DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Pharmacokinetics. Misoprostol is rapidly absorbed after oral
administration and then is rapidly and extensively de-esterified to
form misoprostol acid, the principal and active metabolite of the
drug. Some of this conversion may occur in the parietal cells. A single
dose inhibits acid production within 30 minutes; the therapeutic
effect peaks at 60-90 minutes and lasts for up to 3 hours. Food and
antacids decrease the rate of misoprostol absorption, resulting in
delayed and decreased peak plasma concentrations of the active
metabolite. The free acid is excreted mainly in the urine, with an
elimination t 1/2
of 20-40 minutes.
Adverse Effects. Diarrhea, with or without abdominal pain and
cramps, occurs in up to 30% of patients who take misoprostol.
Apparently dose related, it typically begins within the first 2 weeks
after therapy is initiated and often resolves spontaneously within a
week; more severe or protracted cases may necessitate drug discontinuation.
Misoprostol can cause clinical exacerbations of inflammatory
bowel disease (Chapter 47) and should be avoided in patients
with this disorder. Misoprostol is contraindicated during pregnancy
because it can increase uterine contractility.
Therapeutic Use. Misoprostol is FDA-approved to prevent NSAIDinduced
mucosal injury. However, it rarely is used because of its
adverse effects and the inconvenience of four-times-daily dosing.
SUCRALFATE
Chemistry; Mechanism of Action; Pharmacology. In the
presence of acid-induced damage, pepsin-mediated
hydrolysis of mucosal proteins contributes to mucosal
erosion and ulcerations. This process can be inhibited
by sulfated polysaccharides. Sucralfate (CARAFATE, others)
consists of the octasulfate of sucrose to which
Al(OH) 3
has been added. In an acid environment (pH
<4), sucralfate undergoes extensive cross-linking to
produce a viscous, sticky polymer that adheres to
epithelial cells and ulcer craters for up to 6 hours after
a single dose. In addition to inhibiting hydrolysis of
mucosal proteins by pepsin, sucralfate may have additional
cytoprotective effects, including stimulation of
local production of prostaglandins and epidermal
growth factor. Sucralfate also binds bile salts; thus some
clinicians use sucralfate to treat individuals with the
syndromes of biliary esophagitis or gastritis (the existence
of which is controversial).
Therapeutic Uses. The use of sucralfate to treat peptic acid disease
has diminished in recent years. Nevertheless, because increased gastric
pH may be a factor in the development of nosocomial pneumonia
in critically ill patients, sucralfate may offer an advantage over
proton pump inhibitors and H 2
receptor antagonists for the prophylaxis
of stress ulcers. Due to its unique mechanism of action, sucralfate
also has been used in several other conditions associated with
mucosal inflammation/ulceration that may not respond to acid suppression,
including oral mucositis (radiation and aphthous ulcers)
and bile reflux gastropathy. Administered by rectal enema, sucralfate
also has been used for radiation proctitis and solitary rectal ulcers.
Because it is activated by acid, sucralfate should be taken on
an empty stomach 1 hour before meals. The use of antacids within
30 minutes of a dose of sucralfate should be avoided. The usual
dose of sucralfate is 1 g four times daily (for active duodenal ulcer)
or 1 g twice daily (for maintenance therapy).
Adverse Effects. The most common side effect of sucralfate is
constipation (~2%). Because some aluminum can be absorbed,
sucralfate should be avoided in patients with renal failure who are
at risk for aluminum overload. Likewise, aluminum-containing
antacids should not be combined with sucralfate in these patients.
Sucralfate forms a viscous layer in the stomach that may inhibit
absorption of other drugs, including phenytoin, digoxin, cimetidine,
ketoconazole, and fluoroquinolone antibiotics. Sucralfate
therefore should be taken at least 2 hours after the administration
of other drugs. The “sticky” nature of the viscous gel produced
by sucralfate in the stomach also may be responsible for the development
of bezoars in some patients, particularly in those with
underlying gastroparesis.
ANTACIDS
Although hallowed by tradition, the antacids largely
have been replaced by more effective and convenient
drugs. Nevertheless, they continue to be used by
patients for a variety of indications, and some knowledge
of their pharmacology is important for the medical
professional (Table 45–2 compares some commonly
used antacid preparations).
Many factors, including palatability, determine the effectiveness
and choice of antacid. Although sodium bicarbonate effectively
neutralizes acid, it is very water soluble and rapidly absorbed from
the stomach, and the alkali and sodium loads may pose a risk for
patients with cardiac or renal failure. Depending on particle size and
crystal structure, CaCO 3
rapidly and effectively neutralizes gastric
H + , but the release of CO 2
from bicarbonate- and carbonate-containing
antacids can cause belching, nausea, abdominal distention, and flatulence.
Calcium also may induce rebound acid secretion, necessitating
more frequent administration.
Combinations of Mg 2+ (rapidly reacting) and Al 3+ (slowly
reacting) hydroxides provide a relatively balanced and sustained neutralizing
capacity and are preferred by most experts. Magaldrate is
a hydroxymagnesium aluminate complex that is converted rapidly in
gastric acid to Mg(OH) 2
and Al(OH) 3
, which are absorbed poorly
and thus provide a sustained antacid effect. Although fixed combinations
of magnesium and aluminum theoretically counteract the
adverse effects of each other on the bowel (Al 3+ can relax gastric
smooth muscle, producing delayed gastric emptying and constipation;
Mg 2+ exerts the opposite effects), such balance is not always
achieved in practice.
Simethicone, a surfactant that may decrease foaming and
hence esophageal reflux, is included in many antacid preparations.
However, other fixed combinations, particularly those with aspirin,
that are marketed for “acid indigestion” are irrational choices, are
potentially unsafe in patients predisposed to gastroduodenal ulcers,
and should not be used.
1315
CHAPTER 45
PHARMACOTHERAPY OF ACIDITY, ULCERS, AND REFLUX DISEASE