Drugs for the Treatment of Peptic Ulcers

Drugs for Gastric and Duodenal Ulcers

In the area of a gastric or duodenal peptic
ulcer, the mucosa has been attacked
by digestive juices to such an extent as
to expose the subjacent connective tissue
layer (submucosa). This self-digestion
occurs when the equilibrium
between the corrosive hydrochloric acid
and acid-neutralizing mucus, which
forms a protective cover on the mucosal
surface, is shifted in favor of hydrochloric
acid. Mucosal damage can be
promoted by Helicobacter pylori bacteria
that colonize the gastric mucus.
Drugs are employed with the following
therapeutic aims: (1) to relieve
pain; (2) to accelerate healing; and (3)
to prevent ulcer recurrence. Therapeutic
approaches are threefold: (a) to reduce
aggressive forces by lowering H+
output; (b) to increase protective forces
by means of mucoprotectants; and (c) to
eradicate Helicobacter pylori.
I. Drugs for Lowering Acid
Concentration
Ia. Acid neutralization. H+-binding
groups such as CO3
2–, HCO3
– or OH–, together
with their counter ions, are contained
in antacid drugs. Neutralization
reactions occurring after intake of
CaCO3 and NaHCO3, respectively, are
shown in (A) at left. With nonabsorbable
antacids, the counter ion is dissolved
in the acidic gastric juice in the
process of neutralization. Upon mixture
with the alkaline pancreatic secretion in
the duodenum, it is largely precipitated
again by basic groups, e.g., as CaCO3 or
AlPO4, and excreted in feces. Therefore,
systemic absorption of counter ions or
basic residues is minor. In the presence
of renal insufficiency, however, absorption
of even small amounts may cause
an increase in plasma levels of counter
ions (e.g., magnesium intoxication with
paralysis and cardiac disturbances). Precipitation
in the gut lumen is responsible
for other side effects, such as reduced
absorption of other drugs due to
their adsorption to the surface of precipitated
antacid or, phosphate depletion
of the body with excessive intake of
Al(OH)3.
Na+ ions remain in solution even in
the presence of HCO3
–-rich pancreatic
secretions and are subject to absorption,
like HCO3
–. Because of the uptake of Na+,
use of NaHCO3 must be avoided in conditions
requiring restriction of NaCl intake,
such as hypertension, cardiac failure,
and edema.
Since food has a buffering effect,
antacids are taken between meals (e.g.,
1 and 3 h after meals and at bedtime).
Nonabsorbable antacids are preferred.
Because Mg(OH)2 produces a laxative
effect (cause: osmotic action, p. 170, release
of cholecystokinin by Mg2+, or
both) and Al(OH)3 produces constipation
(cause: astringent action of Al3+),
these two antacids are frequently
used in combination.
Ib. Inhibitors of acid production.
Acting on their respective receptors, the
transmitter acetylcholine, the hormone
gastrin, and histamine released intramucosally
stimulate the parietal cells of
the gastric mucosa to increase output of
HCl. Histamine comes from enterochromaffin-
like (ECL) cells; its release is
stimulated by the vagus nerve (via M1
receptors) and hormonally by gastrin.
The effects of acetylcholine and histamine
can be abolished by orally applied
antagonists that reach parietal cells via
the blood.
The cholinoceptor antagonist pirenzepine,
unlike atropine, prefers cholinoceptors
of the M1 type, does not
penetrate into the CNS, and thus produces
fewer atropine-like side effects.
The cholinoceptors on parietal
cells probably belong to the M3 subtype.
Hence, pirenzepine may act by blocking
M1 receptors on ECL cells or submucosal
neurons.
Histamine receptors on parietal
cells belong to the H2 type and
are blocked by H2-antihistamines. Because
histamine plays a pivotal role in
the activation of parietal cells, H2-antihistamines
also diminish responsivity
to other stimulants, e.g., gastrin (in gas-
trin-producing pancreatic tumors, Zollinger-
Ellison syndrome). Cimetidine,
the first H2-antihistamine used therapeutically,
only rarely produces side effects
(CNS disturbances such as confusion;
endocrine effects in the male, such
as gynecomastia, decreased libido, impotence).
Unlike cimetidine, its newer
and more potent congeners, ranitidine,
nizatidine, and famotidine, do not interfere
with the hepatic biotransformation
of other drugs.
Omeprazole can cause maximal
inhibition of HCl secretion. Given
orally in gastric juice-resistant capsules,
it reaches parietal cells via the blood. In
the acidic milieu of the mucosa, an active
metabolite is formed and binds covalently
to the ATP-driven proton pump
(H+/K+ ATPase) that transports H+ in exchange
for K+ into the gastric juice. Lansoprazole
and pantoprazole produce
analogous effects. The proton pump inhibitors
are first-line drugs for the treatment
of gastroesophageal reflux disease.
II. Protective Drugs
Sucralfate contains numerous aluminum
hydroxide residues. However, it
is not an antacid because it fails to lower
the overall acidity of gastric juice. After
oral intake, sucralfate molecules undergo
cross-linking in gastric juice, forming
a paste that adheres to mucosal defects
and exposed deeper layers. Here sucralfate
intercepts H+. Protected from acid,
and also from pepsin, trypsin, and bile
acids, the mucosal defect can heal more
rapidly. Sucralfate is taken on an empty
stomach (1 h before meals and at bedtime).
It is well tolerated; however, released
Al3+ ions can cause constipation.
Misoprostol is a semisynthetic
prostaglandin derivative with greater
stability than natural prostaglandin,
permitting absorption after oral administration.
Like locally released prostaglandins,
it promotes mucus production
and inhibits acid secretion. Additional
systemic effects (frequent diarrhea; risk
of precipitating contractions of the
gravid uterus) significantly restrict its
therapeutic utility.
Carbenoxolone is a derivative
of glycyrrhetinic acid, which occurs in
the sap of licorice root (succus liquiritiae).
Carbenoxolone stimulates mucus
production. At the same time, it has a
mineralocorticoid-like action (due to inhibition
of 11-!-hydroxysteroid dehydrogenase)
that promotes renal reabsorption
of NaCl and water. It may,
therefore, exacerbate hypertension,
congestive heart failure, or edemas. It is
obsolete.
III. Eradication of Helicobacter pylori
C. This microorganism plays an important
role in the pathogenesis of
chronic gastritis and peptic ulcer disease.
The combination of antibacterial
drugs and omeprazole has proven effective.
In case of intolerance to amoxicillin
or clarithromycin, metronidazole
can be used as a substitute.
Colloidal bismuth compounds
are also effective; however, the problem
of heavy-metal exposure compromises
their long-term use.