Local anaesthetic acts by inhibition of

The nerve resting membrane potential is little affected by local anesthetics. As the concentration of local anesthetic applied to the nerve is increased, a decrease in the rate of depolarization and in the peak amplitude of the action potential occurs until the impulse is abolished. It is not possible, however, to derive data on the binding of local anesthetics to Na+ channels from measurement of the changes in nerve impulses. By using a "voltage-clamp" procedure, Na+ currents and their inhibition by local anesthetics can be directly assayed. When the membrane of isolated neurons is rapidly depolarized to a constant value, the time course of ionic currents is observed. Sodium currents during one initial depolarization are reduced by subclinical doses of local anesthetic (e.g., 0.2mM lidocaine) and totally abolished by clinical doses (e.g., 1% lidocaine, [?]40mM). If the test depolarization is applied repeatedly, for example, at frequencies higher than 5Hz (five pulses per second), the paially depressed (tonically inhibited) Na+ current is fuher reduced incrementally for each pulse until a new steady-state level of inhibition is reached. This frequency-dependent inhibition, also called phasic inhibition. Local anesthetics bind in the inner vestibule of the closed Na+ channel. Amino acid mutations in the S6 segments of D-1, D-3, and D-4 all modify local anesthetic action, thus suggesting either that these regions form a pharmacophore small enough to simultaneously contact the drug at three surfaces or that the local anesthetic molecule moves rapidly among these three segments. X - binding site of LA. Ref: Miller's anesthesia 8th edition Ref: Morgan & Mikhail's clinical anesthesiology 6e