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

462 a model in which benzodiazepines exert their major actions by
increasing the gain of inhibitory neurotransmission mediated by
GABA A
receptors.
GABA A
receptor subunits also may play roles in the targeting
of assembled receptors to their proper locations in synapses. In
knockout mice lacking the γ2 subunit, GABA A
receptors did not
localize to synapses, although they were formed and translocated to
the cell surface (Essrich et al., 1998). The synaptic clustering molecule
gephyrin also plays a role in receptor localization.
SECTION II
NEUROPHARMACOLOGY
GABA A
Receptor-Mediated Electrical Events: in vivo Properties. The
remarkable safety of the benzodiazepines is likely related to the fact
that their effects in vivo depend on the presynaptic release of GABA;
in the absence of GABA, benzodiazepines have no effects on GABA A
receptor function. Although barbiturates also enhance the effects of
GABA at low concentrations, they directly activate GABA receptors
at higher concentrations, which can lead to profound CNS depression
(discussed later). Further, the behavioral and sedative effects of
benzodiazepines can be ascribed in part to potentiation of GABAergic
pathways that serve to regulate the firing of neurons containing
various monoamines (Chapter 14). These neurons are known to promote
behavioral arousal and are important mediators of the inhibitory
effects of fear and punishment on behavior. Finally, inhibitory effects
on muscular hypertonia or the spread of seizure activity can be rationalized
by potentiation of inhibitory GABA-ergic circuits at various
levels of the neuraxis. In most studies conducted in vivo or in situ,
the local or systemic administration of benzodiazepines reduces the
spontaneous or evoked electrical activity of major (large) neurons in
all regions of the brain and spinal cord. The activity of these neurons
is regulated in part by small inhibitory interneurons (predominantly
GABA-ergic) arranged in feedback and feedforward types of circuits.
The magnitude of the effects produced by benzodiazepines varies
widely depending on such factors as the types of inhibitory circuits
that are operating, the sources and intensity of excitatory input, and
the manner in which experimental manipulations are performed and
assessed. For example, feedback circuits often involve powerful
inhibitory synapses on the neuronal soma near the axon hillock,
which are supplied predominantly by recurrent pathways. The synaptic
or exogenous application of GABA to this region increases chloride
conductance and can prevent neuronal discharge by shunting
currents that otherwise would depolarize the membrane of the initial
segment. Accordingly, benzodiazepines markedly prolong the period
after brief activation of recurrent GABA-ergic pathways during which
neither spontaneous nor applied excitatory stimuli can evoke neuronal
discharge; this effect is reversed by the GABA A
receptor antagonist
bicuculline (see Figure 14–10).
The macromolecular complex containing GABA-regulated
chloride channels also may be a site of action of general anesthetics,
ethanol, inhaled drugs of abuse, and certain metabolites of endogenous
steroids (Whiting, 2003). Among the latter, allopregnanolone
(3α-hydroxy, 5α-dihydroprogesterone) is of particular interest. This
compound, a metabolite of progesterone that can be formed in the
brain from precursors in the circulation and also synthesized by glial
cells, produces barbiturate-like effects, including promotion of
GABA-induced chloride currents and enhanced binding of benzodiazepines
and GABA-receptor agonists. As with the barbiturates,
higher concentrations of the steroid activate chloride currents in the
absence of GABA, and its effects do not require the presence of a
γ subunit in GABA A
receptors expressed in transfected cells. Unlike
the barbiturates, however, the steroid cannot reduce excitatory
responses to glutamate (discussed later). These effects are produced
very rapidly and apparently are mediated by interactions at sites on
the cell surface. A congener of allopregnanolone (alfaxalone) was
used previously outside the U.S. for the induction of anesthesia.
Respiration. Hypnotic doses of benzodiazepines are without effect on
respiration in normal subjects, but special care must be taken in the
treatment of children (Kriel et al., 2000) and individuals with
impaired hepatic function, such as alcoholics (Guglielminotti et al.,
1999). At higher doses, such as those used for preanesthetic medication
or for endoscopy, benzodiazepines slightly depress alveolar
ventilation and cause respiratory acidosis as the result of a decrease
in hypoxic rather than hypercapnic drive; these effects are exaggerated
in patients with chronic obstructive pulmonary disease (COPD),
and alveolar hypoxia and CO 2
narcosis may result. These drugs can
cause apnea during anesthesia or when given with opioids. Patients
severely intoxicated with benzodiazepines only require respiratory
assistance when they also have ingested another CNS-depressant
drug, most commonly ethanol.
In contrast, hypnotic doses of benzodiazepines may worsen
sleep-related breathing disorders by adversely affecting control of
the upper airway muscles or by decreasing the ventilatory response
to CO 2
. The latter effect may cause hypoventilation and hypoxemia
in some patients with severe COPD, although benzodiazepines may
improve sleep and sleep structure in some instances. In patients with
obstructive sleep apnea (OSA), hypnotic doses of benzodiazepines
may decrease muscle tone in the upper airway and exaggerate the
impact of apneic episodes on alveolar hypoxia, pulmonary hypertension,
and cardiac ventricular load. Many clinicians consider the
presence of OSA to be a contraindication to the use of alcohol or
any sedative-hypnotic agent, including a benzodiazepine; caution
also should be exercised with patients who snore regularly, because
partial airway obstruction may be converted to OSA under the influence
of these drugs. In addition, benzodiazepines may promote the
appearance of episodes of apnea during REM sleep (associated with
decreases in oxygen saturation) in patients recovering from a
myocardial infarction; however, no impact of these drugs on survival
of patients with cardiac disease has been reported.
Cardiovascular System. The cardiovascular effects of benzodiazepines
are minor in normal subjects except in severe intoxication; the adverse
effects in patients with obstructive sleep disorders or cardiac disease
were noted above. In preanesthetic doses, all benzodiazepines
decrease blood pressure and increase heart rate. With midazolam, the
effects appear to be secondary to a decrease in peripheral resistance,
but with diazepam, they are secondary to a decrease in left ventricular
work and cardiac output. Diazepam increases coronary flow, possibly
by an action to increase interstitial concentrations of
adenosine, and the accumulation of this cardiodepressant metabolite
also may explain the negative inotropic effects of the drug. In
large doses, midazolam decreases cerebral blood flow and oxygen
assimilation considerably (Nugent et al., 1982).
GI Tract. Benzodiazepines are thought by some gastroenterologists
to improve a variety of “anxiety related” gastrointestinal disorders.
There is a paucity of evidence for direct actions. Benzodiazepines
partially protect against stress ulcers in rats, and diazepam
markedly decreases nocturnal gastric secretion in humans. Other