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

Table 46–8
1345
5-HT 3
Antagonists in Chemotherapy-Induced Nausea/Emesis
DRUG CHEMICAL NATURE RECEPTOR INTERACTIONS t 1/2
DOSE (IV)
Ondansetron Carbazole derivative 5-HT 3
antagonist and weak 3.9 h 0.15 mg/kg
5-HT 4
antagonist
Granisetron Indazole 5-HT 3
antagonist 9-11.6 h 10 μg/kg
Dolasetron Indole moiety 5-HT 3
antagonist 7-9 h 1.8 mg/kg
Palonosetron Isoquinoline 5-HT 3
antagonist; highest affinity 40 h 0.25 mg
for 5-HT 3
receptor in this class
IV, intravenous.
extracted from the marijuana plant, Cannabis sativa. The exact
mechanism of the anti-emetic action of dronabinol is not known but
probably relates to stimulation of the CB 1
subtype of cannabinoid
receptors on neurons in and around the vomiting center in the brainstem
(Van Sickle et al., 2001).
CH 3
OH
H
H
H 3 C
CH
H 3
3 C
O DRONABINOL
Pharmacokinetics. Dronabinol is a highly lipid-soluble compound
that is absorbed readily after oral administration; its onset of action
occurs within an hour, and peak levels are achieved within 2-4 hours.
It undergoes extensive first-pass metabolism with limited systemic
bioavailability after single doses (only 10-20%). Active and inactive
metabolites are formed in the liver; the principal active metabolite is
11-OH-delta-9-tetrahydrocannabinol.
These metabolites are excreted primarily via the biliary-fecal
route, with only 10-15% excreted in the urine. Both dronabinol and
its metabolites are highly bound (>95%) to plasma proteins. Because
of its large volume of distribution, a single dose of dronabinol can
result in detectable levels of metabolites for several weeks.
Therapeutic Use. Dronabinol is a useful prophylactic agent in patients
receiving cancer chemotherapy when other anti-emetic medications
are not effective. It also can stimulate appetite and has been used in
patients with acquired immunodeficiency syndrome (AIDS) and
anorexia. As an anti-emetic agent, it is administered at an initial dose
of 5 mg/m 2 given 1-3 hours before chemotherapy and then every 2-
4 hours afterward for a total of four to six doses. If this is not adequate,
incremental increases can be made up to a maximum of 15 mg/m 2
per dose. For other indications, the usual starting dose is 2.5 mg twice
a day; this can be titrated up to a maximum of 20 mg per day.
Adverse Effects. Dronabinol has complex effects on the CNS, including
a prominent central sympathomimetic activity. This can lead to
palpitations, tachycardia, vasodilation, hypotension, and conjunctival
injection (bloodshot eyes). Patient supervision is necessary
because marijuana-like “highs” (e.g., euphoria, somnolence,
detachment, dizziness, anxiety, nervousness, panic, etc.) can occur,
as can more disturbing effects such as paranoid reactions and thinking
abnormalities. After abrupt withdrawal of dronabinol, an abstinence
syndrome (irritability, insomnia, and restlessness) can occur.
Because of its high affinity for plasma proteins, dronabinol can displace
other plasma protein-bound drugs, whose doses may have to
be adjusted as a consequence. Dronabinol should be prescribed with
great caution to persons with a history of substance abuse (alcohol,
drugs) because it also may be abused by these patients.
Nabilone (CESAMET) is a synthetic cannabinoid with a mode
of action similar to that of dronabinol.
Pharmacokinetics. Nabilone, like dronabinol, is a highly lipidsoluble
compound that is rapidly absorbed after oral administration;
its onset of action occurs within an hour, and peak levels are achieved
within 2 hours. The t 1/2
is ~2 hours for the parent compound and 35
hours for metabolites. The metabolites are excreted primarily via the
biliary-fecal route (60%), with only ~25% excreted in the urine.
Therapeutic Use. Nabilone is a useful prophylactic agent in patients
receiving cancer chemotherapy when other anti-emetic medications
are not effective. A dose (1-2 mg) can be given the night before
chemotherapy; usual dosing starts 1-3 hours before treatment and
then every 8-12 hours during the course of chemotherapy and for
2 days following its cessation.
Adverse Effects. The adverse effects are largely the same as for dronabinol,
with significant CNS actions in >10% of patients.
Cardiovascular, GI, and other side effects are also common and
together with the CNS actions limit the usefulness of this agent.
Glucocorticoids and Anti-Inflammatory Agents
Glucocorticoids such as dexamethasone can be useful adjuncts
(Table 46–7) in the treatment of nausea in patients with widespread
cancer, possibly by suppressing peritumoral inflammation and
prostaglandin production. A similar mechanism has been invoked to
explain beneficial effects of NSAIDs in the nausea and vomiting
induced by systemic irradiation. For a detailed discussion of these
drugs, see Chapters 34 and 42.
Benzodiazepines
Benzodiazepines, such as lorazepam and alprazolam, by themselves
are not very effective anti-emetics, but their sedative, amnesic, and
anti-anxiety effects can be helpful in reducing the anticipatory