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

468
SECTION II
NEUROPHARMACOLOGY
incidence of 1% or less. Post-marketing reports of abuse, dependence,
and withdrawal have been recorded.
Unlike the benzodiazepines, zolpidem has little effect on the
stages of sleep in normal human subjects. The drug is as effective as
benzodiazepines in shortening sleep latency and prolonging total
sleep time in patients with insomnia. After discontinuation of
zolpidem, the beneficial effects on sleep reportedly persist for up to
1 week (Herrmann et al., 1993), but mild rebound insomnia on the
first night also has occurred. Tolerance and physical dependence
develop only rarely and under unusual circumstances (Cavallaro
et al., 1993; Morselli, 1993). Indeed, zolpidem-induced improvement
in sleep time of chronic insomniacs was sustained during as
much as 6 months of treatment without signs of withdrawal or
rebound after stopping the drug (Kummer et al., 1993). Nevertheless,
zolpidem is approved only for the short-term treatment of insomnia.
At therapeutic doses (5 to 10 mg), zolpidem infrequently produces
residual daytime sedation or amnesia, and the incidence of other
adverse effects (e.g., GI complaints or dizziness) also is low. As with
the benzodiazepines, large overdoses of zolpidem do not produce
severe respiratory depression unless other agents (e.g., ethanol) also
are ingested (Garnier et al., 1994). Hypnotic doses increase the
hypoxia and hypercarbia of patients with obstructive sleep apnea.
Zolpidem is absorbed readily from the GI tract; first-pass
hepatic metabolism results in an oral bioavailability of ~70%, but
this value is lower when the drug is ingested with food because of
slowed absorption and increased hepatic blood flow. Zolpidem is
eliminated almost entirely by conversion to inactive products in the
liver, largely through oxidation of the methyl groups on the phenyl
and imidazopyridine rings to the corresponding carboxylic acids. Its
plasma t 1/2
is ~2 hours in individuals with normal hepatic blood flow
or function. This value may be increased 2-fold or more in those
with cirrhosis and also tends to be greater in older patients; adjustment
of dosage often is necessary in both categories of patients.
Although little or no unchanged zolpidem is found in the urine, elimination
of the drug is slower in patients with chronic renal insufficiency
largely owing to an increase in its apparent volume of
distribution.
Eszopiclone. Eszopiclone (LUNESTA) is the active S(+)
enantiomer of zopiclone. Eszopiclone has no structural
similarity to benzodiazepines, zolpidem, or zaleplon.
N
N
CH 3
Eszopiclone is used for the long-term treatment
of insomnia and for sleep maintenance. It is prescribed
to patients who have difficulty falling asleep as well as
those who experience difficulty staying asleep, and is
available in 1-, 2-, or 3-mg tablets.
Eszopiclone received FDA approval based on six randomized
placebo-controlled clinical trials that showed it has efficacy in treating
transient (Rosenberg et al., 2005) and chronic insomnia. In the
transient insomnia study subjects receiving the drug showed a
decreased latency to attain sleep, increased sleep efficiency, and
fewer awakenings, as measured by both polysomnography and a
morning questionnaire. There were no observed psychomotor aftereffects
observed the next day. Eszopiclone also possesses efficacy
as a sleep aid when taken chronically, for as long as 12 months
(Melton et al., 2005). All chronic studies conducted to date found
that eszopiclone decreased the latency to onset of sleep. No tolerance
was observed, nor were signs of serious withdrawal, such as
seizures or rebound insomnia, seen upon discontinuation of the drug.
However, there are such reports for zopiclone, the racemate used
outside the U.S. Mild withdrawal consisting of abnormal dreams,
anxiety, nausea, and upset stomach can occur (rate ≤2%). A minor
reported adverse effect of eszopiclone was a bitter taste. Eszopiclone
is a schedule IV controlled substance in the U.S.
Eszopiclone is absorbed rapidly after oral administration,
with a bioavailability of ~80%, and shows wide distribution throughout
the body. It is 50-60% bound to plasma proteins and has a t 1/2
of
~6 hours. It is metabolized by CYPs 3A4 and 2E1. Eszopiclone is
believed to exert its sleep-promoting effects through its enhancement
of GABA A
receptor function at the benzodiazepine binding site
(Hanson et al., 2008; Jia et al., 2009),
FLUMAZENIL: A BENZODIAZEPINE
RECEPTOR ANTAGONIST
Flumazenil (ROMAZICON, generic), the only member of
this class, is an imidazobenzodiazepine (Table 17–1)
that behaves as a specific benzodiazepine receptor
antagonist (Hoffman and Warren, 1993). Flumazenil
binds with high affinity to specific sites on the GABA A
receptor, where it competitively antagonizes the binding
and allosteric effects of benzodiazepines and other
ligands. Flumazenil antagonizes both the electrophysiological
and behavioral effects of agonist and inverseagonist
benzodiazepines and β-carbolines. The drug is
given intravenously.
N
N
O
O
N
N
O
ESZOPICLONE
Cl
In animal models, the intrinsic pharmacological actions of
flumazenil have been subtle; effects resembling those of inverse agonists
sometimes have been detected at low doses, whereas slight
benzodiazepine-like effects often have been evident at high doses.
The evidence for intrinsic activity in human subjects is even more
vague, except for modest anticonvulsant effects at high doses.
However, anticonvulsant effects cannot be relied on for therapeutic
utility because the administration of flumazenil may precipitate
seizures under certain circumstances (discussed later).