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

NK 2
receptors; it is not available in the U.S. but has
been used extensively for patients with IBS in other
parts of the world. Mebeverine hydrochloride is a derivative
of hydroxybenzamide that appears to have a direct
effect on the smooth muscle cell, blocking K + , Na + , and
Ca 2+ channels. It is widely used outside of the U.S. as
an anti-spasmodic agent for patients with IBS.
ANTI-NAUSEANTS AND
ANTI-EMETIC AGENTS
Nausea and Vomiting
The act of emesis and the sensation of nausea that
accompanies it generally are viewed as protective
reflexes that serve to rid the stomach and intestine of
toxic substances and prevent their further ingestion.
Vomiting is a complex process that consists of a preejection
phase (gastric relaxation and retroperistalsis),
retching (rhythmic action of respiratory muscles preceding
vomiting and consisting of contraction of
abdominal and intercostal muscles and diaphragm
against a closed glottis), and ejection (intense contraction
of the abdominal muscles and relaxation of the
upper esophageal sphincter). This is accompanied by
multiple autonomic phenomena including salivation,
shivering, and vasomotor changes. During prolonged
episodes, marked behavioral changes including
lethargy, depression, and withdrawal may occur. The
process appears to be coordinated by a central emesis
center in the lateral reticular formation of the midbrainstem
adjacent to both the chemoreceptor trigger
zone (CTZ) in the area postrema (AP) at the bottom of
the fourth ventricle and the solitary tract nucleus (STN).
The lack of a blood-brain barrier allows the CTZ to
monitor blood and cerebrospinal fluid constantly for
toxic substances and to relay information to the emesis
center to trigger nausea and vomiting. The emesis center
also receives information from the gut, principally
by the vagus nerve (via the STN) but also by splanchnic
afferents via the spinal cord. Two other important
inputs to the emesis center come from the cerebral cortex
(particularly in anticipatory nausea or vomiting) and
the vestibular apparatus (in motion sickness). In turn,
the center sends out efferents to the nuclei responsible
for respiratory, salivary, and vasomotor activity, as well
as to striated and smooth muscle involved in the act.
The CTZ has high concentrations of receptors for serotonin
(5-HT 3
), dopamine (D 2
), and opioids; the STN is
rich in receptors for enkephalin, histamine, and ACh,
and also contains 5-HT 3
receptors. A variety of these
neurotransmitters are involved in nausea and vomiting
(Figure 46–4), and an understanding of their nature has
allowed a rational approach to the pharmacological
treatment of nausea and vomiting (Hornby, 2001;
Scuderi, 2003).
Anti-emetics generally are classified according to
the predominant receptor on which they are proposed to
act (Table 46–5). However, considerable overlap among
these mechanisms exists, particularly for the older
agents (Table 46–6). For treatment and prevention of
the nausea and emesis associated with cancer
chemotherapy, several anti-emetic agents from different
pharmacological classes may be used in combination
(Table 46–7). The individual classes of agents are presented
next.
5-HT 3
Receptor Antagonists
Chemistry, Pharmacological Effects, and Mechanism of Action.
Ondansetron (ZOFRAN, others) is the prototypical drug
in this class. Since their introduction in the early 1990s,
the 5-HT 3
receptor antagonists have become the most
widely used drugs for chemotherapy-induced emesis.
Other agents in this class include granisetron (KYTRIL,
others), dolasetron (ANZEMET), palonosetron (ALOXI),
and tropisetron (available in some countries but not in
the U.S.). The differences among these agents are
related mainly to their chemical structures, 5-HT 3
receptor affinities, and pharmacokinetic profiles
(Table 46–8). Alosetron was discussed separately earlier.
There is evidence that effects at peripheral and central sites
contribute to the efficacy of these agents. 5-HT 3
receptors are present
in several critical sites involved in emesis, including vagal afferents,
the STN (which receives signals from vagal afferents), and the
area postrema itself (Figure 46–4). Serotonin is released by the enterochromaffin
cells of the small intestine in response to chemotherapeutic
agents and may stimulate vagal afferents (via 5-HT 3
receptors)
to initiate the vomiting reflex. Experimentally, vagotomy has been
shown to prevent cisplatin-induced emesis. However, the highest
concentrations of 5-HT 3
receptors in the CNS are found in the STN
and CTZ, and antagonists of 5-HT 3
receptors also may suppress nausea
and vomiting by acting at these sites.
Pharmacokinetics. The anti-emetic effects of these drugs persist
long after they disappear from the circulation, suggesting their continuing
interaction at the receptor level. In fact, all of these drugs
can be administered effectively just once a day.
These agents are absorbed well from the GI tract.
Ondansetron is extensively metabolized in the liver by CYP1A2,
CYP2D6, and CYP3A4, followed by glucuronide or sulfate conjugation.
Patients with hepatic dysfunction have reduced plasma clearance,
and some adjustment in the dosage is advisable. Although
ondansetron clearance also is reduced in elderly patients, no adjustment
in dosage for age is recommended. Granisetron also is metabolized
predominantly by the liver, a process that appears to involve
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CHAPTER 46
TREATMENT OF DISORDERS OF BOWEL MOTILITY AND WATER FLUX