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

1327
OH
HN
NH 2
O
CH 3
N
NH
N
CH 3
HCL
CH 3
O
HN
N
N H H
N
NH
5-HT
Alosetron
(5-HT 3
antagonist)
Tegaserod
(5-HT 4
partial agonist)
CH 3
Figure 46–2. Ligands of 5-HT 3
and 5-HT 4
receptors modulating GI motility.
often when the drug is combined with other drugs that inhibit
CYP3A4 (Chapter 6); such combinations inhibit the metabolism of
cisapride and lead to high plasma concentrations of the drug. Due to
its association with ventricular arrhythmias, cisapride is contraindicated
in patients with a history of prolonged QT interval, renal failure,
ventricular arrhythmias, ischemic heart disease, congestive heart
failure, respiratory failure, uncorrected electrolyte abnormalities (e.g.,
hypokalemia and hypomagnesemia), or concomitant medications
known to prolong the QT interval. At this time, cisapride is available
only through an investigational, limited-access program for patients
with GERD, gastroparesis, pseudo-obstruction, refractory severe
chronic constipation, and neonatal enteral feeding intolerance who
have failed all standard therapeutic modalities and who have undergone
a thorough diagnostic evaluation, including an ECG.
Prucalopride (RESELOR; Figure 46–2) is a benzofuran derivative
and a specific 5-HT 4
-receptor agonist that facilitates cholinergic
neurotransmission. It acts throughout the length of the intestine,
increasing oral-cecal transit and colonic transit without affecting gastric
emptying in healthy volunteers. In patients with chronic idiopathic
constipation, prucalopride was able to improve colonic transit
and stool frequency. Given in doses of 2 and 4 mg orally, once daily,
there were significant normalization of bowel habits including
increased stool frequency and consistency (Gale, 2009). This drug
recently gained approval in Europe for use in women with chronic
constipation in whom laxatives fail to provide adequate relief.
Motilides
O N N
Prucalopride
(5-HT 4
agonist)
Macrolides and Erythromycin. Motilin, a 22–amino acid
peptide hormone found in the GI M cells and in some
enterochromaffin cells of the upper small bowel, is a
H
OH
O
Cl
NH 2
H 2 N
CH 3
C O
Cl
N
H
H 3 C
O
N
Cisapride
(5-HT 4
agonist; 5-HT 3
antagonist)
potent contractile agent of the upper GI tract. Motilin
levels fluctuate in association with the migrating motor
complex and appear to be responsible for the amplification,
if not the actual induction, of phase III activity. In
addition, motilin receptors are found on smooth muscle
cells and enteric neurons.
The effects of motilin can be mimicked by erythromycin,
a discovery that arose from the frequent occurrence
of GI side effects with the use of this antibiotic. This
property is shared to varying extents by other macrolide
antibiotics (Chapter 55), including oleandomycin,
azithromycin, and clarithromycin. In addition to its
motilin-like effects, which are most pronounced at higher
doses (250-500 mg), erythromycin at lower doses (e.g.,
40-80 mg) also may act by other poorly defined mechanisms
that may involve cholinergic facilitation.
Erythromycin induces phase III migrating motor complex
activity in dogs and increases smooth muscle contractility. It has
multiple effects on upper GI motility, increasing lower esophageal
pressure and stimulating gastric and small-bowel contractility. By
contrast, it has little or no effect on colonic motility. At doses higher
than 3 mg/kg, it can produce a spastic type of contraction in the small
bowel, resulting in cramps, impairment of transit, and vomiting.
Therapeutic Use. The best established use of erythromycin as a prokinetic
agent is in patients with diabetic gastroparesis, where it can
improve gastric emptying in the short term. Erythromycin-stimulated
gastric contractions can be intense and result in “dumping” of relatively
O
C
CHAPTER 46
TREATMENT OF DISORDERS OF BOWEL MOTILITY AND WATER FLUX