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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