Mechanism of Action
Local anesthetics (LA) block conduction along nerve pathways by inhibiting the excitatory changes in axon membrane that sustain propagation of the nerve impulse. During depolarization, the major excitatory process is the opening of sodium channels to allow Na+ ions into the nerve. When this local ionic current fails to depolarize a long enough patch of membrane to open enough sodium channels, conduction along the nerve fails. (1)
Nodes of Ranvier
When the active Na+ currents at the node of Ranvier are exposed to a high concentration of LA (sufficient to reduce the Na+ current to zero) only three consecutive nodes of Ranvier of a single myelinated fiber need to be blocked to prevent transmission of the impulse. In a peripheral nerve, however, the inhibition of the Na+ channels at the node of Ranvier is seldom complete and fibers are capable of an attenuated response at clinically realized intraneural LA concentrations. For each sequential node of Ranvier along a nerve, the partial excitatory response is less with a progressive decrement in the action potential. When the attenuated response is too weak to depolarize the next node to threshhold, conduction fails. In order to block conduction under clinical conditions the length of nerve exposed to LA must exceed three nodes of Ranvier. (2)
Sodium Channel
Receptor sites for LA have been postulated within the sodium channel (3). It is accessible to charged LA's only from the cytoplasmic side. Stereoselective inhibition of neuronal sodium channels by LA's suggested the possibility of two sites of action. (4, 5). The sodium channel is a large glycoprotein consisting of four repeating domains, each containing 6 to 8 sequences of amino acids that probably form alpha-helical structures spanning the nerve membrane. The receptor site for LA is on the alpha subunit, probably near the ion-conducting pore. (6). Binding of the LA to the receptor sites prevents the conformational changes of channel activation and, to some degree, also results in occlusion of the ion conductance pathway. (1).
Pregnancy
During pregnancy there is an increase in functional blocking effect in vivo of a given concentration of LA (6, 7). The neural uptake of lidocaine over time in pregnant and non-pregnant rats appears to be the same (8, 9). Hence, the increased potency is probably due to pharmacodynamic, rather than pharmacokinetic, factors.
Conclusion
Local anesthetics inhibit the excitatory changes which result in nerve conduction. LA binds to a receptor on the sodium channel, inhibiting the channel's function so that no sodium current is generated, thereby blocking nerve impulses.
References:
1. Butterworth JF, Strichartz GR Molecular Mechanisms of Local Anesthesia: a review Anesthesiology 72:711-734 1990
2. Raymond SA, Steffensen SC, Gugino LD, Strichartz GR The role of length of nerve exposed to local anesthetics in impulse blocking action Anesth Analg 68:563-70 1989.
3. Hille B. Ionic channels of excitable membranes. Sinuaer Associates Inc. Sunderland, Massachusetts 01375. 1984
4. Lee-Son S, Wang GK, Concus A, Crill E, Strichartz GR Stereoselective inhibition of neuronal sodium channels by local anesthetics; evidence for two sites of action Anesthesiology 77:324-335 1992.
5. Zamponi GW, Sui X, Codding PW, French RJ Dual actions of procaineamide on batrachotoxin-activated sodium channels: open channel block and prevention of inactivation Biophysical Journal 65:2324-2334. 1993
6. Ragsdale DS, McPhee JC, Scheuer T and Catterall WA. Molecular Determinants of State-dependent block of Na+ channels by Local Anesthetics Science 265:1724-1728, 1994.
7. Flanagan HL, Datta S, Lambert DH, Gissen AJ, Covino BG . Effect of pregnancy on bupivacaine-induced conduction blockade in the isolated rabbit vagus nerve Anesth Analg 66:123-126, 1987.
8. Butterworth JF, Walker FO, Lysak SZ Pregnancy increases median nerve susceptibility to lidocaine Anesthesiology 72:962-965, 1990.
9. Popitz-Bergez F, Strichartz GR, Thalhammer JG . Differences in lidocaine uptake in the sciatic nerve of the pregnant rat in vivo Regional Anesthesia 20:2S: 88 1995.