Page 1116 - Basic _ Clinical Pharmacology ( PDFDrive )

1102 SECTION X Special Topics

However, at higher doses they exhibit significant additional granisetron, dolasetron, and palonosetron) have been approved
anticholinergic effects, including dry mouth, visual disturbances, for the prevention and treatment of nausea and vomiting (see
urinary retention, and constipation. For these reasons, antispas- Antiemetics); however, their efficacy in the treatment of IBS
modics are infrequently used. has not been determined. The differences between these 5-HT
3
antagonists that determine their pharmacodynamic effects have
not been well studied.
SEROTONIN 5-HT -RECEPTOR
3
ANTAGONISTS Pharmacokinetics & Pharmacodynamics
Alosetron is a highly potent and selective antagonist of the
5-HT receptors in the gastrointestinal tract activate visceral affer- 5-HT receptor. It is rapidly absorbed from the gastrointestinal
3
3
ent pain sensation via extrinsic sensory neurons from the gut to tract with a bioavailability of 50–60% and has a plasma half-life
the spinal cord and central nervous system. Inhibition of afferent of 1.5 hours but a much longer duration of effect. It undergoes
gastrointestinal 5-HT receptors may reduce unpleasant visceral extensive hepatic cytochrome P450 metabolism with renal excre-
3
afferent sensation, including nausea, bloating, and pain. Blockade tion of most metabolites. Alosetron binds with higher affinity
of central 5-HT receptors also reduces the central response to vis- and dissociates more slowly from 5-HT receptors than other
3
3
ceral afferent stimulation. In addition, 5-HT -receptor blockade 5-HT antagonists, which may account for its long duration of
3
on the terminals of enteric cholinergic neurons inhibits colonic action. 3
motility, especially in the left colon, increasing total colonic transit
time.
Alosetron is a 5-HT antagonist that has been approved Clinical Uses
3
for the treatment of patients with severe IBS with diarrhea Alosetron is approved for the treatment of women with
(Figure 62–5). Four other 5-HT antagonists (ondansetron, severe IBS in whom diarrhea is the predominant symptom
3
O
N
CH 2
NH 2 N
OH CH 3
N
NH CH 3
Serotonin Ondansetron

O NH N CH 3

NH
NH N
N
CH 3 NH
N CH 3
CH 3
NH Granisetron
Tegaserod O

N

O
CH 3
O
N
NH O H
N
N
N
CH 3 H
Alosetron Dolasetron

FIGURE 62–5 Chemical structure of serotonin; the 5-HT 3 antagonists ondansetron, granisetron, dolasetron, and alosetron; and the 5-HT 4
partial agonist tegaserod.