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

The inhalational anesthetics inhibit excitatory synapses and
enhance inhibitory synapses in various preparations. These effects
likely are produced by both pre- and postsynaptic actions of the
inhalational anesthetics. The inhalational anesthetic isoflurane
clearly can inhibit neurotransmitter release, while the small reduction
in presynaptic action potential amplitude produced by isoflurane (3%
reduction at MAC concentration) substantially inhibits neurotransmitter
release (Wu et al., 2004b). The latter effect occurs because
the reduction in the presynaptic action potential is amplified into a
much larger reduction in presynaptic Ca 2+ influx, which in turn is
amplified into an even greater reduction in transmitter release. This
effect may account for the majority of the reduction in transmitter
release by inhalational anesthetics at some excitatory synapses.
Inhalational anesthetics also can act postsynaptically, altering the
response to released neurotransmitter. These actions are thought to
be due to specific interactions of anesthetic agents with neurotransmitter
receptors.
The intravenous anesthetics produce a narrower range of physiological
effects. Their predominant actions are at the synapse, where
they have profound and relatively specific effects on the postsynaptic
response to released neurotransmitter. Most of the intravenous
agents act predominantly by enhancing inhibitory neurotransmission,
whereas ketamine predominantly inhibits excitatory neurotransmission
at glutamatergic synapses.
Molecular Actions of General Anesthetics. A variety of
ligand-gated ion channels, receptors and signal transduction
proteins are modulated by general anesthetics.
Of these, the strongest evidence for a direct effect of
anesthetics exists for the GABA A
and NMDA receptors
and the two-pore K + channels, as described later in this
section.
Chloride channels gated by the inhibitory
GABA A
receptors (Chapters 14 and 17) are sensitive to
clinical concentrations of a wide variety of anesthetics,
including the halogenated inhalational agents and many
intravenous agents (propofol, barbiturates, etomidate,
and neurosteroids). At clinical concentrations, general
anesthetics increase the sensitivity of the GABA A
receptor to GABA, thus enhancing inhibitory neurotransmission
and depressing nervous system activity.
The action of anesthetics on the GABA A
receptor probably
is mediated by binding of the anesthetics to
specific sites on the GABA A
-receptor protein, since
point mutations of the receptor can eliminate the effects
of the anesthetic on ion channel function (Rudolph and
Antkowiak, 2004). Judging from the capacity of mutations
in various regions (and subunits) of the GABA A
receptor to selectively affect the actions of various anesthetics,
there likely are specific binding sites for at least
several classes of anesthetics (Belelli et al., 1997).
Notably, none of the general anesthetics competes with
GABA for its binding site on the receptor. The capacity
of propofol and etomidate to inhibit the response to
noxious stimuli is mediated by a specific site on the β 3
subunit of the GABA A
receptor, whereas the sedative
effects of these anesthetics are mediated by the same
site on the β 2
subunit (Reynolds et al., 2003). These
results indicate that two components of anesthesia can
be mediated by GABA A
receptors. For anesthetics other
than propofol and etomidate, which components of
anesthesia are produced by actions on GABA A
receptors
remains a matter of conjecture.
Structurally related to the GABA A
receptors are
other ligand-gated ion channels including glycine
receptors and neuronal nicotinic acetylcholine receptors.
Glycine receptors may play a role in mediating
inhibition by anesthetics of responses to noxious stimuli.
Clinical concentrations of inhalational anesthetics
enhance the capacity of glycine to activate glycinegated
chloride channels (glycine receptors), which play
an important role in inhibitory neurotransmission in the
spinal cord and brainstem. Propofol, neurosteroids, and
barbiturates also potentiate glycine-activated currents,
whereas etomidate and ketamine do not. Subanesthetic
concentrations of the inhalational anesthetics inhibit
some classes of neuronal nicotinic acetylcholine receptors
(Violet et al., 1997). However, these actions do not
appear to mediate anesthetic immobilization (Eger
et al., 2002); rather, neuronal nicotinic receptors could
mediate other components of anesthesia such as analgesia
or amnesia.
The only general anesthetics that do not have significant
effects on GABA A
or glycine receptors are ketamine,
nitrous oxide, cyclopropane, and xenon. These
agents inhibit a different type of ligand-gated ion channel,
the N-methyl-D-aspartate (NMDA) receptor
(Chapter 14). NMDA receptors are glutamate-gated
cation channels that are somewhat selective for calcium
and are involved in long-term modulation of synaptic
responses (long-term potentiation) and glutamatemediated
neurotoxicity. Ketamine inhibits NMDA
receptors by binding to the phencyclidine site on the
NMDA-receptor protein, and the NMDA receptor is
thought to be the principal molecular target for ketamine’s
anesthetic actions. Nitrous oxide (Jevtovic-
Todorovic et al., 1998), cyclopropane (Raines et al.,
2001), and xenon (de Sousa et al., 2000) are potent and
selective inhibitors of NMDA-activated currents, suggesting
that these agents also may produce unconsciousness
by means of actions on NMDA receptors.
Inhalational anesthetics have two other known
molecular targets that may mediate some of their
actions. Halogenated inhalational anesthetics activate
some members of a class of K + channels known as
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CHAPTER 19
GENERAL ANESTHETICS AND THERAPEUTIC GASES