FIGURE 26–3 Effect of repetitive activity on the block of sodium current produced by a local anesthetic in a myelinated axon. A series of 25 pulses was applied, and the resulting sodium currents (downward deflections) are superimposed. Note that the current produced by the pulses rapidly decreased from the first to the 25th pulse. A long rest period after the train resulted in recovery from block, but the block could be reinstated by a subsequent train. nA, nanoamperes. (Adapted, with permission, from Courtney KR: Mechanism of frequency-dependent inhibition of sodium currents in frog myelinated nerve by the lidocaine derivative GEA. J Pharmacol Exp Ther 1975;195:225.) 4. Other effects—Currently used local anesthetics bind to the sodium channel with low affinity and poor specificity, and there are multiple other sites for which their affinity is nearly the same as that for sodium channel binding. Thus, at clinically relevant concentrations, local anesthetics are potentially active at countless other channels (eg, potassium and calcium), enzymes (eg, adenylyl cyclase, carnitine-acylcarnitine translocase), and receptors (eg, N-methyl-d-aspartate [NMDA], G protein-coupled, 5-HT3, neurokinin-1 [substance P receptor]). The role that such ancillary effects play in achievement of local anesthesia appears to be important but is poorly understood. Further, interactions with these other sites are likely the basis for numerous differences between the local anesthetics with respect to anesthetic effects (eg, differential block) and toxicities that do not parallel anesthetic potency, and thus are not adequately accounted for solely by blockade of the voltage-gated sodium channel.
The actions of circulating local anesthetics at such diverse sites exert a multitude of effects, some of which go beyond pain control, including some that are also potentially beneficial. For example, there is evidence to suggest that the blunting of the stress response and improvements in perioperative outcome that may occur with epidural anesthesia derive in part from an action of the anesthetic beyond its sodium channel block. Circulating anesthetics also demonstrate antithrombotic effects having an impact on coagulation, platelet aggregation, and the microcirculation, as well as modulation of inflammation.
B. Structure-Activity Characteristics of Local Anesthetics
The smaller and more highly lipophilic local anesthetics have a faster rate of interaction with the sodium channel receptor. As previously noted, potency is also positively correlated with lipid solubility. Lidocaine, procaine, and mepivacaine are more water soluble than tetracaine, bupivacaine, and ropivacaine. The latter agents are more potent and have longer durations of local anesthetic action. These long-acting local anesthetics also bind more extensively to proteins and can be displaced from these binding sites by other protein-bound drugs. In the case of optically active agents (eg, bupivacaine), the R(+) isomer can usually be shown to be slightly more potent than the S(–) isomer (levobupivacaine).
C. Neuronal Factors Affecting Block 1.