Local Anesthetic Toxicity—Overview
Local anesthetics are amphipathic chemicals, meaning they have affinity for both lipid and water environments. This characteristic allows local anesthetics to cross plasma membrane and intracellular membranes quickly and also to interact with charged targets such as structural or catalytic proteins and signaling systems. Therefore, local anesthetics produce a variety of toxic effects in several tissue types, mainly heart, brain and skeletal muscle.
While the main site of both the clinically desirable and toxic effects of local anesthetics are thought to be exerted at the voltage gated sodium channel, many alternative sites have also been considered recently. Notably, the most potent, toxic local anesthetics, such as bupivacaine, interrupt practically every metabotropic and ionotropic signal transduction scheme that has been studied. Bupivacaine in particular has also been shown to disrupt each of the four components of oxidative phoshphorylation: substrate transport, electron transport, proton motive force maintenance and ATP synthesis. An interesting observation that suggests the importance of this effect in bupivacaine-induced toxicity is that the pattern of tissues affected includes those with the highest aerobic demand and least tolerance for hypoxia. Consider that local anesthetic toxicity typically presents as seizures followed by cardiac arrhythmias and hypotension, a clinical picture that would be expected for a toxin that targets mitochondrial metabolism.