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

1328 undigested food into the small bowel. This potential disadvantage
can be exploited clinically to clear the stomach of undigestible
residue such as plastic tubes or bezoars. Anecdotally, erythromycin
also has been of benefit in patients with small-bowel dysmotility
such as that seen in scleroderma, ileus, or pseudo-obstruction. Rapid
development of tolerance to erythromycin, possibly by downregulation
of the motilin receptor, and undesirable (in this context) antibiotic
effects have limited the use of this drug as a prokinetic agent.
Several non-antibiotic synthetic analogs of erythromycin and peptide
analogs of motilin have been developed; to date, the clinical results
have been disappointing.
A standard dose of erythromycin for gastric stimulation is
3 mg/kg intravenously or 200-250 mg orally every 8 hours. For
small-bowel stimulation, a smaller dose (e.g., 40 mg intravenously)
may be more useful, as higher doses may actually retard motility of
this organ. Concerns about toxicity, pseudomembranous colitis, and
the induction of resistant strains of bacteria, among other things,
limit the use of erythromycin to acute situations or in circumstances
where patients are resistant to other medications.
Motilin Receptor Agonists. A number of these drugs have been developed
for the treatment of diabetic gastroparesis. Currently, mitemcinal
(GM-611), a macrolide nonantibiotic, shows promise for the
treatment of gastroparesis (Gale, 2009).
SECTION VI
DRUGS AFFECTING GASTROINTESTINAL FUNCTION
Miscellaneous Agents for Stimulating Motility
The GI hormone cholecystokinin (CCK) is released from the intestine
in response to meals and delays gastric emptying, causes contraction
of the gallbladder, stimulates pancreatic enzyme secretion,
increases intestinal motility, promotes satiety, and has a host of other
actions. The C-terminal octapeptide of CCK, sincalide (KINEVAC), is
useful for stimulating the gallbladder and/or pancreas and may also
be used for accelerating barium transit through the small bowel for
diagnostic testing of these organs. This drug is administered intravenously
0.02-0.04 μg/kg over 30-60 seconds or up to 30-45 minutes
depending on the test. Administration of this agent is frequently
accompanied by nausea and abdominal pain, and much less frequently
dizziness. Concerns that should be noted using this agent are related
to the expulsion of small gallstones into the common bile duct or cystic
duct. Dexloxiglumide is a CCK 1
(or CCK-A)–receptor antagonist
that can improve gastric emptying and was investigated as a
treatment for gastroparesis and for constipation-dominant IBS, but
may also have uses in feeding intolerance in critically ill individuals.
Clonidine also has been reported to be of benefit in patients with gastroparesis.
Octreotide acetate (SANDOSTATIN, others), a somatostatin
analogue, also is used in some patients with intestinal dysmotility.
In some disorders of motility, effective treatment does not
necessarily require a “neuroenteric” approach. One such example is
gastroesophageal reflux disease. Acid reflux is associated with transient
lower esophageal sphincter relaxations that occur in the
absence of a swallow. Because the damage to the esophagus ultimately
is inflicted by acid, the most effective therapy for gastroesophageal
reflux disease still is the suppression of acid production by
the stomach (Chapter 45). Neither metoclopramide nor cisapride by
itself is particularly effective in gastroesophageal reflux disease.
However, a new approach under investigation relies on suppression
of the transient lower esophageal sphincter relaxations, as achieved
by CCK 1
-receptor antagonists (such as dexloxiglumide), GABA
agonists (such as baclofen), and inhibitors of NO synthesis.
Agents that Suppress Motility
Smooth muscle relaxants such as organic nitrates and Ca 2+ channel
antagonists (Chapters 27 and 28) often produce temporary, if partial,
relief of symptoms in motility disorders such as achalasia, in which
the lower esophageal sphincter fails to relax, resulting in a functional
obstruction to the passage of food and severe difficulty in swallowing.
A more recent approach relies on the use of preparations of botulinum
toxin (BOTOX, DYSPORT, MYOBLOC), injected directly into the
lower esophageal sphincter via an endoscope, in doses of 80-100 units
(Zhao and Pasricha, 2003). This potent agent inhibits ACh release
from nerve endings (Chapter 11) and can produce partial paralysis
of the sphincter muscle, with significant improvements in symptoms
and esophageal clearance. However, its effects dissipate over a
period of several months, requiring repeated injections; there is also
some potential for post-administration “spread” of the toxin that can
result in life-threatening consequences. Botulinum toxin preparations
likely will be more widely used especially in the elderly and in
those with other risks for pneumatic dilation. Other GI conditions in
which botulinum toxin A has been used include gastroparesis,
sphincter of Oddi dysfunction, and anal fissures, although currently
there are not strong trial data to support its efficacy.
LAXATIVES, CATHARTICS, AND
THERAPY FOR CONSTIPATION
Overview of GI Water and Electrolyte Flux. Fluid content
is the principal determinant of stool volume and
consistency; water normally accounts for 70-85% of
total stool weight. Net stool fluid content reflects a balance
between luminal input (ingestion and secretion of
water and electrolytes) and output (absorption) along
the length of the GI tract. The daily challenge for the
gut is to extract water, minerals, and nutrients from the
luminal contents, leaving behind a manageable pool of
fluid for proper expulsion of waste material via the
process of defecation. Normally ~8-9 L of fluid enter
the small intestine daily from exogenous and endogenous
sources (Figure 46–3). Net absorption of the water
occurs in the small intestine in response to osmotic gradients
that result from the uptake and secretion of ions
and the absorption of nutrients (mainly sugars and
amino acids), with only ~1-1.5 L crossing the ileocecal
valve. The colon then extracts most of the remaining
fluid, leaving ~100 mL of fecal water daily.
Under normal circumstances, these quantities are
well within the range of the total absorptive capacity of
the small bowel (~16 L) and colon (4-5 L). Neurohumoral
mechanisms, pathogens, and drugs can alter these
processes, resulting in changes in either secretion or
absorption of fluid by the intestinal epithelium. Altered
motility also contributes in a general way to this
process, as the extent of absorption parallels transit
time. With decreased motility and excess fluid removal,