Which property of local anesthetics allows them to block voltage-gated sodium channels?

• A. Ionic form of the hydrophobic group
• B. Hydrophobic base form
• C. Ionic form of the hydrophilic group
• D. Protein binding

Answer: (C)

Local anesthetics block voltage-gated sodium channels by a two-step action: they must cross the neuron's membrane in an uncharged (unionized) form, then inside the cell they become ionized and bind to the intracellular portion of the sodium channel to prevent sodium influx. The form that actually binds and blocks the channel is the ionic (charged) form of the hydrophilic group (the amine). This ionized form interacts with the internal site of the channel, stabilizing it in a nonconducting state and stopping action potential propagation. The other aspects, like the unionized form improving membrane penetration or protein binding influencing duration, are supportive but not the primary blocking mechanism.