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

532 two-pore domain channels (Patel et al., 1999); other
two-pore domain channel family members are activated
by xenon, nitrous oxide, and cyclopropane (Franks,
2006). These channels are located in both pre-synaptic
and post-synaptic sites. The post-synaptic channels are
important in setting the resting membrane potential of
neurons and may be the molecular locus through which
these agents hyperpolarize neurons. Activation of presynaptic
channels can lead to hyperpolarization of the
pre-synaptic terminal, thereby reducing neurotransmitter
release. Modulation of neurotransmitter release can
also be modulated by interaction of anesthetics with the
molecular machinery involved in neurotransmitter
release. The action of inhalational anesthetics requires
a protein complex (syntaxin, SNAP-25, synaptobrevin)
involved in synaptic neurotransmitter release (van
Swinderen et al., 1999). These molecular interactions
may explain, in part, the capacity of inhalational anesthetics
to cause presynaptic inhibition in the hippocampus
and could contribute to the amnesic effect of
inhalational anesthetics.
SECTION II
NEUROPHARMACOLOGY
Anatomic Sites of Anesthetic Action. In principle, general anesthetics
could interrupt nervous system function at myriad levels, including
peripheral sensory neurons, the spinal cord, the brainstem, and
the cerebral cortex. Delineation of the precise anatomic sites of
action is difficult because many anesthetics diffusely inhibit electrical
activity in the CNS. For example, isoflurane at 2 MAC can cause
electrical silence in the brain. However, in vitro studies show that
specific cortical pathways exhibit markedly different sensitivities to
both inhalational and intravenous anesthetics (MacIver and Roth,
1988), suggesting that anesthetics produce specific components of
the anesthetic state through actions at specific sites in the CNS.
Consistent with this possibility, inhalational anesthetics produce
immobilization in response to a surgical incision (the end point used
in determining MAC) by action on the spinal cord (Rampil, 1994).
Given that amnesia or unconsciousness cannot result from anesthetic
actions in the spinal cord, one concludes that different components
of anesthesia are produced at different sites in the CNS. Indeed,
recent studies show that the sedative effects of pentobarbital and
propofol (GABA-ergic anesthetics) are mediated by GABA A
receptors
in the tuberomammillary nucleus (Nelson et al., 2002), and the
sedative effects of the intravenous anesthetic dexmedetomidine (an
α 2
adrenergic receptor agonist) are produced by actions in the locus
ceruleus (Mizobe et al., 1996). These findings suggest that the sedative
actions of some anesthetics share the neuronal pathways
involved in endogenous sleep.
Functional imaging studies of the awake and anesthetized
brain have revealed that most anesthetics cause, with some exceptions,
a global reduction in cerebral metabolic rate (CMR) and in
cerebral blood flow (CBF); agent-specific effects on CMR and CBF
will be described later in the chapter. A consistent feature of general
anesthesia is a suppression of metabolism in the thalamus (Alkire et al.,
2008). This is not surprising given the demonstration that inhalational
anesthetics depress the excitability of thalamic neurons. The
thalamus serves as a major relay by which sensory input from the
periphery ascends to the cortex. Suppression of thalamic activity
might isolate the cortex from ascending input. Thus, the thalamus
may serve as a switch between the awake and anesthetized states
(Franks, 2008). In addition, general anesthesia results in the suppression
of activity in specific regions of the cortex, including the mesial
parietal cortex, posterior cingulate cortex, precuneus, and inferior
parietal cortex. Of interest is the recent observation that electrical
activity in the cortex is suppressed before that in the thalamus. This
suggests that it is cortical suppression that, via the corticothalamic
fibers, leads to thalamic suppression, thereby making the cortex the
primary target of anesthetics (Alkire et al., 2008). However, the temporal
relationships between thalamus and cortical activity (and deactivation)
under general anesthesia need further clarification before
the relative importance of each site to anesthetic induced loss of consciousness
is known (Franks, 2008).
The similarities between natural sleep and the anesthetized
state suggest that anesthetics might also modulate endogenous sleep
regulating pathways, which include ventrolateral preoptic (VLPO)
and tuberomammillary nuclei. VLPO projects inhibitory GABAergic
fibers to ascending arousal nuclei, which in turn project to the
cortex, forebrain, and subcortical areas; release of histamine, 5-HT,
orexin, NE, and ACh mediate wakefulness (Sanders and Maze,
2007). Intravenous and inhalational agents with activity at GABA A
receptors can increase the inhibitory effects of VLPO, thereby suppressing
consciousness. Dexmedetomidine, an α 2
agonist, also
increases VLPO-mediated inhibition by suppressing the inhibitory
effect of locus ceruleus neurons on VLPO (Sanders et al., 2007).
Finally, both intravenous and inhalational anesthetics depress hippocampal
neurotransmission (Kendig et al., 1991), a probable locus
for their amnestic effects.
Summary. Current evidence supports the view that most
intravenous general anesthetics act predominantly
through GABA A
receptors and perhaps through some
interactions with other ligand-gated ion channels such as
NMDA receptors and two-pore K + channels. The halogenated
inhalational agents have a variety of molecular
targets, consistent with their status as complete (all components)
anesthetics. Nitrous oxide, ketamine, and xenon
constitute a third category of general anesthetics that are
likely to produce unconsciousness by inhibition of the
NMDA receptor and/or activation of two-pore-domain
K + channels.
PARENTERAL ANESTHETICS
Pharmacokinetic Principles
Parenteral anesthetics are small, hydrophobic, substituted
aromatic or heterocyclic compounds (Figure 19–1).
Hydrophobicity is the key factor governing their pharmacokinetics.
After a single intravenous bolus, these
drugs preferentially partition into the highly perfused
and lipophilic tissues of the brain and spinal cord where
they produce anesthesia within a single circulation