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

Table 19–1
Properties of Inhalational Anesthetic Agents
EC 50c
FOR VAPOR
SUPPRESSION PRESSURE
ANESTHETIC MAC a b
MAC AWAKE
OF MEMORY (mm Hg
PARTITION COEFFICIENT AT 37°C
RECOVERED AS
AGENT (vol %) (vol %) (vol %) at 20°C) Blood:Gas Brain:Blood Fat:Blood METABOLITES (%)
Halothane 0.75 0.41 — 243 2.3 2.9 51 20
Isoflurane 1.2 0.4 0.24 250 1.4 2.6 45 0.2
Enflurane 1.6 0.4 — 175 1.8 1.4 36 2.4
Sevoflurane 2 0.6 — 160 0.65 1.7 48 3
Desflurane 6 2.4 — 664 0.45 1.3 27 0.02
Nitrous oxide 105 60.0 52.5 Gas 0.47 1.1 2.3 0.004
Xenon 71 32.6 — Gas 0.12 — — 0
a
MAC (minimum alveolar concentration) values are expressed as vol %, the percentage of the atmosphere that is anesthetic. A value of MAC greater
than 100% means that hyperbaric conditions would be required.
b
MAC awake
is the concentration at which appropriate responses to commands are lost.
c
EC 50
is the concentration that produces memory suppression in 50% of patients. —, Not available.
of MAC. Furthermore, the ratio of the anesthetic concentrations
required to produce amnesia and immobility vary significantly among
different inhalational anesthetic agents (nitrous oxide versus isoflurane)
(Table 19–1), suggesting that anesthetic agents may produce
these behavioral end points through different cellular and molecular
mechanisms. The potency of intravenous anesthetic agents is somewhat
more difficult to measure; we lack methods to measure blood or
plasma anesthetic concentration continuously, and we cannot determine
the free concentration of the drug at its site of action. Generally,
the potency of intravenous agents is defined as the free plasma concentration
(at equilibrium) that produces loss of response to surgical
incision (or other end points) in 50% of subjects.
Mechanisms of Anesthesia
The molecular and cellular mechanisms by which general
anesthetics produce their effects have remained one
of the great mysteries of pharmacology. For most of the
20th century, it was theorized that all anesthetics act by
a common mechanism (the unitary theory of anesthesia).
The leading unitary theory was that anesthesia is
produced by perturbation of the physical properties of
cell membranes. This thinking was based largely on the
observation that the anesthetic potency of a gas correlated
with its solubility in olive oil. This correlation,
referred to as the Meyer-Overton rule, was interpreted
as implicating the lipid bilayer as the likely target of
anesthetic action. Clear exceptions to the Meyer-
Overton rule have now been noted (Franks, 2006). For
example, inhalational and intravenous anesthetics can
be enantioselective in their action as anesthetics (etomidate,
steroids, isoflurane). The fact that enantiomers
with identical physical properties have unique actions
indicates that properties other than bulk solubility are
important in determining anesthetic action. Consequently,
the lipid theory of anesthesia has largely been discarded
(Franks, 2006). This realization has focused thinking
on identification of specific protein binding sites for
anesthetics.
A substantial body of work indicates that an anesthetic agent
produces different components of the anesthetic state by means of
actions at different anatomic loci in the nervous system and may produce
these component effects through different cellular and molecular
actions. Moreover, increasing evidence supports the hypothesis
that different anesthetic agents produce specific components of anesthesia
by actions at different molecular targets. Given these insights,
the unitary theory of anesthesia has been largely discarded.
Cellular Mechanisms of Anesthesia. General anesthetics
produce two important physiologic effects at the cellular
level.
First, the inhalational anesthetics can hyperpolarize
neurons. This may be an important effect on neurons
serving a pacemaker role and on pattern-generating circuits.
It also may be important in synaptic communication,
since reduced excitability in a postsynaptic neuron
may diminish the likelihood that an action potential will
be initiated in response to neurotransmitter release.
Second, at anesthetizing concentrations, both
inhalational and intravenous anesthetics have substantial
effects on synaptic transmission and much smaller
effects on action-potential generation or propagation.