Molecular Mechanisms of Local Anesthetic Toxicity: From Ion Channel Dysregulation to Mitochondrial Dysfunction and...

Area of Science:

• Pharmacology
• Toxicology
• Anesthesiology

Background:

• Local anesthetics (LAs) are essential in anesthesia, pain management, and dentistry, primarily acting via sodium channel blockade.
• LA toxicity extends beyond sodium channel inhibition, involving complex molecular and cellular mechanisms.
• Understanding systemic and tissue-specific toxicity is crucial for safe clinical application.

Purpose of the Study:

• To review and integrate molecular evidence on the mechanisms of systemic and tissue-specific local anesthetic toxicity.
• To elucidate the factors influencing local anesthetic toxicity, including drug properties and patient-specific variables.
• To identify gaps in current research and suggest future directions for improving safety assessments.

Main Methods:

• This study is a narrative review integrating molecular evidence from experimental, translational, and stem cell-based models.
• It synthesizes data on the mechanisms underlying local anesthetic toxicity across various cell types and tissues.
• Focuses on bupivacaine as a model cardiotoxic agent.

Main Results:

• Bupivacaine exemplifies cardiotoxicity due to lipophilicity, persistent ion channel effects, myocardial accumulation, and mitochondrial dysfunction.
• Local anesthetics can induce broad cytotoxicity in various cell types, primarily dependent on concentration and exposure time.
• Toxicity is modulated by administration route, tissue perfusion, metabolism, and patient vulnerability.

Conclusions:

• Local anesthetic toxicity involves multifaceted molecular pathways beyond sodium channel blockade.
• Current models offer mechanistic insights but direct clinical dose extrapolation is not feasible.
• Future research must correlate drug specifics, exposure parameters, and patient factors with tissue-specific outcomes for improved safety.