Local anesthesia is induced when propagation of action potentials is prevented, so that sensation cannot be transmitted from the source of stimulation to the brain. Local anesthetics work by blocking sodium ion channels to prevent the transient increase in permeability of the nerve membrane to sodium that is required for an action potential to occur. They cause depolarization Local anesthetics gain access to their receptors from the cytoplasm or the membrane. 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. 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.