Summary of Local Anesthetic Mechanisms

Impulse blockade by local anesthetics may be summarized by the following chronology^[4] :

1. Solutions of local anesthetic are deposited near the nerve. Diffusion of drug molecules away from this locus is a function of tissue binding, removal by the circulation, and local hydrolysis of aminoester anesthetics. The net result is penetration of the nerve sheath by the remaining drug molecules.
2. Local anesthetic molecules then permeate the nerve's axon membranes and reside there and in the axoplasm. The speed and extent of these processes depend on a particular drug's pK_a and the lipophilicity of its base and cation species.
3. Binding of local anesthetic to sites on voltage-gated Na⁺ channels prevents opening of the channels by inhibiting the conformational changes that underlie channel activation. Local anesthetics bind in the channel's pore and also occlude the path of Na⁺ ions.

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4. During onset and recovery from local anesthesia, impulse blockade is incomplete, and partially blocked fibers are further inhibited by repetitive stimulation, which produces an additional, use-dependent binding to Na⁺ channels.
5. One local anesthetic binding site on the Na⁺ channel may be sufficient to account for the drug's resting (tonic) and use-dependent (phasic) actions. Access to this site may potentially involve multiple pathways, but for clinical local anesthetics, the primary route is the hydrophobic approach from within the axon membrane.
6. The clinically observed rates of onset and recovery from blockade are governed by the relatively slow diffusion of local anesthetic molecules into and out of the whole nerve, not by their much faster binding and dissociation to ion channels.

Figure 14-10 Spontaneous ectopic impulses in "abnormal" nerves are blocked by very low concentrations of local anesthetics. When 10% to 20% of the Na⁺ channels close very slowly, as caused here by the addition of a peptide neurotoxin (ATX), but otherwise an intrinsic property of channels that are upregulated after nerve injury, spontaneous impulses appear (trace B). Occurring as bursts of action potentials separated by quiet periods, these impulses appear similar to the ectopic discharges in a peripheral nerve after injury. Very low concentrations of lidocaine, equal to plasma levels during intravenous infusions that can reverse neuropathic pain, strongly suppress (C) and eventually abolish (D) these spontaneous discharges, an effect that is reversed when lidocaine is removed from the nerve (E). In contrast, electrically stimulated action potentials are unaffected by such low lidocaine concentrations (e.g., see Fig 14-8B ). (From Persaud N, Strichartz G: Micromolar lidocaine selectively blocks propagating ectopic impulses at a distance from their site of origin. Pain 99:333–340, 2002.)

A clinically effective block that may last for hours can be achieved with local anesthetic drugs that dissociate from Na⁺ channels in a few seconds.