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

with K + channels requires higher concentrations of
drug, blockade of conduction is not accompanied by
any large or consistent change in resting membrane
potential.
Quaternary analogs of local anesthetics block conduction
when applied internally to perfused giant axons of squid but are relatively
ineffective when applied externally. These observations suggest
that the site at which local anesthetics act, at least in their
charged form, is accessible only from the inner surface of the membrane
(Narahashi and Frazier, 1971; Strichartz and Ritchie, 1987).
Therefore, local anesthetics applied externally first must cross the
membrane before they can exert a blocking action.
Although a variety of physicochemical models have been
proposed to explain how local anesthetics achieve conduction block
(Courtney and Strichartz, 1987), it now is generally accepted that
the major mechanism of action of these drugs involves their interaction
with one or more specific binding sites within the Na + channel
(Butterworth and Strichartz, 1990). The Na + channels of the mammalian
brain are complexes of glycosylated proteins with an aggregate
molecular size in excess of 300,000 Da; the individual subunits
are designated α (260,000 Da) and β 1
to β 4
(33,000-38,000 Da). The
large α subunit of the Na + channel contains four homologous
domains (I-IV); each domain is thought to consist of six transmembrane
segments in α-helical conformation (S1-S6; Figure 20–2)
and an additional, membrane-reentrant pore (P) loop. The Na + -selective
transmembrane pore of the channel presumably resides in the
center of a nearly symmetrical structure formed by the four homologous
domains. The voltage dependence of channel opening is
hypothesized to reflect conformational changes that result from the
movement of “gating charges” within the voltage-sensor module of
the sodium channel in response to changes in the transmembrane
potential. The gating charges are located in the S4 transmembrane
helix; the S4 helices are both hydrophobic and positively charged,
containing lysine or arginine residues at every third position. It is
postulated that these residues move perpendicular to the plane of the
membrane under the influence of the transmembrane potential, initiating
a series of conformational changes in all four domains, which
leads to the open state of the channel (Figure 20–2) (Catterall, 2000;
Yu et al., 2005).
The transmembrane pore of the Na + channel is thought to be
surrounded by the S5 and S6 transmembrane helices and the short
membrane-associated segments between them that form the P loop.
Amino acid residues in these short segments are the most critical
determinants of the ion conductance and selectivity of the channel.
After it opens, the Na + channel inactivates within a few milliseconds
due to closure of an inactivation gate. This functional gate
is formed by the short intracellular loop of protein that connects
homologous domains III and IV (Figure 20–2). This loop folds over
the intracellular mouth of the transmembrane pore during the process
of inactivation and binds to an inactivation gate “receptor” formed by
the intracellular mouth of the pore.
Amino acid residues important for local anesthetic binding
are found in the S6 segments in domains I, III, and IV (Ragsdale
et al., 1994; Yarov-Yarovoy et al., 2002). Hydrophobic amino acid
residues near the center and the intracellular end of the S6 segment
may interact directly with bound local anesthetics (Figure 20–3).
Experimental mutation of a large hydrophobic amino acid residue
(isoleucine) to a smaller one (alanine) near the extracellular end of
this segment creates a pathway for access of charged local anesthetic
drugs from the extracellular solution to the receptor site. These findings
place the local anesthetic receptor site within the intracellular
half of the transmembrane pore of the Na + channel, with part of its
structure contributed by amino acids in the S6 segments of domains
I, III, and IV.
Frequency- and Voltage-Dependence of Local
Anesthetic Action. The degree of block produced by a
given concentration of local anesthetic depends on how
the nerve has been stimulated and on its resting membrane
potential. Thus, a resting nerve is much less sensitive
to a local anesthetic than one that is repetitively
stimulated; higher frequency of stimulation and more
positive membrane potential cause a greater degree of
anesthetic block. These frequency- and voltage-dependent
effects of local anesthetics occur because the local anesthetic
molecule in its charged form gains access to its
binding site within the pore only when the Na + channel
is in an open state and because the local anesthetic
binds more tightly to and stabilizes the inactivated state
of the Na + channel (Butterworth and Strichartz, 1990;
Courtney and Strichartz, 1987). Local anesthetics
exhibit these properties to different extents depending
on their pK a
, lipid solubility, and molecular size. In general,
the frequency dependence of local anesthetic
action depends critically on the rate of dissociation
from the receptor site in the pore of the Na + channel. A
high frequency of stimulation is required for rapidly
dissociating drugs so that drug binding during the
action potential exceeds drug dissociation between
action potentials. Dissociation of smaller and more
hydrophobic drugs is more rapid, so a higher frequency
of stimulation is required to yield frequency-dependent
block. Frequency-dependent block of ion channels is
most important for the actions of antiarrhythmic drugs
(Chapter 29).
Differential Sensitivity of Nerve Fibers to Local
Anesthetics. Although there is great individual variation,
for most patients treatment with local anesthetics
causes the sensation of pain to disappear first, followed
by loss of the sensations of temperature, touch, deep
pressure, and finally motor function (Table 20–1).
Classical experiments with intact nerves showed that
the δ wave in the compound action potential, which represents
slowly conducting, small-diameter myelinated
fibers, was reduced more rapidly and at lower concentrations
of cocaine than was the α wave, which represents
rapidly conducting, large-diameter fibers (Gasser
and Erlanger, 1929). In general, autonomic fibers, small
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CHAPTER 20
LOCAL ANESTHETICS