and all neurons in the central nervous system (CNS). Thus the actions of these compounds can be restricted by administering them locally. Certain practical pharmacokinetic properties make these agents particularly useful in temporarily blocking the sensory transmission of pain impulses. The greatest advantage of local anesthetics is their reversibility—that is, once the drug is eliminated by metabolism, diffusion from its injection site, or excreted, the nerve resumes normal function. There are generally no long-term consequences from the use of local anesthetics. Thus these drugs are highly effective in providing regional or localized reversible pain relief.

The molecular targets for local anesthetics are the voltage-gated sodium channels (VGSCs), which exist in all neurons. These channels are responsible for producing the regenerative action potentials that occur along axons and carry messages from cell bodies to nerve terminals. VGSCs are usually closed at normal resting membrane potentials, which prevents the high concentration of Na⁺ in the extracellular fluid from entering the cell. When membranes are depolarized, these channels open and allow Na⁺ to flow into the cell down its concentration gradient. This influx of positively charged ions leads to further depolarization, causing more channels to open and leading to a self-regenerating action potential. Sustained depolarization causes:

• Spontaneous inactivation of VGSC, which shuts off Na⁺ influx

• Concurrent opening of voltage-gated K⁺ channels

The resultant K⁺ efflux through these and non–voltage-gated K⁺ channels returns the membrane potential to its normal resting value. This mechanism is depicted in Figure 13-1.

FIGURE 13–1 Sequence of events occurring during an action potential.

The cellular physiological mechanism by which local anesthetics block the conduction of nerve impulses is well understood. These drugs bind selectively to VGSCs at the intracellular surface of the channel pore near the pore’s vestibule and thereby block the pathway for Na⁺ and prevent the channels from opening (Fig. 13-2). By blocking Na⁺ influx, these drugs prevent the depolarization necessary for action potential propagation and, at sufficient concentrations, block impulse conduction. Because local anesthetics dissociate from the VGSC very rapidly, once drug administration is stopped, the drug diffuses away from the nerve and/or is absorbed by the local circulation, and impulse activity is restored.

FIGURE 13–2 Transmission of nerve impulses under normal conditions and its prevention in the presence of a local anesthetic agent (producing nerve block).

The ability of local anesthetics to block VGSC is highly dependent on the activity (or state) of the channel. Na⁺ channels exist in three major states (Fig.13-3). In the resting closed state, the channels do not allow Na⁺ influx and are highly sensitive to depolarization-induced opening. In the open state, the channels allow Na⁺ influx, whereas in the inactivated closed state, they do not allow Na⁺ influx and are not opened by depolarization. Local anesthetics have different potencies for binding to these different states. They are much more likely to bind when the channels are active, open, or inactivated and are less likely to bind to the resting state. This modulation of affinity is called activity (or state) dependence and has great practical importance. Because local anesthetics preferentially block nerves in which Na⁺ channels are open or inactivated (activity-dependent), they are more potent in rapidly firing nerves than in nerves in which action potentials occur less frequently. Because sensory neurons fire at greater frequencies in response to more intense noxious stimuli, the effectiveness of impulse blockade is greater under these conditions.

FIGURE 13–3 Unidirectional nature of axonal impulse conduction. Na⁺ channels are depicted in the resting (A), open (B), or inactivated (C) state. The inactivated channels prevent the depolarization from proceeding in more than one direction.

Pharmacokinetics

The structures of the local anesthetics have a direct bearing on their therapeutic actions (Fig. 13-4). All of these agents contain a hydrophobic group linked by either an ester or an amide bond to a relatively hydrophilic group (usually a tertiary or quaternary amine). This hydrophilic group makes the drug H₂O-soluble, enabling the agent to diffuse to the nerve. The hydrophobic group makes the agent lipid soluble and enables the drug to penetrate the lipid membranes (sheath, perineural tissue, and nerve membrane) to reach its binding site on the inner surface of the VGSC. The more hydrophobic local anesthetics bind more tightly to the channel.