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

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SECTION II
NEUROPHARMACOLOGY
Abuse and Dependence. Like other CNS depressant drugs, barbiturates
are abused, and some individuals develop a dependence on
them (Chapter 24). Moreover, the barbiturates may have euphoriant
effects.
Peripheral Nervous Structures. Barbiturates selectively depress transmission
in autonomic ganglia and reduce nicotinic excitation by
choline esters. This effect may account, at least in part, for the fall
in blood pressure produced by intravenous oxybarbiturates and by
severe barbiturate intoxication. At skeletal neuromuscular junctions,
the blocking effects of both tubocurarine and decamethonium are
enhanced during barbiturate anesthesia. These actions probably
result from the capacity of barbiturates at hypnotic or anesthetic concentrations
to inhibit the passage of current through nicotinic cholinergic
receptors. Several distinct mechanisms appear to be involved,
and little stereoselectivity is evident.
Respiration. Barbiturates depress both the respiratory
drive and the mechanisms responsible for the rhythmic
character of respiration. The neurogenic drive is diminished
by hypnotic doses but usually no more so than
during natural sleep. However, neurogenic drive is
essentially eliminated by a dose three times greater than
that used normally to induce sleep. Such doses also suppress
the hypoxic drive and, to a lesser extent, the
chemoreceptor drive. At still higher doses, the powerful
hypoxic drive fails. However, the margin between
the lighter planes of surgical anesthesia and dangerous
respiratory depression is sufficient to permit the ultrashort-acting
barbiturates to be used, with suitable precautions,
as anesthetic agents.
The barbiturates only slightly depress protective reflexes until
the degree of intoxication is sufficient to produce severe respiratory
depression. Coughing, sneezing, hiccoughing, and laryngospasm
may occur when barbiturates are employed as intravenous anesthetic
agents. Indeed, laryngospasm is one of the chief complications of
barbiturate anesthesia.
Cardiovascular System. When given orally in sedative or
hypnotic doses, barbiturates do not produce significant
overt cardiovascular effects except for a slight decrease
in blood pressure and heart rate such as occurs in normal
sleep. In general, the effects of thiopental anesthesia on
the cardiovascular system are benign in comparison with
those of the volatile anesthetic agents; there usually is
either no change or a fall in mean arterial pressure
(Chapter 19).
Apparently, a decrease in cardiac output usually is sufficient
to offset an increase in peripheral resistance, which sometimes is
accompanied by an increase in heart rate. Cardiovascular reflexes are
obtunded by partial inhibition of ganglionic transmission. This is most
evident in patients with congestive heart failure or hypovolemic shock,
whose reflexes already are operating maximally and in whom barbiturates
can cause an exaggerated fall in blood pressure. Because barbiturates
also impair reflex cardiovascular adjustments to inflation of
the lung, positive-pressure respiration should be used cautiously and
only when necessary to maintain adequate pulmonary ventilation in
patients who are anesthetized or intoxicated with a barbiturate.
Other cardiovascular changes often noted when thiopental and
other intravenous thiobarbiturates are administered after conventional
preanesthetic medication include decreased renal and cerebral blood
flow with a marked fall in CSF pressure. Although cardiac arrhythmias
are observed only infrequently, intravenous anesthesia with barbiturates
can increase the incidence of ventricular arrhythmias,
especially when epinephrine and halothane also are present. Anesthetic
concentrations of barbiturates have direct electrophysiological effects
on the heart; in addition to depressing Na + channels, they reduce the
function of at least two types of K + channels (Nattel et al., 1990;
Pancrazio et al., 1993). However, direct depression of cardiac contractility
occurs only when doses several times those required to cause
anesthesia are administered, which probably contributes to the cardiovascular
depression that accompanies acute barbiturate poisoning.
GI Tract. The oxybarbiturates tend to decrease the tone of the GI
musculature and the amplitude of rhythmic contractions. The locus
of action is partly peripheral and partly central, depending on the
dose. A hypnotic dose does not significantly delay gastric emptying
in humans. The relief of various GI symptoms by sedative doses is
probably largely due to the central-depressant action.
Liver. The best-known effects of barbiturates on the
liver are those on the microsomal drug-metabolizing
system (Chapter 6), a site at which significant drug-drug
interactions can occur. These effects vary with the duration
of exposure to the barbiturate.
Acutely, the barbiturates combine with several CYPs and
inhibit the biotransformation of a number of other drugs and endogenous
substrates, such as steroids; other substrates may reciprocally
inhibit barbiturate biotransformations. Drug interactions may result
even when the other substances and barbiturates are oxidized by different
microsomal enzyme systems.
Chronic administration of barbiturates markedly increases
the protein and lipid content of the hepatic smooth endoplasmic
reticulum, as well as the activities of glucuronyl transferase and
CYPs 1A2, 2C9, 2C19, and 3A4. The induction of these enzymes
increases the metabolism of a number of drugs and endogenous substances,
including steroid hormones, cholesterol, bile salts, and vitamins
K and D. This also results in an increased rate of barbiturate
metabolism, which partly accounts for tolerance to barbiturates.
Many sedative-hypnotics, various anesthetics, and ethanol also are
metabolized by and/or induce the microsomal enzymes, and some
degree of cross-tolerance therefore can occur. Not all microsomal
biotransformations of drugs and endogenous substrates are affected
equally, but a convenient rule of thumb is that at maximal induction
in humans, the rates are approximately doubled. The inducing effect
is not limited to the microsomal enzymes; for example, there are
increases in δ-aminolevulinic acid (ALA) synthetase, a mitochondrial
enzyme, and aldehyde dehydrogenase, a cytosolic enzyme. The
effect of barbiturates on ALA synthetase can cause dangerous disease
exacerbations in persons with intermittent porphyria.
Kidney. Severe oliguria or anuria may occur in acute barbiturate poisoning
largely as a result of the marked hypotension.