LOCAL ANESTHETICS: BASIC SCIENCE


When applied to peripheral nerves, local anesthetics reversibly inhibit signal transmission by blocking sodium influx via membrane sodium channels. The agents used are marketed as water-soluble hydrochloride salts. In an aqueous solution, the local anesthetic's fixed dissociation constant (pka) determines the equilibrium between the charged local anesthetic cation and the uncharged base. It is the uncharged base that freely diffuses through the lipid bilayer of neurons. After crossing a neuron's lipid bilayer the local anesthetic molecule again dissociates into its basic and cationic forms with the uncharged cation entering the protein based sodium channel. It is the presence of the local anesthetic molecule within the ion channel that renders the channel impermeable to sodium, thus preventing the propagation of action potentials and impulse conduction. With time, the local anesthetic diffuses out of the channel rendering the neurons once again susceptible to depolarization.

All local anesthetics in clinical use consist of a benzene ring connected to a hydrocarbon chain; the linkage can be an ester or amide. This distinction between ester and amide may seem arcane, but it is of clinical value because allergic reactions can occur, quite frequently, with esters, whereas allergic reactions to amides are extremely rare. Esters such as benzocaine and procaine break down to structures similar to PABA (p-amino benzoic acid), a common component of cosmetics and sunscreens, and should be avoided in patients with known sensitivity to such compounds.

The lipid solubility is usually quite high, but is pH-dependent, with high pH favoring increased lipid solubility, anesthetic potency and speed of onset. Ester-linked anesthetics are: tetracaine, procaine, 2-chloroprocaine and cocaine. Amide-linked anesthetics include bupivacaine, mepivacaine, prilocaine, etidocaine, ropivacaine and lidocaine. Substitutions on the benzene ring or tertiary amine portion of the local anesthetic molecule alters its pka, lipid solubility and protein binding, determining respectively the speed of onset, potency and duration of action.