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

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CHAPTER 20
Figure 20–3. The local anesthetic receptor site. A. A drawing of the pore structure of a bacterial K + channel (KcsA), which is related
to the sodium channel. The KcsA channel has two transmembrane segments, analogous to the S5 and S6 segments of sodium channels.
The S6-like segment forms the walls of the inner pore while the P loop forms the narrow ion selectivity filter at its extracellular
(top) end. Four separate KcsA subunits form the pore in their center; only two of the subunits are shown here. B. A structural model
of the local anesthetic receptor site. The S6 segments from domains I, III, and IV of the sodium channel α subunit are illustrated, based
on the structure of the KcsA channel (panel A). The amino acid residues in these three transmembrane segments that contribute to the
local anesthetic receptor site are indicated in single letter code and are presented in space-filling representation (light blue). An etidocaine
molecule (black) is illustrated bound in the receptor site. Substitutions of the light blue residues with alanine reduce the affinity
for local anesthetic block of sodium channels. It therefore is likely that the side chains of these amino acid residues contact bound
local anesthetics in their receptor site. I1760 and I409 likely form the outer boundary of the local anesthetic receptor site. Mutations
of I1760 allow drug access to the receptor site from the extracellular side. (This figure was originally published in the Journal of
Biological Chemistry. Yarov-Yarovoy V, McPhee JC, Idsvoog D, Pate C, Scheuer T, Catterall WA: Role of amino acid resides in transmembrane
segments IS6 and IIS6 of the Na + channel alpha subunit in voltage-dependent gating and drug block. J Biol Chem 2002:277,
35393. © the American Society for Biochemistry and Molecular Biology.)
LOCAL ANESTHETICS
unmyelinated C fibers (mediating pain sensations), and
small myelinated Aδ fibers (mediating pain and temperature
sensations) are blocked before the larger
myelinated Aγ, Aβ, and Aα fibers (mediating postural,
touch, pressure, and motor information) (Raymond and
Gissen, 1987). The differential rate of block exhibited
by fibers mediating different sensations is of considerable
practical importance in the use of local anesthetics.
The precise mechanisms responsible for this apparent specificity
of local anesthetic action on pain fibers are not known, but several
factors may contribute. The initial hypothesis from the classical
work on intact nerves was that sensitivity to local anesthetic block
increases with decreasing fiber size, consistent with high sensitivity
for pain sensation mediated by small fibers and low sensitivity for
motor function mediated by large fibers (Gasser and Erlanger, 1929).
However, when nerve fibers are dissected from nerves to allow direct
measurement of action potential generation, no clear correlation of
the concentration dependence of local anesthetic block with fiber
diameter is observed (Fink and Cairns, 1984; Franz and Perry, 1974;
Huang et al., 1997). Therefore, it is unlikely that the fiber size per se
determines the sensitivity to local anesthetic block under steady-state
conditions. However, the spacing of nodes of Ranvier increases with
the size of nerve fibers. Because a fixed number of nodes must be
blocked to prevent conduction, small fibers with closely spaced
nodes of Ranvier may be blocked more rapidly during treatment of
intact nerves, because the local anesthetic reaches a critical length of
nerve more rapidly (Franz and Perry, 1974). Differences in tissue
barriers and location of smaller C fibers and Aδ fibers in nerves also
may influence the rate of local anesthetic action.
Effect of pH. Local anesthetics tend to be only slightly
soluble as unprotonated amines. Therefore, they generally
are marketed as water-soluble salts, usually
hydrochlorides. Inasmuch as the local anesthetics are
weak bases (typical pK a
values range from 8-9), their
hydrochloride salts are mildly acidic. This property
increases the stability of the local anesthetic esters and
the catecholamines added as vasoconstrictors. Under
usual conditions of administration, the pH of the local
anesthetic solution rapidly equilibrates to that of the
extracellular fluids.
Although the unprotonated species of the local anesthetic is
necessary for diffusion across cellular membranes, it is the cationic