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

REM cycles, the number of shifts to lighter sleep stages (1 and 0) and
the amount of body movement are diminished. Nocturnal peaks in
the secretion of growth hormone, prolactin, and luteinizing hormone
are not affected. During chronic nocturnal use of benzodiazepines,
the effects on the various stages of sleep usually decline within a few
nights. When such use is discontinued, the pattern of drug-induced
changes in sleep parameters may “rebound,” and an increase in the
amount and density of REM sleep may be especially prominent. If the
dosage has not been excessive, patients usually will note only a shortening
of sleep time rather than an exacerbation of insomnia.
Although some differences in the patterns of effects exerted
by the various benzodiazepines have been noted, their use usually
imparts a sense of deep or refreshing sleep. It is uncertain to which
effect on sleep parameters this feeling can be attributed. As a result,
variations in the pharmacokinetic properties of individual benzodiazepines
appear to be much more important determinants of their
effects on sleep than are any potential differences in their pharmacodynamic
properties.
Molecular Targets for Benzodiazepine Actions in the CNS.
Benzodiazepines appear to exert most of their effects by interacting
with inhibitory neurotransmitter receptors directly activated by GABA
(Chapter 14). The ionotropic GABA A
receptors consist of five subunits
that co-assemble to form an integral chloride channel (Figure
14–11). GABA A
receptors are responsible for most inhibitory neurotransmission
in the CNS. Benzodiazepines act at GABA A
receptors by
binding directly to a specific site that is distinct from that of GABA
binding. Unlike barbiturates, benzodiazepines do not activate GABA A
receptors directly; rather, benzodiazepines act allosterically by modulating
the effects of GABA. Benzodiazepines and GABA analogs
bind to their respective sites on brain membranes with nanomolar
affinity. Benzodiazepines modulate GABA binding, and GABA alters
benzodiazepine binding in an allosteric fashion.
Benzodiazepines and related compounds can act as agonists,
antagonists, or inverse agonists at the benzodiazepine-binding site
on GABA A
receptors. Agonists at the binding site increase, and
inverse agonists decrease, the amount of chloride current generated
by GABA A
-receptor activation. Agonists at the benzodiazepine binding
site shift the GABA concentration-response curve to the left,
whereas inverse agonists shift the curve to the right. Both these
effects are blocked by antagonists at the benzodiazepine binding site.
In the absence of an agonist or inverse agonist for the benzodiazepine
binding site, an antagonist for this binding site does not affect
GABA A
receptor function. One such antagonist, flumazenil, is used
clinically to reverse the effects of high doses of benzodiazepines.
The behavioral and electrophysiological effects of benzodiazepines
also can be reduced or prevented by prior treatment with antagonists
at the GABA binding site (e.g., bicuculline).
The strongest evidence that benzodiazepines act directly on
GABA A
receptors comes from recombinant expression of cDNAs
encoding subunits of the receptor complex, which resulted in highaffinity
benzodiazepine binding sites and GABA-activated chloride
conductances that were enhanced by benzodiazepine receptor agonists
(Burt, 2003). The properties of the expressed receptors generally
resemble those of GABA A
receptors found in most CNS
neurons. Each GABA A
receptor is believed to consist of a pentamer
of homologous subunits. Thus far 16 different subunits have been
identified and classified into seven subunit families: six α, three β,
three γ, and single δ, ε, π, and θ subunits. Additional complexity
arises from RNA splice variants of some of these subunits (e.g., γ2
and α6). The exact subunit structures of native GABA receptors still
are unknown, but it is thought that most GABA receptors are composed
of α, β, and γ subunits that co-assemble with some uncertain
stoichiometry. The multiplicity of subunits generates heterogeneity
in GABA A
receptors and is responsible, at least in part, for the pharmacological
diversity in benzodiazepine effects in behavioral, biochemical,
and functional studies. Studies of cloned GABA A
receptors have shown that the co-assembly of a γ subunit with α and
β subunits confers benzodiazepine sensitivity to GABA A
receptors
(Burt, 2003). Receptors composed solely of α and β subunits produce
functional GABA A
receptors that also respond to barbiturates,
but they neither bind nor are affected by benzodiazepines.
Benzodiazepines are believed to bind at the interface between α and
γ subunits, and both subunits determine the pharmacology of the
benzodiazepine binding site (Burt, 2003). For example, receptors
containing the α1 subunit are pharmacologically distinct from receptors
containing α2, α3, or α5 subunits (Pritchett and Seeburg, 1990),
reminiscent of the pharmacological heterogeneity detected with
radioligand-binding studies using brain membranes. Receptors containing
the α6 subunit do not display high-affinity binding of
diazepam and appear to be selective for the benzodiazepine receptor
inverse agonist RO 15-4513, which has been tested as an alcohol
antagonist (Lüddens et al., 1990). The subtype of γ subunit also
modulates benzodiazepine pharmacology, with lower-affinity binding
observed in receptors containing the γ1 subunit. Although theoretically
~1 million different GABA A
receptors could be assembled
from all these different subunits, constraints for the assembly of these
receptors apparently limit their numbers (Sieghart et al., 1999).
An understanding of which GABA A
receptor subunits are
responsible for particular effects of benzodiazepines in vivo has
emerged. The mutation to arginine of a histidine residue at position
101 of the GABA A
receptor α1 subunit renders receptors containing
that subunit insensitive to the GABA-enhancing effects of diazepam
(Kleingoor et al., 1993). Mice bearing these mutated subunits fail to
exhibit the sedative, the amnestic, and in part the anticonvulsant
effects of diazepam while retaining sensitivity to the anxiolytic, musclerelaxant,
and ethanol-enhancing effects. Conversely, mice bearing
the equivalent mutation in the α2 subunit of the GABA A
receptor
are insensitive to the anxiolytic effects of diazepam (Burt, 2003).
The attribution of specific behavioral effects of benzodiazepines to
individual receptor subunits will aid in the development of new compounds
exhibiting fewer undesired side effects.
Electrophysiological studies in vitro have shown that the
enhancement of GABA-induced chloride currents by benzodiazepines
results primarily from an increase in the frequency of bursts
of chloride channel opening produced by submaximal amounts of
GABA (Twyman et al., 1989). Inhibitory synaptic transmission
measured after stimulation of afferent fibers is potentiated by
benzodiazepines at therapeutically relevant concentrations.
Prolongation of spontaneous miniature inhibitory postsynaptic currents
(IPSCs) by benzodiazepines also has been observed. Although
sedative barbiturates also enhance such chloride currents, they do so
by prolonging the duration of individual channel-opening events.
Macroscopic measurements of GABA A
receptor-mediated currents
indicate that benzodiazepines shift the GABA concentrationresponse
curve to the left without increasing the maximum current
evoked with GABA. These findings collectively are consistent with
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CHAPTER 17
HYPNOTICS AND SEDATIVES