Intravascular injection of 3 mg/kg of bupivacaine causes cardiovascular toxicity that is more refractory to resuscitation than that of lignocaine. What is the primary mechanism responsible for bupivacaine's enhanced cardiotoxicity?

• A Bupivacaine is 1000-fold more potent than lignocaine at alpha-adrenergic receptors
• B Bupivacaine binds mitochondrial calcium channels causing irreversible cardiomyocyte calcium overload
• C Bupivacaine has twice the half-life of lignocaine due to higher plasma protein binding
• D Bupivacaine causes irreversible inhibition of cardiac Na+ channels as it does not dissociate during diastole ✓

Explanation

Bupivacaine's severe cardiotoxicity is due to its high lipid solubility and strong binding to inactivated (closed) cardiac sodium channels — it follows 'fast in, slow out' kinetics, meaning it dissociates from Na+ channels very slowly during diastole (unlike lignocaine which rapidly dissociates). This results in accumulation during repeated cardiac cycles causing progressive conduction block, re-entrant arrhythmias, and ventricular fibrillation. Additionally, bupivacaine inhibits mitochondrial fatty acid oxidation in cardiomyocytes, contributing to direct myocardial depression. This is why lipid emulsion therapy (lipid sink hypothesis) is the rescue treatment for LAST.

Reference: Morgan & Mikhail's Clinical Anesthesiology, 6th ed.

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