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

depression in the neonate. Abuse by the pregnant mother can result
in a withdrawal syndrome in the newborn.
Except for additive effects with other sedative or hypnotic
drugs, reports of clinically important pharmacodynamic interactions
between benzodiazepines and other drugs have been infrequent.
Ethanol increases both the rate of absorption of benzodiazepines and
the associated CNS depression. Valproate and benzodiazepines in
combination may cause psychotic episodes. Pharmacokinetic interactions
were discussed earlier.
Novel Benzodiazepine Receptor Agonists
Hypnotics in this class are commonly referred to as “Z
compounds”. They include zolpidem (AMBIEN), zaleplon
(SONATA), zopiclone (not marketed in the U.S.), and
eszopiclone (LUNESTA), which is the S(+) enantiomer of
zopiclone. Although the Z compounds are structurally
unrelated to each other and to benzodiazepines, their
therapeutic efficacy as hypnotics is due to agonist effects
on the benzodiazepine site of the GABA A
receptor.
Compared to benzodiazepines, Z compounds are less
effective as anticonvulsants or muscle relaxants, which
may be related to their relative selectivity for GABA A
receptors containing the α1 subunit. Over the last
decade, Z compounds have largely replaced benzodiazepines
in the treatment of insomnia. Z compounds
were initially promoted as having less potential for
dependence and abuse than traditional benzodiazepines.
However, based on post-marketing clinical experience
with zopiclone and zolpidem, tolerance and physical
dependence can be expected during long-term use of Z
compounds, especially with higher doses (Zammit,
2009). Reports of abuse of Z compounds are on the rise
world-wide (Victorri-Vigneau, 2007). Zopiclone and its
isomers are classified as schedule IV drugs in the U.S.
The clinical presentation of overdose with Z compounds
is similar to that of benzodiazepine overdose and can be
treated with the benzodiazepine antagonist flumazenil.
Zaleplon and zolpidem are effective in relieving sleep-onset
insomnia. Both drugs have been approved by the FDA for use for up
to 7-10 days at a time. Zaleplon and zolpidem have sustained hypnotic
efficacy without occurrence of rebound insomnia on abrupt discontinuation
(Mitler, 2000; Walsh et al., 2000). Zaleplon and zolpidem
have similar degrees of efficacy. Zolpidem has a t 1/2
of ~2 hours, which
is sufficient to cover most of a typical 8-hour sleep period, and is
presently approved for bedtime use only. Zaleplon has a shorter t 1/2
~1
hour, which offers the possibility for safe dosing later in the night,
within 4 hours of the anticipated rising time. As a result, zaleplon is
approved for use immediately at bedtime or when the patient has difficulty
falling asleep after bedtime. Because of its short t 1/2
, zaleplon
has not been shown to be different from placebo in measures of duration
of sleep and number of awakenings. Zaleplon and zolpidem differ
in residual side effects; late-night administration of zolpidem has
been associated with morning sedation, delayed reaction time, and
anterograde amnesia, whereas zaleplon does not differ from placebo.
Zaleplon. Zaleplon (SONATA, generic) is a non-benzodiazepine
and is a member of the pyrazolopyrimidine
class of compounds.
N
N
N
N
Zaleplon preferentially binds to the benzodiazepine-binding
site on GABA A
receptors containing the α1 receptor subunit.
Zaleplon is absorbed rapidly and reaches peak plasma concentrations
in ~1 hour. Its bioavailability is ~30% because of presystemic
metabolism. Zaleplon has a volume of distribution of ~1.4 L/kg and
plasma-protein binding of ~60%. Zaleplon is metabolized largely by
aldehyde oxidase and to a lesser extent by CYP3A4. Its oxidative
metabolites are converted to glucuronides and eliminated in urine.
Less than 1% of zaleplon is excreted unchanged in urine. None of
zaleplon’s metabolites are pharmacologically active.
Zaleplon (usually administered in 5-, 10-, or 20-mg doses)
has been studied in clinical trials of patients with chronic or transient
insomnia (Dooley and Plosker, 2000), focusing on the drug’s
effects in decreasing sleep latency. Zaleplon-treated subjects with
either chronic or transient insomnia have experienced shorter periods
of sleep latency than have placebo-treated subjects.
Zolpidem. Zolpidem (AMBIEN, others) is a non-benzodiazepine
sedative-hypnotic drug. It is classified as an
imidazopyridine:
Although the actions of zolpidem are due to agonist effects on
GABA A
receptors and generally resemble those of benzodiazepines,
it produces only weak anticonvulsant effects in experimental animals,
and its relatively strong sedative actions appear to mask anxiolytic
effects in various animal models of anxiety (Langtry and
Benfield, 1990). Although chronic administration of zolpidem to
rodents produces neither tolerance to its sedative effects nor signs
of withdrawal when the drug is discontinued and flumazenil is
injected (Perrault et al., 1992), tolerance and physical dependence
have been observed with chronic administration of zolpidem to
baboons (Griffiths et al., 1992). During U.S. clinical trials, withdrawal
effects within 48 hours of drug discontinuation occurred at an
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ZALEPLON
N
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CHAPTER 17
HYPNOTICS AND SEDATIVES