Neurophysiologic Aspects of Phasic Inhibition

Different fiber types in the nerve are affected differently during local anesthesia. At least part of this difference arises from pharmacokinetic factors. At the onset and during recovery from clinical block, in particular, longitudinal and radial diffusion of drug will produce concentration variations within and along the nerve. This variation is superimposed on the dynamic use-dependent inhibition to provide variable propagation that depends on a fiber's geometry, position within the nerve, and functional as well as electrophysiologic properties.

Different fiber types are also differentially sensitive to local anesthetic blockade. In vivo experiments involving equilibration of local anesthetics by continuous superfusion of peripheral nerves, as well as experiments using percutaneous bolus injection analogous to clinical peripheral nerve block, show unequivocally that small myelinated axons (Aγ motor and Aδ sensory fibers) are the most susceptible to impulse annihilation. Next in order of block are the large myelinated (Aα and Aβ) fibers, and the least susceptible are the small, nonmyelinated C fibers. In fact, among this last group, impulses in the slowest conducting population (conduction velocity = 0.5 to 0.8 msec^-1 ) are the most resistant to local anesthetic.^[26] The generalized notion "that local anesthetics block the smallest fibers first or most" is clearly wrong.

Selective Susceptibility of Na⁺ Channel Isoforms

Ten different Na⁺ channels have been physiologically identified and biochemically sequenced. At least four of them are found in peripheral neurons, some exclusively associated with nociceptive afferents. Obviously, it would be clinically advantageous to selectively inhibit these channels and thus prevent or reduce pain while sparing other functions. Unfortunately, as of this writing (2003), no such selective compounds have been reported, either because the local anesthetic pharmacophore is too similar among the different channel isoforms or because the same drug features that favor inhibition of "therapeutic" target channels also result in blockade of "toxic" target channels (e.g. cardiac Na⁺ channels).

On the other hand, the aberrant impulses that are often considered the hallmark of various diseases of excitable membranes, such as abnormal repetitive firing in neuropathic pain from sites of peripheral nerve injury, are unusually susceptible and are abolished by systemic lidocaine doses that do not block normal propagating impulses. The conditions for such sensitivity to these local anesthetics (i.e., lidocaine) appear to result from the

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Figure 14-9 Structural features of the Na⁺ channel that determine local anesthetic (LA) interactions. A, Consensus arrangement of the single peptide of the Na⁺ channel α-subunit in a plasma membrane. Four domains with homologous sequences (D-1 through D-4) each contain six α-helical segments that span the membrane (S1 to S6). Each domain folds within itself to form one cylindrical bundle of segments, and these bundles converge to form the functional channel's quaternary structure (B). Activation gating that leads to channel opening results from primary movement of the positively charged S4 segments in response to membrane depolarization (see panel C). Fast inactivation of the channel follows binding to the cytoplasmic end of the channel of part of the small loop that connects D-3 to D-4. Ions travel through an open channel along a pore defined at its narrowest dimension by the P region formed by partial membrane penetration of the four extracellular loops of protein connecting S5 and S6 in each domain. Intentional, directed mutations of different amino acids on the channel indicate residues that are involved in LA binding in the inner vestibule of the channel (X, on S6 segments) and at the interior regions of the ion-discriminating "selectivity filter (, square, on the P region), and they are also known to influence stereoselectivity for phasic inhibition (O, also on S6 segments). C, Schematic cross section of the channel speculating on the manner in which S6 segments, which form a "gate," may realign during activation to open the channel and allow entry and departure of a bupivacaine molecule by the "hydrophilic" pathway. The closed (inactivated) channel has a more intimate association with the LA molecule, whose favored pathway for dissociation is no longer between S6 segments (the former pore), but now, much more slowly, laterally between segments and then through the membrane, the "hydrophobic" pathway. Na⁺ ions entering the pore will compete with the LA for a site in the channel, and H⁺ ions, which pass very slowly through the pore, can enter and leave from the extracellular opening, thereby protonating and deprotonating a bound LA molecule and thus regulating its rate of dissociation from the channel.