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

474
SECTION II
NEUROPHARMACOLOGY
enzyme induction enhances metabolism of endogenous steroid hormones,
which may cause endocrine disturbances, as well as of oral
contraceptives, which may result in unwanted pregnancy.
Barbiturates also induce the hepatic generation of toxic metabolites
of chlorocarbons (chloroform, trichloroethylene, carbon tetrachloride)
and consequently promote lipid peroxidation, which facilitates
periportal necrosis of the liver caused by these agents.
Other Untoward Effects. Because barbiturates enhance porphyrin
synthesis, they are absolutely contraindicated in patients with
acute intermittent porphyria or porphyria variegata. In hypnotic
doses, the effects of barbiturates on the control of respiration are
minor; however, in the presence of pulmonary insufficiency, serious
respiratory depression may occur, and the drugs thus are contraindicated.
Rapid intravenous injection of a barbiturate may
cause cardiovascular collapse before anesthesia ensues, so the
CNS signs of depth of anesthesia may fail to give an adequate
warning of impending toxicity. Blood pressure can fall to shock
levels; even slow intravenous injection of barbiturates often produces
apnea and occasionally laryngospasm, coughing, and other
respiratory difficulties.
Barbiturate Poisoning. The incidence of barbiturate poisoning has
declined markedly, largely as a result of their decreased use as sedative-hypnotic
agents. Nevertheless, poisoning with barbiturates is a
significant clinical problem, and death occurs in a few percent of
cases (Gary and Tresznewksy, 1983). Most of the cases are the result
of deliberate attempts at suicide, but some are from accidental poisonings
in children or in drug abusers. The lethal dose of barbiturate
varies, but severe poisoning is likely to occur when >10 times
the full hypnotic dose has been ingested at once. If alcohol or other
depressant drugs also are present, the concentrations that can cause
death are lower.
In severe intoxication, the patient is comatose; respiration is
affected early. Breathing may be either slow or rapid and shallow.
Eventually, blood pressure falls because the effect of the drug and of
hypoxia on medullary vasomotor centers; depression of cardiac contractility
and sympathetic ganglia also contributes. Pulmonary complications
(e.g., atelectasis, edema, and bronchopneumonia) and
renal failure are likely to be the fatal complications of severe barbiturate
poisoning.
The treatment of acute barbiturate intoxication is based on
general supportive measures, which are applicable in most respects
to poisoning by any CNS depressant. Hemodialysis or hemoperfusion
is necessary only rarely, and the use of CNS stimulants is contraindicated
because they increase the mortality rate. If renal and
cardiac functions are satisfactory, and the patient is hydrated, forced
diuresis and alkalinization of the urine will hasten the excretion of
phenobarbital. Measures to prevent or treat atelectasis should be taken,
and mechanical ventilation should be initiated when indicated. See
Chapter 4, Drug Toxicity and Poisoning.
In severe acute barbiturate intoxication, circulatory collapse
is a major threat. Often the patient is admitted to the hospital with
severe hypotension or shock, and dehydration frequently is severe.
Hypovolemia must be corrected, and if necessary, the blood pressure
can be supported with dopamine. Acute renal failure consequent
to shock and hypoxia accounts for perhaps one-sixth of the deaths.
In the event of renal failure, hemodialysis should be instituted.
MISCELLANEOUS SEDATIVE-
HYPNOTIC DRUGS
Many drugs with diverse structures have been used for
their sedative-hypnotic properties, including ramelteon,
paraldehyde, chloral hydrate, and meprobamate. With
the exception of ramelteon and meprobamate, the pharmacological
actions of these drugs generally resemble
those of the barbiturates: they all are general CNS
depressants that can produce profound hypnosis with
little or no analgesia; their effects on the stages of sleep
are similar to those of the barbiturates; their therapeutic
index is limited, and acute intoxication, which produces
respiratory depression and hypotension, is
managed similarly to barbiturate poisoning; their
chronic use can result in tolerance and physical dependence;
and the syndrome after chronic use can be severe
and life-threatening. The properties of meprobamate
bear some resemblance to those of the benzodiazepines,
but the drug has a distinctly higher potential for abuse
and has less selective anti-anxiety effects.
The clinical use of these agents has decreased
markedly, and deservedly so. Some of them may be
useful in certain settings, particularly in hospitalized
patients. The chemical structures and major pharmacological
properties of paraldehyde, ethchlorvynol
(PLACIDYL, others), chloral hydrate (NOCTEC, others),
meprobamate, glutethimide, methyprylon, and ethinamate
can be found in previous editions of this book.
Paraldehyde. Paraldehyde is a polymer of acetaldehyde, basically a
cyclic polyether. It has a strong odor and a disagreeable taste. Orally,
it is irritating to the throat and stomach, and it is not administered
parenterally because of its injurious effects on tissues. Use of paraldehyde
has been discontinued in the U.S.
Chloral Hydrate. Chloral hydrate is formed by adding one molecule
of water to the carbonyl group of chloral (2,2,2-trichloroacetaldehyde).
Chloral hydrate may be used to treat patients with
paradoxical reactions to benzodiazepines. Chloral hydrate is
reduced rapidly to the active compound, trichloroethanol
(CCl 3
CH 2
OH), largely by hepatic alcohol dehydrogenase; significant
amounts of chloral hydrate are not found in the blood after its
oral administration. Therefore, its pharmacological effects probably
are caused by trichloroethanol. Indeed, the latter compound can
exert barbiturate-like effects on GABA A
receptor channels in vitro
(Lovinger et al., 1993).
Chloral hydrate is best known in the U.S. as a literary poison,
the “knock-out drops” added to a strong alcoholic beverage to
produce a “Mickey Finn” or “Mickey,” a cocktail given to an unwitting
imbiber to render him malleable or unconscious, most famously
Sam Spade in Dashiell Hammett’s 1930 novel, The Maltese Falcon.
Now that detectives drink wine rather than whiskey, this off-label
use of chloral hydrate has waned.