Local anesthetics (LAs) block sensory and motor impulses by inhibiting the sodium channels on the nerve cell membranes. This induces temporary loss of sensation, relieving pain in a specific body area.

Local anesthetics are amphiphilic molecules consisting of a hydrophobic aromatic part linked to a hydrophilic group by an ester or amide linkage. They are weak bases and are usually available as salts, which increases their solubility and stability. Once administered, LAs exist in the body either as an uncharged base or a cation. The pKa of LAs and the pH of body fluids govern the relative proportions of these two forms.

The ionization rate of LA is a critical factor in determining its onset of action. The binding site for LA is located in the intracellular domain of sodium channels, and the charged form of LA penetrates the membrane poorly. As a result, the uncharged form of LA is essential for cell penetration. Once inside the cell, the cytoplasmic acidic pH induces the formation of the charged cation. The cationic LA binds strongly to its receptor within the sodium channel in its open state, i.e., when the inactivation gate is open. The bound LA then locks the channel in its inactive conformation, i.e., when the inactivation gate is closed. As a result, it prolongs the blocking of sodium ion influx and produces a clinical effect.

LAs with lower pKa, like lidocaine, are fast acting since a large percentage of LA in its uncharged form is present to penetrate the cell membrane. In contrast, LAs with higher pKa have slow activity.