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

Meprobamate. Meprobamate a bis-carbamate ester, was introduced
as an anti-anxiety agent and this remains its only approved use in
the U.S. However, it also became popular as a sedative-hypnotic drug
and is discussed here mainly because of its continued use for such
purposes. The question of whether the sedative and anti-anxiety
actions of meprobamate differ is unanswered, and clinical proof for
the efficacy of meprobamate as a selective anti-anxiety agent in
humans is lacking.
The pharmacological properties of meprobamate resemble
those of the benzodiazepines in a number of ways. Meprobamate
can release suppressed behaviors in experimental animals at doses
that cause little impairment of locomotor activity, and although it
can cause widespread depression of the CNS, it cannot produce anesthesia.
However, ingestion of large doses of meprobamate alone can
cause severe or even fatal respiratory depression, hypotension,
shock, and heart failure. Meprobamate appears to have a mild analgesic
effect in patients with musculoskeletal pain, and it enhances the
analgesic effects of other drugs.
Meprobamate is well absorbed when administered orally.
Nevertheless, an important aspect of intoxication with meprobamate
is the formation of gastric bezoars consisting of undissolved
meprobamate tablets; hence treatment may require endoscopy,
with mechanical removal of the bezoar. Most of the drug is
metabolized in the liver, mainly to a side-chain hydroxy derivative
and a glucuronide; the kinetics of elimination may depend
on the dose. The t 1/2
of meprobamate may be prolonged during its
chronic administration, even though the drug can induce some
hepatic CYPs.
The major unwanted effects of the usual sedative doses of
meprobamate are drowsiness and ataxia; larger doses produce considerable
impairment of learning and motor coordination and prolongation
of reaction time. Like the benzodiazepines, meprobamate
enhances the CNS depression produced by other drugs.
The abuse of meprobamate has continued despite a substantial
decrease in the clinical use of the drug. Carisoprodol
(SOMA), a skeletal muscle relaxant whose active metabolite is
meprobamate, also has abuse potential and has become a popular
“street drug” (Reeves et al., 1999). Meprobamate is preferred to
the benzodiazepines by subjects with a history of drug abuse.
After long-term medication, abrupt discontinuation evokes a withdrawal
syndrome usually characterized by anxiety, insomnia,
tremors, and, frequently, hallucinations; generalized seizures
occur in ~10% of cases. The intensity of symptoms depends on
the dosage ingested.
Other Agents. Etomidate (AMIDATE, generic) is used in the U.S. and
other countries as an intravenous anesthetic, often in combination
with fentanyl. It is advantageous because it lacks pulmonary and vascular
depressant activity, although it has a negative inotropic effect
on the heart. Its pharmacology and anesthetic uses are described in
Chapter 13. It also is used in some countries as a sedative-hypnotic
drug in intensive care units, during intermittent positive-pressure
breathing, in epidural anesthesia, and in other situations. Because it
is administered only intravenously, its use is limited to hospital settings.
The myoclonus commonly seen after anesthetic doses is not
seen after sedative-hypnotic doses.
Clomethiazole has sedative, muscle relaxant, and anticonvulsant
properties. It is used outside the U.S. for hypnosis in elderly
and institutionalized patients, for preanesthetic sedation, and especially
in the management of withdrawal from ethanol (Symposium,
1986b). Given alone, its effects on respiration are slight, and the therapeutic
index is high. However, deaths from adverse interactions
with ethanol are relatively frequent.
Propofol (DIPRIVAN) is a rapidly acting and highly lipophilic
diisopropylphenol used in the induction and maintenance of general
anesthesia (Chapter 19), as well as in the maintenance of longterm
sedation. Propofol sedation is of a similar quality to that
produced by midazolam. Emergence from sedation occurs quickly
owing to its rapid clearance (McKeage and Perry, 2003). Propofol
has found use in intensive care sedation in adults (McKeage and
Perry, 2003), as well as for sedation during gastrointestinal
endoscopy procedures (Heuss and Inauen, 2004) and transvaginal
oocyte retrieval (Dell and Cloote, 1998). Although its mechanism
of action is not understood completely, propofol is believed to act
primarily through enhancement of GABA A
receptor function.
Effects on other ligand-gated channels and GPCRs also have been
reported (Trapani et al., 2000).
Nonprescription Hypnotic Drugs. As part of the ongoing systematic
review of over-the-counter (OTC) drug products, the FDA has
ruled that diphenhydramine is the only antihistamine that is recognized
as generally safe and effective for use in nonprescription sleep
aids. Despite the prominent sedative side effects encountered during
the use of doxylamine and pyrilamine, these agents subsequently
were eliminated as ingredients in the OTC nighttime sleep aids marketed
in the U.S.. In 2004, doxylamine regained FDA approval as
an OTC sleep aid and re-entered the market as Unisom Nighttime
Sleep Aid (doxylamine 25-mg tablets). With elimination t 1/2
of ~9
hours (diphenhydramine) and 10 hours (doxylamine), these antihistamines
can be associated with prominent residual daytime sleepiness
when taken the prior evening as a sleep aid.
MANAGEMENT OF INSOMNIA
Insomnia is one of the most common complaints in
general medical practice, and its treatment is predicated
on proper diagnosis. Although the precise function of
sleep is not known, adequate sleep improves the quality
of daytime wakefulness, and hypnotics should be
used judiciously to avoid its impairment.
A number of pharmacological agents are available
for the treatment of insomnia. The “perfect” hypnotic
would allow sleep to occur with normal sleep
architecture rather than produce a pharmacologically
altered sleep pattern. It would not cause next-day
effects, either of rebound anxiety or of continued sedation.
It would not interact with other medications. It
could be used chronically without causing dependence
or rebound insomnia on discontinuation. Regular moderate
exercise meets these criteria but often is not effective
by itself, and many patients may not be able to
exercise. However, even small amounts of exercise
often are effective in promoting sleep.
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CHAPTER 17
HYPNOTICS AND SEDATIVES