Mechanism of Action

The application of a local anesthetic to a nerve that is actively conducting impulses will inhibit the inward migration of Na+.This elevates the threshold for electrical excitation, reduces the rate of rise of the action potential, slows the propagation of the impulse, and if the drug concentration is sufficiently high, completely blocks conduction. The local anesthetics interfere with the process fundamental to the generation of the action potential, namely, the large, transient voltage-dependent rise in the permeability of the membrane to Na+.

While the physiological basis for the local anesthetic action is known, the precise molecular nature of the process is not completely clear. Almost all local anesthetics can exist as either the uncharged base or as a cation. The uncharged base is important for adequate penetration to the site of action, and the charged form of the molecule is required at the site of action. The cation forms of local anesthetics appear to be required for binding to specific sites in or near the Na+ channels. The presence of the local anesthetic at these sites interferes with the normal passage of Na+ through the cell membrane by stopping a conformational change in the subunits of the voltage-gated Na+ channel.

Studies suggest that the receptor for the local anesthetic is near the inner (axoplasmic) surface of the cell membrane, because quaternary analogues of local anesthetics are quite effective when applied to the inside of the axonal membrane but are inactive when placed on the outside of the membrane. These permanently charged molecules cannot penetrate to the receptor sites.

Nerves that are rapidly depolarizing are inherently particularly susceptible to the effects of local anesthetics. This is termed frequency-dependent blockade and is thought to occur because the local anesthetics get to their receptor sites only when the Na+ channel is open (depolarizing).

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