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 from the cytoplasm or the membrane (Figure 26–1). 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 follows the same rules of use dependence and voltage dependence that were described for the sodium channel-blocking antiarrhythmic drugs (see Chapter 14). In particular, if other factors are equal, rapidly firing fibers are usually blocked before slowly firing fibers. High concentrations of extracellular K+ may enhance local anesthetic activity, whereas elevated extracellular Ca2+ may antagonize it.