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

458 searches for agents with more selective effects on CNS functions.
As a result, relatively non-sedating anticonvulsants, notably
phenytoin and trimethadione, were developed in the late 1930s
and early 1940s (Chapter 21). The advent of chlorpromazine and
meprobamate in the early 1950s, with their taming effects in animals,
and the development of increasingly sophisticated methods
for evaluating the behavioral effects of drugs set the stage in the
1950s for the synthesis of chlordiazepoxide by Sternbach and the
discovery of its unique pattern of actions by Randall. The introduction
of chlordiazepoxide into clinical medicine in 1961 ushered
in the era of benzodiazepines. Most of the benzodiazepines
that have reached the marketplace were selected for high anxiolytic
potency in relation to their depression of CNS function.
However, all benzodiazepines possess sedative-hypnotic properties
to varying degrees; these properties are exploited extensively
clinically, especially to facilitate sleep. Mainly because of their
remarkably low capacity to produce fatal CNS depression, the
benzodiazepines have displaced the barbiturates as sedative-hypnotic
agents.
SECTION II
NEUROPHARMACOLOGY
BENZODIAZEPINES
All benzodiazepines in clinical use have the capacity to
promote the binding of the major inhibitory neurotransmitter
γ-aminobutyric acid (GABA) to the GABA A
subtype
of GABA receptors, which exist as multi-subunit,
ligand-gated chloride channels, thereby enhancing the
GABA-induced ionic currents through these channels
(see Figure 14–11). Pharmacological data suggest heterogeneity
among sites of binding and action of benzodiazepines;
biochemical and molecular biological
investigations reveal the numerous varieties of subunits
that make up the GABA-gated chloride channels
expressed in different neurons. Since receptor subunit
composition appears to govern the interaction
of various allosteric modulators with these channels,
there has been a surge in efforts to find agents displaying
different combinations of benzodiazepine-like properties
that may reflect selective actions on one or more
subtypes of GABA receptors. These efforts led to the
development of zolpidem (AMBIEN), an imidazopyridine,
the pyrazolopyrimidines zaleplon (SONATA) and
the cyclopyrrolones zopiclone and eszopiclone
(LUNESTA); these so-called “Z compounds” all apparently
exert sedative-hypnotic effects by interacting with
a subset of benzodiazepine binding sites.
Although the benzodiazepines exert qualitatively
similar clinical effects, important quantitative differences
in their pharmacodynamic spectra and pharmacokinetic
properties have led to varying patterns of
therapeutic application. A number of distinct mechanisms
of action are thought to contribute to the
sedative-hypnotic, muscle-relaxant, anxiolytic, and
anticonvulsant effects of the benzodiazepines, and specific
subunits of the GABA A
receptor are responsible
for specific pharmacological properties of benzodiazepines.
While only the benzodiazepines used primarily
for hypnosis are discussed in detail, this chapter
describes the general properties of the group and important
differences among individual agents (see also
Chapters 15 and 21).
Chemistry. The structures of the benzodiazepines in use in the U.S.
are shown in Table 17–1, as are those of a few related compounds
discussed later.
The term benzodiazepine refers to the portion of the structure
composed of a benzene ring (A) fused to a seven-membered
diazepine ring (B). Since all the important benzodiazepines contain
a 5-aryl substituent (ring C) and a 1,4-diazepine ring, the term has
come to mean the 5-aryl-1,4-benzodiazepines. Various modifications
in the structure of the ring systems have yielded compounds
with similar activities, including 1,5-benzodiazepines (e.g.,
clobazam) and compounds in which the fused benzene ring is
replaced with heteroaromatic systems such as thieno (e.g., brotizolam).
The chemical nature of substituents at positions 1 to 3 can
vary widely and can include triazolo or imidazolo rings fused at
positions 1 and 2. Replacement of ring C with a keto function at
position 5 and a methyl substituent at position 4 is an important
structural feature of the benzodiazepine receptor antagonist
flumazenil (ROMAZICON).
In addition to various benzodiazepine or imidazobenzodiazepine
derivatives, a large number of non-benzodiazepine compounds
compete with classic benzodiazepines or flumazenil for
binding at specific sites in the CNS. These include representatives
from the β-carbolines (containing an indole nucleus fused to a
pyridine ring), imidazopyridines (e.g., zolpidem, discussed later), imidazopyrimidines,
imidazoquinolones, and cyclopyrrolones (e.g.,
eszopiclone).
Pharmacological Properties
Virtually all effects of the benzodiazepines result from
their actions on the CNS. The most prominent of these
effects are sedation, hypnosis, decreased anxiety, muscle
relaxation, anterograde amnesia, and anticonvulsant
activity. Only two effects of these drugs result from
peripheral actions: coronary vasodilation, seen after
intravenous administration of therapeutic doses of certain
benzodiazepines, and neuromuscular blockade,
seen only with very high doses.
A number of benzodiazepine-like effects have
been observed in vivo and in vitro and have been classified
as full agonistic effects (i.e., faithfully mimicking
agents such as diazepam with relatively low fractional
occupancy of binding sites) or partial agonistic effects
(i.e., producing less intense maximal effects or requiring
relatively high fractional occupancy compared with
agents such as diazepam). Some compounds produce