ANTINAUSEANTS AND ANTIEMETIC AGENTS

Nausea and Vomiting

Nausea and vomiting are protective reflexes that serve to rid the stomach and intestine of
toxic substances and prevent their further ingestion. Vomiting is complex, consisting 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. The process appears to be coordinated by a central emesis center in
the lateral reticular formation of the mid-brainstem 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) of the vagus nerve. 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-HT3), dopamine (D2), and opioids, while the STN is rich in receptors for
enkephalin, histamine, and ACh, and also contains 5-HT3 receptors. A variety of these
neurotransmitters are involved in nausea and vomiting (Figure 37–3), and an understanding
of their nature has allowed a rational approach to pharmacological treatment.
Antiemetics generally are classified according to the predominant receptor on which they
are proposed to act (Table 37–5). However, these mechanisms overlap considerably,
particularly for the older agents (Table 37–6). For treatment and prevention of the nausea
and emesis associated with cancer chemotherapy, several antiemetic agents from different
pharmacological classes may be combined (Table 37–7).
FIGURE 37–3 Pharmacologist’s view of emetic stimuli. Myriad signaling pathways lead from
the periphery to the emetic center. Stimulants of these pathways are noted in italics. These
pathways involve specific neurotransmitters and their receptors (bold type). Receptors are
shown for dopamine (D2), acetylcholine (muscarinic, M), histamine (H1), and 5-
hydroxytryptamine (5-HT3). Some of these receptors also may mediate signaling in the
emetic center.
5-HT3-Receptor Antagonists
CHEMISTRY, PHARMACOLOGICAL EFFECTS, AND MECHANISM OF ACTION
The 5-HT3-receptor antagonists are the most widely used drugs for chemotherapy-induced
emesis. Ondansetron (ZOFRAN) is the prototypical drug in this class; other agents include
granisetron (KYTRIL), dolasetron (ANZEMET), palonosetron (ALOXI; intravenous use only)
and tropisetron (available in some countries but not in the U.S.). Differences among these
agents relate mainly to their chemical structures, 5-HT3 receptor affinities, and
pharmacokinetic profiles (Table 37–8).
PHARMACOKINETICS
The antiemetic effects of these drugs persist long after they disappear from the circulation,
suggesting continued interaction at the receptor level. In fact, all of these drugs can be
administered effectively once daily.
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. Dolasetron is converted rapidly by plasma carbonyl reductase to
its active metabolite, hydrodolasetron. A portion of this compound then undergoes
subsequent biotransformation by CYP2D6 and CYP3A4 in the liver, while about one-third is
excreted unchanged in the urine. Palonosetron is metabolized principally by CYP2D6 and
excreted in the urine as the metabolized and the unchanged form in about equal
proportions.

THERAPEUTIC USE
All three agents appear to be equally efficacious in chemotherapyinduced nausea and in
treating nausea secondary to upper abdominal irradiation, They also are effective against
hyperemesis of pregnancy, and to a lesser degree, postoperative nausea, but not against
motion sickness. Unlike other agents in this class, palonosetron also may be helpful in
delayed emesis (see below).
These agents are available as tablets, oral solution, and intravenous preparations for
injection. For patients on cancer chemotherapy, these drugs can be given in a single
intravenous dose (Table 37–8) infused over 15 minutes, beginning 30 minutes before
chemotherapy, or in two to three divided doses, with the first usually given 30 minutes
before and subsequent doses at various intervals after chemotherapy. The drugs also can be
used intramuscularly or orally.
These drugs generally are very well tolerated, with the most common adverse effects
being constipation or diarrhea, headache, and light-headedness.