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

Table 46–6
Receptor Specificity of Anti-emetic Agents
PHARMACOLOGIC CLASS DOPAMINE ACETYLCHOLINE
Drugs in Class (D 2
) (MUSCARINIC) HISTAMINE SEROTONIN
Anticholinergics
Scopolamine + ++++ + –
Antihistamines
Cyclizine + +++ ++++ –
Dimenhydrinate, diphenhydramine, + ++ ++++ –
hydroxyzine
Promethazine ++ ++ ++++ –
Anti-serotonins
Dolasetron, granisetron, – – – ++++
ondansetron, palonosetron,
ramosetron
Benzamides
Domperidone ++++ – – +
Metoclopramide +++ – – ++
Butyrophenones
Droperidol ++++ – + +
Haloperidol ++++ – + –
Phenothiazines
Chlorpromazine ++++ ++ ++++ +
Fluphenazine ++++ + ++ –
Perphenazine ++++ + ++ +
Prochlorperazine ++++ ++ ++ +
Steroids
Betamethasone, dexamethasone – – – –
For details, see Scuderi, 2003. Plus signs indicate some (+) to considerable (++++) interaction. (–) indicates no effect.
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the CYP3A family, as it is inhibited by ketoconazole. 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 of it is excreted unchanged in the urine.
Palonosetron is metabolized principally by CYP2D6 and excreted
in the urine as the metabolized and the unchanged forms in about
equal proportions.
Therapeutic Use. These agents are most effective in treating
chemotherapy-induced nausea and in treating nausea secondary to
upper abdominal irradiation, where all three agents appear to be
equally efficacious. 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, perhaps a
reflection of its long t 1/2
.
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 46–8)
infused over 15 minutes, beginning 30 minutes before chemotherapy,
or in 2-3 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 (ondansetron only) or orally.
Granisetron is available as a transdermal formulation that is applied
24-48 hours before chemotherapy and worn for up to 7 days.
Adverse Effects. In general, these drugs are very well tolerated, with
the most common adverse effects being constipation or diarrhea,
headache, and lightheadedness. As a class, these agents have been
shown experimentally to induce minor electrocardiographic changes,
but these are not expected to be clinically significant in most cases.
Dopamine-Receptor Antagonists
Phenothiazines such as prochlorperazine, thiethylperazine (discontinued
in the U.S.), and chlorpromazine (Chapter 16) are among the
most commonly used “general-purpose” anti-nauseants and antiemetics.
Their effects in this regard are complex, but their principal
mechanism of action is D 2
receptor antagonism at the CTZ.
Compared with metoclopramide or ondansetron, these drugs do not
appear to be as uniformly effective in cancer chemotherapy–induced
emesis. But they also possess antihistaminic and anticholinergic activities,
which are of value in other forms of nausea, such as motion
sickness.