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

1340 involvement in sensitization of nociceptor neurons in inflammatory
conditions. This has led to the development of specific receptor modulators,
such as the 5-HT 3
antagonist alosetron (Figure 46–2).
Buspirone and sumatriptan are 5-HT 1
receptor agonists (Chapter 13)
that can reduce gastric and colonic sensitivity to distention and are
being evaluated in clinical trials.
The most effective class of agents in this regard has been the
tricyclic anti-depressants (Chapter 15), which can have neuromodulatory
and analgesic properties independent of their anti-depressant
effect. Tricyclic anti-depressants have a proven track record in the
management of chronic “functional” visceral pain. Effective analgesic
doses of these drugs (e.g., 25-75 mg per day of nortryptiline)
are significantly lower than those required to treat depression.
Although changes in mood usually do not occur at these doses, there
may be some diminution of anxiety and restoration of sleep patterns,
which can be considered desirable effects in this group of patients.
Selective serotonin reuptake inhibitors have fewer side effects and
have been advocated particularly for patients with functional constipation
because they can increase bowel movements and even
cause diarrhea. However, they probably are not as effective as tricyclic
anti-depressants in the management of visceral pain.
a 2
Adrenergic agonists, such as clonidine (Chapter 12),
also can increase visceral compliance and reduce distention-induced
pain. The SST analog octreotide has selective inhibitory effects on
peripheral afferent nerves projecting from the gut to the spinal cord
in healthy human beings and has been shown to blunt the perception
of rectal distention in patients with IBS. Fedotozine, an investigational
opioid that appears to be a peripherally active, selective κ
receptor antagonist, produces marginal improvement in symptoms in
patients with IBS and functional dyspepsia. The lack of CNS effects
is an advantage in such patients in whom chronic medication use is
anticipated. Other agents of unproven value include leuprolide, a
gonadotropin-releasing hormone analog (Chapter 42).
SECTION VI
DRUGS AFFECTING GASTROINTESTINAL FUNCTION
Alosetron and Other 5-HT 3
Antagonists
The 5-HT 3
receptor participates in several important processes in
the gut, including sensitization of spinal sensory neurons, vagal signaling
of nausea, and peristaltic reflexes. Some of these effects in
experimental models are potentially conflicting, with release of
excitatory and inhibitory neurotransmitters. However, the clinical
effect of 5-HT 3
antagonism is a general reduction in GI contractility
with decreased colonic transit, along with an increase in fluid
absorption. In general, therefore, these antagonists produce the
opposite effects seen with 5-HT 4
agonists. Although they also may
blunt visceral sensation, a direct effect on spinal afferents has not
been fully established. Alosetron (LOTRONEX) was the first agent in
this class specifically approved for the treatment of diarrheapredominant
IBS in women. Alosetron is a much more potent antagonist
of the 5-HT 3
receptor than ondansetron and causes significant
(although modest) improvements in abdominal pain as well as stool
frequency, consistency, and urgency in these patients. Shortly after
its initial release, alosetron was withdrawn from the U.S. market
because of an unusually high incidence of ischemic colitis (up to
3 per 1000 patients), leading to surgery and even death in a small
number of cases. The mechanism of this effect is not fully established
but may result from the drug’s ability to suppress intestinal
relaxation, thereby causing severe spasm in segments of the colon
in susceptible individuals. It is not clear whether this is a nonspecific
effect or involves serotoninergic mechanisms. Nevertheless, the
FDA has reapproved this drug for diarrhea-predominant IBS under
a limited distribution system. However, concerns about the consequences
of prescribing this drug are important, and the manufacturer
requires a prescription program that includes physician
certification and an elaborate patient education and consent protocol
before dispensing.
Alosetron is rapidly absorbed from the GI tract; its duration
of action (~10 hours) is longer than expected from its t 1/2
of 1.5 hours.
It is metabolized by hepatic CYPs. The drug should be started at 1 mg
per day for the first 4 weeks and advanced to a maximum of 1 mg
twice daily if an adequate response is not achieved.
Other 5-HT 3
antagonists currently available in the U.S. are
approved for nausea and vomiting (see later in this chapter and
Chapter 13).
ANTI-SPASMODICS AND OTHER AGENTS
Anticholinergic agents (“spasmolytics” or “antispasmodics”)
often are used in patients with IBS. The
most common agents of this class available in the U.S.
are nonspecific antagonists of the muscarinic receptor
(Chapter 9) and include the tertiary amines dicyclomine
(BENTYL, others) and hyoscyamine (LEVSIN, others) and
the quaternary ammonium compounds glycopyrrolate
(ROBINUL, others) and methscopolamine (PAMINE, others).
The advantage of the latter two compounds is that
they have a limited propensity to cross the blood-brain
barrier and hence a lower risk for neurological side
effects such as lightheadedness, drowsiness, or nervousness.
These agents typically are given either on an
as-needed basis (with the onset of pain) or before meals
to prevent the pain and fecal urgency that predictably
occur in some patients with IBS (with presumed exaggerated
gastrocolic reflex).
Dicyclomine is given in doses of 20 mg orally every 6 hours
initially and increased to 40 mg every 6 hours unless limited by side
effects. Doses <160 mg/day are not usually effective and should be
discontinued after a 2-week trial period. Hyoscyamine is available as
immediate-release oral capsules, tablets, elixir, drops, and a nonaerosol
spray (all administered as 0.125-0.25 mg every 4 hours as needed),
and extended-release forms for oral use (0.25-0.375 mg every 12 hours
as needed). An injectable is available for subcutaneous, intravenous,
or intramuscular administration. Regardless of the formulation, the
adult dose of hyoscyamine usually should not exceed 1.5 mg in
24 hours. Glycopyrrolate is available as immediate-release tablets; the
dose is 1-2 mg two or three times daily, not to exceed 8 mg/day.
Methscopolamine is provided as 2.5-mg and 5-mg tablets; the dose is
2.5 mg a half hour before meals and 2.5-5 mg at bedtime.
Other Drugs. Cimetropium, an antimuscarinic compound
that reportedly is effective in patients with IBS,
is not available in the U.S. Otilonium bromide is a quaternary
ammonium salt with antimuscarinic effects that
also appears to block Ca 2+ channels and neurokinin