Mechanism of Action of Bupivacaine
Bupivacaine blocks voltage-gated sodium channels in nerve cell membranes, preventing the generation and conduction of nerve impulses, thereby producing local anesthesia. 1
Primary Mechanism: Sodium Channel Blockade
Bupivacaine reversibly binds to sodium channels to disrupt nerve transmission and block pain signals, functioning as an aminoacyl local anesthetic with an amide linkage between the aromatic nucleus and the piperidine group. 2, 1
The drug exhibits a "foot-in-the-door" voltage-dependent pore block mechanism, physically obstructing the sodium channel pore and preventing sodium ion influx necessary for action potential generation. 3
Bupivacaine is chemically related to lidocaine and mepivacaine but differs from procaine-type local anesthetics which have an ester linkage rather than an amide linkage. 1
Secondary Mechanisms: Multi-Target Effects
NMDA Receptor Inhibition
Bupivacaine inhibits NMDA receptor-mediated synaptic transmission in the dorsal horn of the spinal cord, an area critically involved in central sensitization and chronic pain. 3
The NMDA receptor blockade occurs through both voltage-dependent pore block and allosteric gating effects, decreasing channel open probability by increasing mean closure duration and decreasing mean opening duration. 3
This inhibition is GluN2 subunit-independent and pH-independent, occurring via both extracellular and intracellular inhibitory sites through hydrophilic and hydrophobic pathways. 3
The NMDA receptor effect is state-independent, occurring to the same degree whether bupivacaine is applied before or after glutamate stimulation. 3
Synaptic Transmission Effects
Bupivacaine alters both presynaptic and postsynaptic mechanisms in sympathetic ganglia, producing dose-dependent depression or complete blockade of synaptic transmission. 4
Presynaptic effects include increased latency of axonal conduction (from 11.2 ± 0.9 ms to 16.5 ± 1.4 ms) before complete blockade of presynaptic fiber conduction. 4
Postsynaptic membrane alterations include: decreased membrane resistance (from 40 ± 3 to 32 ± 3 MΩ), increased firing threshold (from 14 ± 0.5 to 18 ± 0.5 mV), and decreased action potential amplitude or complete blockade of action potential generation. 4
Additional Cardiac Effects
Bupivacaine is a more potent cardiotoxin than ropivacaine and lidocaine due to greater affinity and longer binding duration to cardiac sodium channels. 2
The drug may cause reentry dysrhythmias, suppress conduction pathways, and block calcium channels, contributing to its cardiovascular toxicity profile. 2
Clinical Pharmacology
Onset of anesthesia occurs in 4-10 minutes with maximum anesthesia in 15-35 minutes, producing complete sensory anesthesia of integumentary and musculoskeletal systems. 5
Motor blockade ranges from minimal to complete depending on concentration (0.25%, 0.5%, or 0.75%), with 0.75% consistently producing profound muscle relaxation for intra-abdominal surgery. 5
Liposomal formulations (Exparel) encapsulate bupivacaine in biodegradable liposomes providing sustained release over 72-96 hours compared to standard bupivacaine's 8-12 hours, with slower release leading to lower peak plasma concentrations and theoretically reduced systemic toxicity risk. 6
Critical Safety Considerations
Bupivacaine toxicity manifests as early neurologic symptoms (lightheadedness, dizziness, disorientation) progressing to severe cardiovascular effects (hypotension, arrhythmias, cardiac and respiratory arrest). 2
Bupivacaine is known to be more potently toxic than other local anesthetics, particularly regarding cardiotoxicity, though complications from local infiltration are rare. 2
Maximum safe dose is 2.5 mg/kg for plain solutions and up to 3 mg/kg when combined with epinephrine 1:200,000, with doses calculated based on actual body weight in normal-weight patients and ideal body weight in obese patients. 7