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Describe the mechanism of action of local anesthetics.
Local anesthetics produce conduction blockade of neural impulses by impairing propagation of the action potential in axons. They interact directly with sodium (Na+) channels in nerve membranes and inhibit the passage of Na+. This does not alter the resting transmembrane potential or threshold potential, but it slows the rate of depolarization such that the threshold potential is not reached and an action potential is not propagated. However, the exact mechanism of how these drugs inhibit Na+ ion influx is still unknown.
Local anesthetic bases are marketed most often as water-soluble hydrochloride salts because they are otherwise poorly soluble in water. The pKa of the drug and the tissue pH determine the amount of drug that exists in solution as free base (lipid-soluble) or as positively charged cation (water-soluble) when injected into tissues. The free base form penetrates across the neural sheath and nerve membrane to reach the nerve axon, where the positively charged cation acts on the Na+ channel.
During onset and recovery from local-anesthetic-induced conduction blockade, some nerve fibers exist in a partially blocked state. Impulse transmission through these fibers is inhibited by repetitive stimulation, which fosters further local anesthetic binding to Na+ channels. This is known as use-dependent binding to Na+ channels. The clin-ically observed rates of onset and recovery from conduction blockade are primarily dependent on slow diffusion of local anesthetic molecules into and out of the nerve.
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