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

Flumazenil is available only for intravenous administration.
On intravenous administration, flumazenil is eliminated almost
entirely by hepatic metabolism to inactive products with a t 1/2
of
~1 hour; the duration of clinical effects usually is only 30-60 minutes.
Although absorbed rapidly after oral administration, <25% of the
drug reaches the systemic circulation owing to extensive first-pass
hepatic metabolism; effective oral doses are apt to cause headache
and dizziness.
The primary indications for the use of flumazenil are the
management of suspected benzodiazepine overdose and the reversal
of sedative effects produced by benzodiazepines administered
during either general anesthesia or diagnostic and/or therapeutic
procedures.
The administration of a series of small injections is preferred
to a single bolus injection. A total of 1 mg flumazenil given over
1-3 minutes usually is sufficient to abolish the effects of therapeutic
doses of benzodiazepines; patients with suspected benzodiazepine
overdose should respond adequately to a cumulative dose of 1-5 mg
given over 2-10 minutes; a lack of response to 5 mg flumazenil
strongly suggests that a benzodiazepine is not the major cause of
sedation. Additional courses of treatment with flumazenil may be
needed within 20-30 minutes should sedation reappear.
Flumazenil is not effective in single-drug overdoses with
either barbiturates or tricyclic antidepressants. To the contrary, the
administration of flumazenil in these settings may be associated with
the onset of seizures, especially in patients poisoned with tricyclic
antidepressants (Spivey, 1992). Seizures or other withdrawal symptoms
also may be precipitated in patients who had been taking benzodiazepines
for protracted periods and in whom tolerance and/or
dependence may have developed.
MELATONIN CONGENERS
Ramelteon. Ramelteon (ROZEREM) is a synthetic tricyclic
analog of melatonin with the chemical name (S)-N-[2-
(1,6,7,8-tetrahydro-2H-indeno[5,4-b] furan-8-yl)ethyl]
propionamide. It was approved in the U.S. in 2005 for the
treatment of insomnia, specifically sleep onset difficulties.
Unlike other drugs licensed by the FDA for insomnia,
ramelteon is not a controlled substance.
H 3 C
O
HN
HN
MELATONIN
O
CH 3
RAMELTEON
Mechanism of Action. Melatonin levels in the suprachiastmatic
nucleus rise and fall in a circadian fashion, with concentrations
increasing in the evening as an individual prepares for sleep, and
then reaching a plateau and ultimately decreasing as the night progresses.
Two GPCRs for melatonin, MT 1
and MT 2
, are found in the
suprachiasmatic nucleus, each playing a different role in sleep.
Binding of agonists, such as melatonin, to MT 1
receptors promotes
O
H
N
O
the onset of sleep while melatonin binding to MT 2
receptors shifts
the timing of the circadian system (Liu et al., 1997). Ramelteon
binds to both MT 1
and MT 2
receptors with high affinity but, unlike
melatonin, it does not bind appreciably to quinone reductase 2, the
structurally unrelated MT 3
receptor (Nosjean et al., 2000).
Ramelteon is not known to bind to any other classes of receptors,
such as nicotinic acetylcholine, neuropeptide, dopamine, or opiate
receptors, or the benzodiazepine-binding site on GABA A
receptors.
Clinical Pharmacology. Prescribing guidelines suggest that an 8-mg
tablet be taken ~30 minutes before bedtime. Ramelteon is rapidly
absorbed from the GI tract and a peak serum concentration is
obtained within an hour (Hibberd and Stevenson 2004). Because of
the significant first-pass metabolism that occurs after oral administration,
ramelteon bioavailability is <2% (Amakye et al., 2004). In
the bloodstream, ~80% of ramelteon is protein bound (Takeda
Pharmaceuticals North America, 2006). The drug is largely metabolized
by the hepatic CYPs 1A2, 2C, and 3A4, with t 1/2
of ~2 hours
in humans. Of the four metabolites, one, M-II, acts as an agonist at
MT 1
and MT 2
receptors and may contribute to the sleep-promoting
effects of ramelteon.
Ramelteon is efficacious in combating both transient and
chronic insomnia. Subjects given 16 or 64 mg of ramelteon in a
clinical trial showed a significantly shorter latency to sleep onset, as
well as increased total sleep time, compared to placebo controls
(Roth et al., 2005); the drug was generally well tolerated by patients
and did not impair next-day cognitive function. Ramelteon is also
useful in the treatment of chronic insomnia, with no tolerance
occurring in its reduction of sleep onset latency even after 6 months
of drug administration (Mayer et al., 2009). Sleep latency, evaluated
by polysomnography as well as by subject questionnaires, was
consistently found to be shorter in patients given ramelteon compared
to placebo controls (Erman et al., 2006; Zammit et al., 2007).
No evidence of rebound insomnia or withdrawal effects were noted
upon ramelteon withdrawal. Ramelteon appears to act by producing
a phase advance of the endogenous circadian rhythm (Richardson
et al., 2008).
In animals, ramelteon does not produce discriminative stimulus
effects similar to those of benzodiazepine receptor agonists, and
long-term administration has no effects on spontaneous or operant
behaviors, motor activity or posture (France et al., 2006). In addition,
ramelteon has no demonstrated positive reinforcing effects in intravenous
self-administration experiments performed in rhesus monkeys
and there is no indication of abuse liability in humans (Griffiths
and Johnson, 2005).
BARBITURATES
The barbiturates were once used extensively as
sedative-hypnotic drugs. Except for a few specialized
uses, they have been largely replaced by the much safer
benzodiazepines.
Chemistry. Barbituric acid is 2,4,6-trioxohexahydropyrimidine. This
compound lacks central depressant activity, but the presence of alkyl
or aryl groups at position 5 confers sedative-hypnotic and sometimes
other activities. The general structural formula for the barbiturates
and the structures of selected compounds are included in Table 17–4.
469
CHAPTER 17
HYPNOTICS AND SEDATIVES