Mechanism of Action of Local Anesthetics on Sodium Channels
Local anesthetics work by blocking voltage-gated sodium channels in nerve cell membranes, preventing sodium ion influx and thereby inhibiting the generation and conduction of action potentials along nerve fibers. 1, 2
Primary Mechanism: Sodium Channel Blockade
Local anesthetics inhibit voltage-gated sodium channels at the cell membrane, which limits action potential generation and blocks nerve signal conduction. 1 This blockade affects the membrane potential by reducing sodium passage through these channels, reversibly blocking both the generation and conduction of sensory nerve impulses. 2
Dual Pathway Access to the Sodium Channel
Local anesthetics can reach their binding site through two distinct pathways:
Charged (ionized) form: The protonated, positively charged form of local anesthetics accesses a receptor site within the aqueous pore of the sodium channel from the intracellular (axoplasmic) surface of the membrane. 3 This binding site is only accessible when the channel gate is open, meaning charged anesthetics preferentially bind to open and inactivated channel states. 3
Uncharged (neutral) form: The free base, lipid-soluble form penetrates through the lipid bilayer of the membrane itself, bypassing the channel gates entirely to reach the binding site. 3 This pathway allows access regardless of channel state.
State-Dependent Binding
Local anesthetics exhibit state-dependent blockade, binding with higher affinity to open and/or inactivated states of the sodium channel compared to resting closed states. 4 This property explains why local anesthetics are more effective at blocking rapidly firing nerves (use-dependent block).
Effects on Channel Gating Mechanisms
Beyond simple pore occlusion, local anesthetics modify the voltage-sensing apparatus of sodium channels:
Charged anesthetics interfere with the normal "gating" mechanism of the channel after binding to their receptor site. 3
Local anesthetics can either enhance or inhibit the normal inactivation mechanism of sodium channels, depending on the specific agent. 3
Lidocaine and QX-314 shift the voltage-sensing segments of domain III by 57-65 mV in the hyperpolarizing direction, while shifting domain I in the depolarizing direction, indicating disruption of energetic coupling between voltage sensors. 4
Additional Ion Channel Effects
While sodium channel blockade is the primary mechanism, local anesthetics also affect other ion channels:
Potassium channels: Local anesthetics potently inhibit background tandem pore domain potassium channels (TASK-2), with bupivacaine showing IC50 values of 17 μM for R-(+)-bupivacaine and 43 μM for S-(-)-bupivacaine. 5 This inhibition causes membrane depolarization and may enhance conduction blockade. 5
Cardiac effects: In addition to sodium channel blockade, local anesthetics cause stereospecific inhibition of intracardiac conduction and nonspecific inhibition of myocardial energy supply and other ion channels. 6
Clinical Implications of Systemic Toxicity
When local anesthetics reach systemic circulation in toxic concentrations, the same sodium channel blockade that produces anesthesia causes life-threatening complications:
CNS toxicity: Initial selective blockade of cortical inhibitory neurons enables seizure formation, followed by blockade of excitatory neurons causing coma and respiratory depression at higher concentrations. 6
Cardiac toxicity: Sodium channel blockade in cardiac tissue leads to conduction delays, QRS prolongation, arrhythmias, and potentially refractory cardiac arrest. 1, 7 Bupivacaine is particularly cardiotoxic due to its high lipid solubility and strong sodium channel binding. 1, 7
Pharmacokinetic Factors Affecting Mechanism
The FDA notes that bupivacaine has 95% plasma protein binding, high lipid solubility, and readily crosses biological membranes in its nonionized form. 8 These properties influence both therapeutic efficacy and toxicity potential, as only free, unbound drug is available for sodium channel interaction. 8