, pK a values 2.1
and 8.1. Pirenzepine is available as dihydrochlo-
ride monohydrate, M r 442.36, soluble in water.
Because of its unfavorable balance between
weak antisecretory and frequent anticholiner-
gic adverse effects (dry mouth, blurred vision),
pirenzepine is considered obsolete [128].
Trade names: Gastrozepin (Thomae) and
many others (see [23]).
3.4.4. Sucralfate
Sucralfate [54182-58-0], sucrose hydro-
gen sulfate basic aluminum salt (WHO),
C12 H54 Al16 O75 S8 , M r 2086.74, insoluble in
water, soluble in dilute HCl or NaOH, pK a
0.43 – 1.19.
Sucralfate was first introduced in Japan in the
late 1960s. Numerous active components of su-
cralfate have been described which act in con-
cert to make sucralfate a gastroprotective antiul-
cer drug [159], [160] that even displays “cy-
toprotective” actions (i.e., on a cellular level)
in vitro [161]. Maintenance of mucosal blood
flow ensures rapid repair of mucosal damage;
increased mucosal bicarbonate and mucus se-
cretion protects the mucosa; and binding of fi-
broblast growth factor and epidermal growth
factor to the sucralfate gel adhering to the in-
jured mucosa enhances angiogenesis and epithe-
lization of ulcerated areas [160]. Stimulation of
PG biosynthesis and release of somatostatin may
contribute to these actions and may further ex-
plain reduction of both parietal cell responsive-
ness and ulcer relapse rate following ulcer heal-
ing by sucralfate [159]. These effects may also
explain reduced acid secretion under sucralfate
therapy [162]. In addition, sucralfate may inter-
fere with the attachment of H.p. to the gastric
epithelium and may thereby suppress to some
extent (but not eradicate) H.p. infection [159],
[162]. Healing rates with sucralfate are simi-
lar to, and ulcer relapse rates are even lower
than those after, H2 -receptor antagonists [132],

[163]. Tolerability is excellent, with aluminum-
induced constipation being the most prominent
side effect seen in 2 – 4 % of the patients [132],
[164].
Trade names: Ulcogant (Merck) and many
others (see [23]).
3.4.5. Bismuth Compounds
A variety of bismuth compounds are available
as antiulcer drugs.
Bismuth aluminate [12284-76-3],
Bi2 (Al2 O4 )3 .
Trade name: Noemin (Trommsdorf) and oth-
ers (see [23]).
Bismuth citrate is on the market as a col-
loidal ammonium – potassium salt which is a
mixture of the corresponding salts of the bismuth
citrate complex [BiC6 H4 O7 ]− (K or NH4 )+
(see below) and citric acid [C6 H5 O7 ]3− 3(K or
NH4 )+ . The so-called “colloidal bismuth subci-
trate, CBS” in fact contains the aforementioned
bismuth citrate complex [165] in which H+ of
one citric acid carboxyl group is substituted by
either K+ or NH+ 4 . These units are further com-
plexed to a colloidal material [166]. Bismuth cit-
rate is highly soluble in water.
Trade names: Telen (Yamanouchi) and others
(see [23]).
Bismuth subgallate [99-26-3], C7 H7 BiO7 ,
lipid solubility leads to a high rate of absorption,
in contrast to the other salts (but see bismuth cit-
rate).
Trade names: Bismofalk (Falk) and others
(see [23]).
Bismuth subnitrate [1304-85-4],
BiO(NO3 )·H2 O.
Trade name: Angass (Medice).
Antiulcer Drugs 13
Bismuth subsalicylate [14882-18-9],
C7 H5 BiO4 .
Trade names: Jatrox (Procter & Gamble) and
others (see [23]).
Mode of Action. These colloidal, basic bis-
muth preparations are, with the exception of bis-
muth citrate, almost insoluble in water. Depend-
ing on the actual pH, they form either colloidal
solutions, highly hydrated gels, or thin films
[167]. These cover the ulcerated areas, predom-
inantly due to formation of bismuth oxychlo-
ride BiOCl, but also more complex structures
containing free COOH and BiO+ groups. These
structures are precipitated from bismuth salts by
gastric acid. Bismuth citrate is highly soluble in
water but precipitates in an acid medium when
the solubility product of its free acid (formed ac-
cording to R–CH2 CO− +
2 + H
R–CH2 CO2 H)
is exceeded [168]. Apart from the tenacious
layer formed on the mucosa at low pH (see
above), bismuth salts display a variety of addi-
tional action components that may be partially
related to their reaction with thiol groups [169]
and proteins [170], [171]. These additional ef-
fects include stimulation of PGE2 biosynthesis
and bicarbonate secretion, and either stimula-
tion of mucus secretion or inhibition of its en-
zymatic degradation. Bismuth compounds also
depress pepsin activity by either chief cell inhi-
bition or pepsin complexation, and inhibit many
enzymes of H.p., thus limiting mucus degra-
dation. Bismuth salts bind and thereby inacti-
vate bile acids at low pH, and accumulate epi-
dermal growth factor in the ulcer area which
may accelerate healing due to its trophic ac-
tions. Bismuth salts exert antimicrobial activity,
also in H.p. infections [172]. The above phar-
macodynamics of bismuth have been reviewed
in [168], [173], with special reference to bis-
muth citrate, and in general in [132]. Substantial
bismuth concentrations in the mucus or within
the mucosa are observed for only a few hours
following administration. Therefore, the low ul-
cer relapse rate with bismuth compounds may
partially be due to trace amounts of bismuth
systematically absorbed and, due to slow ex-
cretion, still available in the gastric tissue over
up to 3 months. Nonetheless, safety of therapy
with bismuth compounds seems to be excellent
with only mild and infrequent side effects [174].
Probably due to its pK a value in the order of 3
14 Antiulcer Drugs
and, therefore, its comparatively fair ability to
penetrate the stomach wall under acidic condi-
tions as an uncharged molecule, bismuth citrate
may produce higher (although transient) peak
plasma concentrations of bismuth than some of
the other bismuth salts which are unstable un-
der these conditions. However, no major toxic
effects have been reported [174].
Ranitidine bismuth citrate (RBC) [128345-
62-0], C19 H27 BiN4 O10 S, M r 712.48, is a novel
salt of the base ranitidine and the monobasic
acid bismuth citrate (note that a widely used
nomenclature is subcitrate instead of citrate, see
above and [165]). Ranitidine bismuth citrate
forms a suspension in water but is soluble at
low pH values to release its components. Ac-
cording to [175] RBC inactivates pepsin and
H.p. more efficiently than an admixture of its
components due to its better solubility. How-
ever, as discussed in page 13, bismuth citrate
released at low pH will again precipitate as
soon as the solubility product of its free acid is
exceeded. Ranitidine bismuth citrate has been
developed for combination therapy with antibi-
otics for eradication of H.p. Depending on the
co-prescription, eradication ranged from 15 to
92 % in an intention-to-treat analysis [176]. It is
claimed to combine the antisecretory action of
ranitidine with the antimicrobial and gastropro-
tective actions of bismuth.
Trade name: Pylorid (GlaxoWellcome).
4. Prospect for Future Developments
4.1. Reversibly Binding Acid Pump
Antagonists
In contrast to PPIs which bind covalently to the
proton (acid) pump (see Section 3.1), acid pump
antagonists (APAs) bind reversibly and compete
with potassium on the luminal (extracytoplas-
mic) side of the H+ /K+ -ATPase to interrupt its
catalytic cycle [20]. This reversible blockade not
only regards the activated pumps already incor-
porated into the apical membrane, but also the
resting pumps [177] still present in cytoplasmic
vesicles. The latter are devoid of any proton gra-
dient, they are unable to activate PPIs for this
reason, and probably amount to about one-third
of the total pumps in a parietal cell during meal
stimulation [33], [177]. APAs will therefore re-
sult in a more rapid and complete inhibition of
acid secretion than PPIs on a first administration.
The duration of this inhibition by APAs corre-
sponds to the drug’s actual plasma concentration
as opposed to a prolonged inhibition with cova-
lently binding PPIs [178], [179]. APAs with dif-
ferent chemical structures have been synthesized
(for example, imidazopyridines and acylquino-
lines; see [178]) but not one has reached the mar-
ket so far. Although these weak nitrogen bases,
like the PPIs, accumulate within the acidic space
of the parietal cell, their selectivity for the acid
pump is based on a specific fit between their
chemical structure and that of the acid pump,
being in line with a competitive mode of action.
Pumaprazole [158364-59-1], methyl
2-[[(2,3-dimethylimidazo[1,2-a]pyridin-8-
yl)amino]methyl]-3-methylcarbanilate (WHO),
C19 H22 N4 O2 . Pumaprazole has been aban-
doned in favor of a pharmacologically better
follow up compound presently under develop-
ment at Byk Gulden. The WHO decided to
label the APAs by the stem syllable “-prazole”
in order “to maintain the number of stems at
a manageable level”, irrespective of the com-
pletely different (i.e., reversible vs. covalent)
modes of drug – target interactions by APAs and
PPIs (WHO decision communicated on Nov. 30,
1995). Unfortunately, this pharmacologically
misleading but legally binding decision will con-
fuse the rational use and differential perception
of APAs vs. PPIs in the future and counteracts
the effort for an unambiguous terminology in
pharmacology. It should be noted that the terms
APAs and PPIs have been coined specifically
to make a clearly recognizable distinction be-
tween the two chemically and mechanistically
different classes of drugs.
4.2. Drugs Directed Against
Helicobacter pylori
Helicobacter pylori (H.p.) has been recognized
as a causal factor of most peptic ulcers (see
Chap. 2). While companies worldwide try to
develop antimicrobials both specific for H.p.
and effective as a monotherapy, current ther-
apy still takes advantage of the available reper-

toire of antibiotics [180–183] (→ Antibiotics).
Although it has been claimed that antibiotics
alone can eradicate H.p. infection and heal DU
[184], present eradication regimes include one
of the PPIs (see [180–183]) to enhance the effect
of the antibiotics by a mode of interaction still
under debate [185]. One-week triple therapies
consisting of a PPI in combination with two of
the three antibiotics amoxicillin (→ Antibiotics,
Chap. 4.), clarithromycin, and metronidazole
(→ Imidazole and Derivatives, Chap. 4.3.) are
the therapies of choice according to the Maas-
tricht consensus report [186].
5. Relative Drug Assessment
Burget et al. [187] have published a model
predicting the healing rates in DU, increasing
up to an optimum defined by both a pH thresh-
old and the percentage time the intragastric pH
was above this threshold during a 24-h-period. A
similar relationship in GERD treatment was later
reviewed by Hunt [188]. It generally means that
the longer the duration and the higher the degree
of pH elevation by a certain drug is, the better
the healing rate will be, up to an optimum which
depends on the particular disease (GERD, GU,
DU, Zollinger – Ellison Syndrome). This clearly
favors the PPIs (see Section 3.1) for treatment
of the H.p.-unrelated reflux esophagitis [189],
[190]. The superiority of PPIs also shows in
treatment of GU and DU with the limitation that
any therapy eradicating H.p. (see Section 4.2) or
suppressing H.p. in addition to gastroprotective
effects (see Sections 3.4.4 and 3.4.5) seems to
reduce the ulcer relapse rate compared to exclu-
sively antisecretory drugs [191]. An interesting
observation in this context is that eradication of
H.p. may provoke GERD [192] or DU [193].
This may be due to the loss of neutralizing (NH3 )
or antisecretory compounds that had been pro-
duced by H.p. in the patient’s stomach before
eradication therapy [194]. Obviously, this ob-
servation of DU induction by H.p. eradication
therapy relates to the well known, low percent-
age of peptic ulcer cases causally independent
of H.p. infection.
NSAID-induced peptic ulcers [195] can be
prevented by prophylactic treatment with sub-
antisecretory doses of misoprostol (see Sec-
tion 3.4.1) but less so with H2 -receptor antag-
Antiulcer Drugs 15
onists [196]. Of course, also PPIs are very ef-
fective prophylactic drugs [197]. Antacids have
maintained their place in “common heartburn”,
gastritis, and less severe cases of GERD or GU
and DU [132], although they constitute an in-
ferior treatment option. Their major application
will only be as cheap self-medication remedies.
6. References
1. P. J. Kahrilas: “Gastroesophageal reflux
disease,” in G. Friedman, E. D. Jacobson,
R. W. McCallum (eds.): Gastrointestinal
Pharmacology and Therapeutics,
Lippincott-Raven Publishers, Philadelphia
1997, pp. 31 – 44.
2. P. Malfertheiner, J. W. Freston: “Helicobacter
pylori-induced gastritis, ulceration and
neoplasia,” in G. Friedman, E. D. Jacobson,
R. W. McCallum (eds.): Gastrointestinal
Pharmacology and Therapeutics,
Lippincott-Raven Publishers, Philadelphia
1997, pp. 21 – 29.
3. C. W. Howden: “Gastric and Duodenal ulcers,”
in G. Friedmann, E. D. Jacobson, R. W.
McCallum (eds.): Gastrointestinal
Pharmacology and Therapeutics,
Lippincott-Raven Publishers, Philadelphia
1997, pp. 45 – 51.
4. N. M. Agrawal, E. Z. Dajani: “Drug-induced
Ulcerogenesis,” in G. Friedman, E. D.
Jacobson, R. W. McCallum (eds.):
Gastrointestinal Pharmacology and
Therapeutics, Lippincott-Raven Publishers,
Philadelphia 1997, pp. 55 – 63.
5. P. N. Maton: “Management of acid
hypersecretion in patients with
Zollinger-Ellison syndrome,” in G. Friedman,
E. D. Jacobson, R. W. McCallum (eds.):
Gastrointestinal Pharmacology and
Therapeutics, Lippincott-Raven Publishers,
Philadelphia 1997, pp. 65 – 73.
6. D. J. Cook: “Stress Ulcer Prophylaxis,” in G.
Friedman, E. D. Jacobson, R. W. McCallum
(eds.): Gastrointestinal Pharmacology and
Therapeutics, Lippincott-Raven Publishers,
Philadelphia 1997, pp. 75 – 78.
7. J. H. Kurata, Gastroenterology 96 (1989)
569 – 580.
8. K. H. Holtermüller: “Magen-Darm-Mittel,” in
U. Schwabe, D. Paffrath (eds.):
Arzneiverordnungs-Report ’96, Gustav
Fischer Verlag, Stuttgart 1996, pp. 305 – 324.
16 Antiulcer Drugs
9. J. H. Kurata, A. N. Nogawa, J. Clin.
Gastroenterol. 24 (1997) 2 – 17.
10. N. Banatvala, K. Mayo, F. Mégraud, R.
Jennings, J. J. Deeks, R. A. Feldmann, J.
Infect. Dis. 168 (1993) 219 – 221.
11. D. J. E. Cullen, B. J. Collins, K. J.
Christiansen, J. Epis, J. R. Warren, I. Surveyor,
K. J. Cullen, Gut 34 (1993) 1681 – 1682.
12. P. Sahay, A. T. R. Axon, Helicobacter 1
(1996) 175 – 182.
13. F. Hornemann, M. Nilius, P. Malfertheiner, P.
Bartmann, Helicobacter 2 (1997) 176 – 179.
14. K. Schwarz, Beitr. Klin. Chir. 67 (1910)
96 – 128.
15. A. H. Soll: “Gastric duodenal and stress ulcer,”
in M. H. Sleisenger, J. S. Fordtran (eds.):
Gastrointestinal Disease, 5th ed., vol. 1, W. B.
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