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Old 05-10-2010
Dr.MonMon's Avatar
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Drug Mechanism of Local Anesthetics

Hello dear colleagues,

While studying from Kaplan and Reviewing from FA, I encountered some information that is rather confusing to me.

In Kaplan (Pharmacology), it is stated that the mechanism of action of local anesthetics is to block the inactivated Na+ channels (pg. 147), while in FA it is stated that the mechanism of action is by binding to activated Na+ channels (pg. 411).

If anyone has an input it would be very much appreciated.

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Old 05-12-2010
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Arrow They block the activated channels

All local anesthetics are membrane stabilizing drugs; they reversibly decrease the rate of depolarization and repolarization of excitable membranes (like nociceptors). Though many other drugs also have membrane stabilizing properties, all are not used as local anesthetics, for example propranolol. Local anesthetic drugs act mainly by inhibiting sodium influx through sodium-specific ion channels in the neuronal cell membrane, in particular the so-called voltage-gated sodium channels. When the influx of sodium is interrupted, an action potential cannot arise and signal conduction is inhibited. The receptor site is thought to be located at the cytoplasmic (inner) portion of the sodium channel. Local anesthetic drugs bind more readily to sodium channels in activated state, thus onset of neuronal blockade is faster in neurons that are rapidly firing. This is referred to as state dependent blockade.
Local anesthetics are weak bases and are usually formulated as the hydrochloride salt to render them water-soluble. At the chemical's pKa the protonated (ionized) and unprotonated (unionized) forms of the molecule exist in an equilibrium but only the unprotonated molecule diffuses readily across cell membranes. Once inside the cell the local anesthetic will be in equilibrium, with the formation of the protonated (ionized form), which does not readily pass back out of the cell. This is referred to as "ion-trapping". In the protonated form, the molecule binds to the local anesthetic binding site on the inside of the ion channel near the cytoplasmic end.
Acidosis such as caused by inflammation at a wound partly reduces the action of local anesthetics. This is partly because most of the anesthetic is ionized and therefore unable to cross the cell membrane to reach its cytoplasmic-facing site of action on the sodium channel.
All nerve fibers are sensitive to local anesthetics, but generally, those with a smaller diameter tend to be more sensitive than larger fibers. Local anesthetics block conduction in the following order: small myelinated axons (e.g. those carrying nociceptive impulses), non-myelinated axons, then large myelinated axons. Thus, a differential block can be achieved (i.e. pain sensation is blocked more readily than other sensory modalities).
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Dr.MonMon (05-12-2010), erickven (03-08-2016), neel patel (06-15-2016), venky2600 (09-20-2012)


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