Editing Local anesthetic (section)

== Mechanism of action ==
All LAs are [[Plasma membrane|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, not all are used as LAs ([[propranolol]], for example, though it has LA properties).
LA drugs act mainly by inhibiting [[sodium]] influx through sodium-specific [[ion channel]]s in the [[neuron]]al [[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 an activated state, thus onset of neuronal blockade is faster in rapidly firing neurons. This is referred to as state-dependent blockade.

LAs are weak [[base (chemistry)|bases]] and are usually formulated as the hydrochloride salt to render them water-soluble. At a pH equal to the protonated base's pKa, the protonated (ionized) and unprotonated (unionized) forms of the molecule exist in equimolar amounts, but only the unprotonated base 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 LA binding site on the inside of the ion channel near the cytoplasmic end. Most LAs work on the internal surface of the membrane - the drug has to penetrate the cell membrane, which is achieved best in the nonionised form. This is exemplified by the permanently ionised LA [[RAC 421-II]] which cannot [[diffusion|diffuse]] across the cell membrane but, if injected into the cytosol of a nerve fibre, can induce NaKATPase blockage and anesthetic effects.

Acidosis such as caused by inflammation at a wound partly reduces the action of LAs. 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.

===Sensitivity of nerve fibers to local anesthetics===
For most patients, administration of local anesthetics causes the sensation of pain to be lost first, followed by temperature, touch, deep pressure, and finally motor function.<ref name=Catterall2023>{{cite book | vauthors = Catterall WA, Mackie K | date = 2023 | chapter = Local Anesthetics | veditors = Brunton LL, Knollmann BC | title = Goodman & Gilman's: The Pharmacological Basis of Therapeutics | edition = 14th | publisher = McGraw Hill | chapter-url = https://accessanesthesiology.mhmedical.com/content.aspx?bookid=3191&sectionid=268045025 | isbn =  978-1-264-25807-9 }}</ref> The sensitivity of nerve fibers to blockade depends on a combination of diameter and myelination. Their different sensitivities to LA blockade is termed differential blockade. Myelinated fibers are more sensitive to blockade as they are interrupted by [[nodes of Ranvier]], thus interruption of only consecutive nodes of Ranvier will prevent action potential propagation. In turn, in unmyelinated nerves, an entire length needs to be blocked.<ref name=Piehl2015>{{cite book | vauthors = Piehl E, Bucklin BA | date = 2015 | chapter = Drugs commonly used in obstetric anesthesia. | veditors = Santos AC, Epstein JN, Chaudhuri K | title = Obstetric Anesthesia | publisher = McGraw Hill | chapter-url = https://accessanesthesiology.mhmedical.com/content.aspx?bookid=1364&sectionid=82007590 | isbn = 978-0-07-178613-3 }}</ref> Regarding diameter, the generally accepted principle is that susceptibility to local anesthesia depends inversely on fiber diameter.<ref name=Gretchen2001>{{cite journal | vauthors = Henkel G | title = Susceptibility of Nerve Fibers to Local Anesthesia:"Size Principle" Challenged. | journal = The Journal of the American Society of Anesthesiologists | date = December 2001 | volume = 95 | issue = 6 | pages = 5A–6A | doi = 10.1097/00000542-200112000-00003 }}</ref>

In general, autonomic fibers [[Group B nerve fiber|Type B fibers]], small unmyelinated [[Group C nerve fiber|type C]] (pain sensation), and small myelinated [[Group A nerve fiber|Aδ fibers]](pain and temperature sensations) are blocked before the larger myelinated Aγ, Aβ, and Aα fibers (mediating postural, touch, pressure, and motor information).<ref  name=Catterall2023/>