Local anesthetics block the generation and conduction of nerve impulses at the level of the cell membrane. They bind directly within the intracellular portion of voltage-gated sodium channels in their ionized form when the channels are open. The penetration of local anesthetics through the channels depends on the ionized form and therefore their relative hydrophilicity. On the other hand, the local anesthetic diffusion across membrane depends on the molecular weight and the liposolubility of the molecule. Because all local anesthetics have almost the same molecular weight, the diffusibility of the local anesthetic molecules from the injection site depends on their hydrophilicity. The hydrophilic and nonionized form of the molecule is more lipid soluble than the ionized one and can therefore cross the cell membrane more easily but diffuses less easily. Thus, local anesthetics with a higher pKa are more likely to be ionized at physiologic pH than drugs with a lower pKa; therefore, they are typically more potent at the neuronal sites but are also more likely to be absorbed before reaching the neuronal tissue. Moderate hydrophobicity is required for passing through the neuronal sheath.

The choice for a local anesthetic solution is based on the expected onset time, the desired duration of the block, the need to produce a preferential sensory, and the relative toxicity of the mixture. These characteristics are primarily determined by their physicochemical properties, described as follows:

In general, small nerve fibers are more sensitive to local anesthetics than are large nerve fibers. However, myelinated fibers are blocked before nonmyelinated fibers of the same diameter. Autonomic fibers, small unmyelinated C fibers, and small myelinated A-δ fibers are blocked before larger myelinated A-γ, A-β, or A-α fibers. Clinically, the loss of nerve function typically progresses as do loss of pain, temperature, touch, proprioception, and skeletal muscle tone.

There are two classes of local anesthetics: amides and esters (Table 3-1). The primary differences between the two classes are in their relative metabolism (amides have primarily a hepatic metabolism, whereas esters are metabolized by plasma cholinesterases) and their potential for allergic reactions (esters have a greater potential than do amides).

Important differences can be found among local anesthetics within the same class, primarily regarding their onset, duration of action, and potential for toxicity. Clinical characteristics of local anesthetics, onset time, duration of the block, and even toxicity vary significantly according to the type of block, the approach, the concentration of the local anesthetic solution, and the volume administered. Table 3-2 describes the onset time and duration of different nerve blocks with a number of local anesthetic solutions.

Though rare, administration of local anesthetic can produce allergic reactions. These reactions are mostly related to aminoester drugs. The allergic reaction is related to the preservative, the para-aminobenzoic acid. Nonetheless, risk for allergic reactions is present also with aminoamide anesthetic, especially when using formulations containing preservatives or antibacterial additives, like those in multidose preparations.