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

Absorption, Fate, and Excretion. For sedative-hypnotic
use, the barbiturates usually are administered orally
(Table 17–4). Such doses are absorbed rapidly and
probably completely; Na + salts are absorbed more rapidly
than the corresponding free acids, especially from
liquid formulations. The onset of action varies from
10-60 minutes, depending on the agent and the formulation,
and is delayed by the presence of food in the
stomach. When necessary, intramuscular injections of
solutions of the Na + salts should be placed deeply into
large muscles to avoid the pain and possible necrosis
that can result at more superficial sites. The intravenous
route usually is reserved for the management of status
epilepticus (phenobarbital sodium) or for the induction
and/or maintenance of general anesthesia (e.g., thiopental
or methohexital).
Barbiturates are distributed widely, and they readily cross the
placenta. The highly lipid-soluble barbiturates, led by those used to
induce anesthesia, undergo redistribution after intravenous injection.
Uptake into less vascular tissues, especially muscle and fat, leads to
a decline in the concentration of barbiturate in the plasma and brain.
With thiopental and methohexital, this results in the awakening of
patients within 5-15 minutes of the injection of the usual anesthetic
doses (Chapter 19).
Except for the less lipid-soluble aprobarbital and phenobarbital,
nearly complete metabolism and/or conjugation of barbiturates
in the liver precedes their renal excretion. The oxidation of radicals
at C5 is the most important biotransformation that terminates biological
activity. Oxidation results in the formation of alcohols, ketones,
phenols, or carboxylic acids, which may appear in the urine as such
or as glucuronic acid conjugates. In some instances (e.g., phenobarbital),
N-glycosylation is an important metabolic pathway. Other biotransformations
include N-hydroxylation, desulfuration of
thiobarbiturates to oxybarbiturates, opening of the barbituric acid
ring, and N-dealkylation of N-alkyl barbiturates to active metabolites
(e.g., mephobarbital to phenobarbital). About 25% of phenobarbital
and nearly all of aprobarbital are excreted unchanged in the
urine. Their renal excretion can be increased greatly by osmotic
diuresis and/or alkalinization of the urine.
The metabolic elimination of barbiturates is more rapid in
young people than in the elderly and infants, and t 1/2
are increased
during pregnancy partly because of the expanded volume of distribution.
Chronic liver disease, especially cirrhosis, often increases
the t 1/2
of the biotransformable barbiturates. Repeated administration,
especially of phenobarbital, shortens the t 1/2
of barbiturates
that are metabolized as a result of the induction of microsomal
enzymes.
None of the barbiturates used for hypnosis in the U.S. appears
to have an elimination t 1/2
that is short enough for elimination to be
virtually complete in 24 hours (Table 17–4). However, the relationship
between duration of action and t 1/2
of elimination is complicated
by the fact that enantiomers of optically active barbiturates
often differ in both biological potencies and rates of biotransformation.
All of these barbiturates will accumulate during repetitive
administration unless appropriate adjustments in dosage are made.
Furthermore, the persistence of the drug in plasma during the day
favors the development of tolerance and abuse.
Therapeutic Uses
The major uses of individual barbiturates are listed in
Table 17–4. As with the benzodiazepines, the selection of
a particular barbiturate for a given therapeutic indication
is based primarily on pharmacokinetic considerations.
CNS Uses. Benzodiazepines and other compounds for sedation have
largely replaced barbiturates. Barbiturates, especially butabarbital
and phenobarbital, are used sometimes to antagonize unwanted
CNS-stimulant effects of various drugs, such as ephedrine, dextroamphetamine,
and theophylline, although a preferred approach is
adjustment of dosage or substitution of alternative therapy for the
primary agents (see Chapter 24).
Untoward Effects
After-Effects. Drowsiness may last for only a few hours after a hypnotic
dose of barbiturate, but residual CNS depression sometimes is
evident the following day, and subtle distortions of mood and impairment
of judgment and fine motor skills may be demonstrable. For
example, a 200-mg dose of secobarbital has been shown to impair
performance of driving or flying skills for 10-22 hours. Residual
effects also may take the form of vertigo, nausea, vomiting, or diarrhea,
or sometimes may be manifested as overt excitement. The user
may awaken slightly intoxicated and feel euphoric and energetic;
later, as the demands of daytime activities challenge possibly
impaired faculties, the user may display irritability and temper.
Paradoxical Excitement. In some persons, barbiturates produce
excitement rather than depression, and the patient may appear to be
inebriated. This type of idiosyncrasy is relatively common among
geriatric and debilitated patients and occurs most frequently with
phenobarbital and N-methylbarbiturates. Barbiturates may cause
restlessness, excitement, and even delirium when given in the presence
of pain and may worsen a patient’s perception of pain.
Hypersensitivity. Allergic reactions occur, especially in persons with
asthma, urticaria, angioedema, or similar conditions. Hypersensitivity
reactions include localized swellings, particularly of the eyelids,
cheeks, or lips, and erythematous dermatitis. Rarely, exfoliative dermatitis
may be caused by phenobarbital and can prove fatal; the skin
eruption may be associated with fever, delirium, and marked degenerative
changes in the liver and other parenchymatous organs.
Drug Interactions. Barbiturates combine with other CNS depressants
to cause severe depression; ethanol is the most frequent offender,
and interactions with first-generation antihistamines also are common.
Isoniazid, methylphenidate, and monoamine oxidase inhibitors
also increase the CNS-depressant effects.
Barbiturates competitively inhibit the metabolism of certain
other drugs; however, the greatest number of drug interactions
results from induction of hepatic CYPs and the accelerated disappearance
of many drugs and endogenous substances. The metabolism
of vitamins D and K is accelerated, which may hamper bone
mineralization and lower Ca 2+ absorption in patients taking phenobarbital
and may be responsible for the reported coagulation defects
in neonates whose mothers had been taking phenobarbital. Hepatic
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CHAPTER 17
HYPNOTICS AND SEDATIVES