Molecular Mechanisms of Local Anesthetic Toxicity: From Ion Channel Dysregulation to Mitochondrial Dysfunction and Tissue-Specific Injury

Local anesthetics are widely used across local and regional anesthesia, pain medicine, emergency care, and dentistry. Their therapeutic effect is based mainly on reversible voltage-gated sodium channel inhibition, but toxicity is not limited to this mechanism. This narrative review integrates molecular evidence on systemic and tissue-specific local anesthetic toxicity. Bupivacaine remains the prototypical cardiotoxic agent, reflecting the convergence of high lipophilicity, persistent cardiac ion channel effects, myocardial accumulation, impaired mitochondrial bioenergetics, altered fatty acid metabolism, calcium dyshomeostasis, and membrane-level injury. Across experimental and translational models, local anesthetics may also induce broad cytotoxicity in various cell types. These effects are primarily concentration- and exposure time-dependent and are modified by route, tissue perfusion, local clearance, metabolic reserve, developmental or physiological vulnerability, and repair capacity. Current experimental, translational, and stem cell-based models provide mechanistic insight but cannot be interpreted as direct clinical dose equivalents. Future studies should link drug type, concentration, formulation, route, exposure duration, patient vulnerability, and tissue-specific outcomes to improve route-specific safety assessment.