Local anesthetics block voltage-dependent sodium channels and
reduce the influx of sodium ions, thereby preventing depolarization
of the membrane and blocking conduction of the action potential.
Local anesthetics gain access to their receptors on the channels
from the cytoplasm or the membrane (Figure 16–2). Because
the drug molecule must cross the lipid membrane to reach the cytoplasm,
the more lipid-soluble (nonionized, uncharged) form reaches effective
intracellular concentrations more rapidly than does the ionized
form. On the other hand, once inside the axon, the ionized (charged)
form of the drug is the more effective blocking entity. Thus, both
the nonionized and the ionized forms of the drug play important
roles, the first in reaching the receptor site and the second in
causing the effect. The affinity of the receptor site within the
sodium channel for the local anesthetic is a function of the state
of the channel, whether it is resting, open, or inactivated, and
therefore is both voltage- and time-dependent, following the same
rules of sodium channel blocking as antiarrhythmic drugs (Chapter 10). More rapidly firing nerve fibers (e.g., sensory fibers) are
usually blocked before more slowly firing fibers (e.g., motor fibers).