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

1326 Metoclopramide is available in oral dosage forms (tablets and
solution) and as a parenteral preparation for intravenous or intramuscular
use. The usual initial oral dose range is 10 mg, 30 minutes
before each meal and at bedtime. The onset of action is within
30-60 minutes after an oral dose. In patients with severe nausea, an
initial dose of 10 mg can be given intramuscularly (onset of action
10-15 minutes) or intravenously (onset of action 1-3 minutes). For
prevention of chemotherapy-induced emesis, metoclopramide can
be given as an infusion of 1-2 mg/kg administered over at least
15 minutes, beginning 30 minutes before the chemotherapy is begun
and repeated as needed every 2 hours for two doses, then every 3 hours
for three doses.
Adverse Effects. The major side effects of metoclopramide include
extrapyramidal effects, such as those seen with the phenothiazines
(Chapter 16). Dystonias, usually occurring acutely after intravenous
administration, and parkinsonian-like symptoms that may occur several
weeks after initiation of therapy generally respond to treatment
with anticholinergic or antihistaminic drugs and are reversible upon
discontinuation of metoclopramide. Tardive dyskinesia also can
occur with chronic treatment (months to years) and may be irreversible.
Extrapyramidal effects appear to occur more commonly in
children and young adults and at higher doses. Like other DA antagonists,
metoclopramide also can cause galactorrhea by blocking
the inhibitory effect of dopamine on prolactin release, but this
adverse effect is relatively infrequent in clinical practice.
Methemoglobinemia has been reported occasionally in premature
and full-term neonates receiving metoclopramide.
SECTION VI
DRUGS AFFECTING GASTROINTESTINAL FUNCTION
Domperidone; D 2
Receptor Antagonists
In contrast to metoclopramide, domperidone predominantly
antagonizes the D 2
receptor without major
involvement of other receptors. It is not available for
use in the U.S. but has been used elsewhere (MOTILIUM,
others) and has modest prokinetic activity in doses of
10-20 mg three times a day. Although it does not readily
cross the blood-brain barrier to cause extrapyramidal
side effects, domperidone exerts effects in the parts
of the CNS that lack this barrier, such as those regulating
emesis, temperature, and prolactin release. As is the
case with metoclopramide, domperidone does not
appear to have any significant effects on lower GI
motility. Other D 2
receptor antagonists being explored
as prokinetic agents include levosulpiride, the levoenantiomer
of sulpiride.
Serotonin Receptor Agonists
5-HT plays an important role in the normal motor and
secretory function of the gut (Gershon and Tack, 2007)
(Chapter 13). Indeed, >90% of the total 5-HT in the
body exists in the GI tract. The enterochromaffin cell,
a specialized cell found in the epithelium lining the
mucosa of the gut, produces most of this 5-HT and
rapidly releases 5-HT in response to chemical and
mechanical stimulation (e.g., food boluses; noxious
agents such as cisplatin; certain microbial toxins; adrenergic,
cholinergic, and purinergic receptor agonists).
5-HT triggers the peristaltic reflex (Figure 46–1) by
stimulating intrinsic sensory neurons in the myenteric
plexus (via 5-HT 1p
and 5-HT 4
receptors), as well as
extrinsic vagal and spinal sensory neurons (via 5-HT 3
receptors). Additionally, stimulation of submucosal
intrinsic afferent neurons activates secretomotor
reflexes resulting in epithelial secretion. 5-HT receptors
also are found on other neurons in the enteric nervous
system, where they can be either stimulatory
(5-HT 3
and 5-HT 4
) or inhibitory (5-HT 1a
). In addition,
serotonin also stimulates the release of other neurotransmitters,
depending on the receptor subtype. Thus,
5-HT 1
stimulation of the gastric fundus results in
release of NO and reduces smooth muscle tone. 5-HT 4
stimulation of excitatory motor neurons enhances ACh
release at the neuromuscular junction, and both 5-HT 3
and 5-HT 4
receptors facilitate interneuronal signaling.
Developmentally, 5-HT acts as a neurotrophic factor for
enteric neurons via the 5-HT 2B
and 5-HT 4
receptors.
Reuptake of serotonin by enteric neurons and
epithelium is mediated by the same transporter (SERT;
Chapters 5 and 13) as 5-HT reuptake by serotonergic
neurons in the CNS. This reuptake therefore also is
blocked by selective serotonin reuptake inhibitors
(SSRIs, Chapter 15), which explains the common side
effect of diarrhea that accompanies the use of these
agents. Modulation of the multiple, complex, and sometimes
opposing effects of 5-HT on gut motor function
has become a major target for drug development.
The availability of serotonergic prokinetic drugs has in recent
years been restricted because of serious adverse cardiac events.
Tegaserod maleate (ZELNORM) was discontinued in 2007 and cisapride
is available only via a restricted investigational drug protocol.
A novel 5-HT 4
agonist, prucalopride (RESOLOR), is approved
for use in Europe for symptomatic treatment of chronic constipation
in women in whom laxatives fail to provide adequate relief.
Cisapride. Cisapride (PROPULSID) is a substituted piperidinyl benzamide
(Figure 46–2) that appears to stimulate 5-HT 4
receptors and
increase adenylyl cyclase activity within neurons. It also has weak
5-HT 3
antagonistic properties and may directly stimulate smooth
muscle. Cisapride was a commonly used prokinetic agent, particularly
for gastroesophageal reflux disease and gastroparesis. However,
it no longer is generally available in the U.S. because of its potential
to induce serious and occasionally fatal cardiac arrhythmias, including
ventricular tachycardia, ventricular fibrillation, and torsades de
pointes. These arrhythmias result from a prolonged QT interval
through an interaction with pore-forming subunits of the HERG K +
channel. HERG K + channels conduct the rapid delayed rectifier K +
current that is important for normal repolarization of the ventricle
(Chapter 29). Cisapride-induced ventricular arrhythmias occur most