"B BipfffB |M
Fig. 1. Local anesthetic molecules' access to the membrane sodium channel. The uncharged lipophilic tertiary amine (B) diffuses across lipid membrane barriers and interacts with the channel through the axolemma interior. Within the axoplasm, the charged quaternary amine (BH+) is formed. The charged molecule then binds to a specific receptor via an open sodium channel pore.
conducting tiny electrical currents or impulses. The nerve's resting potential is generated by the cross-membrane potassium ion concentration gradient, and the action potential is maintained across the membrane by the sodium ion concentration. These cross-membrane ionic gradients, which govern nerve excitability, are maintained by metabolically fueled sodium-potassium pumps. The stabilization and deactivation of the sodium channel is the key mechanism of action of local anesthetics (37). The first step in the initiation of a nerve action potential is the generation of a sodium current resulting in bidirectional signal propagation. This impulse generation is suppressed by local anesthetics, which act to block and thus close the transmembrane sodium channels, preventing the inward membrane-depolarizing surge of sodium ions (36). The resting membrane potential is maintained, but the nerve is completely inexcitable. The positively charged local anesthetic binds to negatively charged fatty acid tails in the transmembrane gate, locking the movement of the protein subunits and blocking sodium ion flow. The local anesthetic must be lipophilic because it can enter the sodium channel only from inside the axoplasm. Therefore, the highly lipid-soluble agent will first traverse the lipid nerve membrane, dissociate into a local anesthetic cation, and then ascend into the sodium channel to lock up the mobile gating structures (Fig. 1).
Relative therapeutic potency is measured by the minimum blocking concentration, defined as the lowest drug concentration necessary to halt impulse traffic and to block the nerve and thus relieve pain. Bupivacaine is severalfold more potent than lidocaine, which in turn is severalfold more potent than procaine. The degree of anesthetic block is also affected by the state of the sodium channel. The receptor accessibility status of the channel, whether open, inactivated, closed, or resting, will determine the depth of the nerve block in response to local anesthetic administration (Fig. 2). In addition, the frequency of stimulation will also determine the degree of block. As the frequency of nerve stimulation is increased, the membrane channels are more likely to be open and more accessible to local anesthetic for a greater proportion oftime, and thus the more profound the degree of block will be noted in nerves that fire faster. The size of the nerve fiber can also play a role in the degree of block. The thin A-5 and C fibers are more easily blocked at lower drug concentrations than are the larger, A-a, motor fibers (38). This unique differential nerve block is the basis for treatment of pain syndromes. At appropriate doses, the patient will experience no pain sensation, but would be able to perceive touch and pressure as well as voluntarily contract muscles. Because preganglionic autonomic axons, spinal B fibers, are similar in size to the smallest sensory (cold) fibers, most epidural local anesthetic injections result in a local sympathetic block that often extends several segments higher and lasts longer than the desired nociceptive block. As nerve impulses can skip over one or two consecutively blocked nodes, at least 5 mm, and preferably 8 mm, of nerve length must be immersed in local anesthetic to ensure nerve blockade (Fig. 3). Thus larger volumes of diluents, such as preservative-free saline, are necessary to ensure adequate penetration of local anesthetic agent to the nerves undergoing blockade.
Local anesthetics are organic amines, which are lipid soluble but water insoluble and unstable. The lipophilic ringed head of the molecule is separated from its hydro-philic hydrocarbon tail by an intermediary ester or amide
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