Local anesthetics reversibly inhibit impulse generation and propagation in nerves. In sensory nerves, such an effect is desired when painful procedures must be performed, e.g., surgical or dental operations.
Mechanism of action. Nerve impulse conduction occurs in the form of an action potential, a sudden reversal in resting transmembrane potential lasting less than 1 ms. The change in potential is triggered by an appropriate stimulus and involves a rapid influx of Na+ into the interior of the nerve axon (A). This inward flow proceeds through a channel, a membrane pore protein, that, upon being opened (activated), permits rapid movement of Na+ down a chemical gradient ([Na+]ext - 150 mM, [Na+]int ~ 7 mM). Local anesthetics are capable of inhibiting this rapid inward flux of Na+; initiation and propagation of excitation are therefore blocked (A).
Most local anesthetics exist in part in the cationic amphiphilic form (cf. p. 208). This physicochemical property favors incorporation into membrane interphases, boundary regions between polar and apolar domains. These are found in phospholipid membranes and also in ion-channel proteins. Some evidence suggests that Na+-channel blockade results from binding of local anesthetics to the channel protein. It appears certain that the site of action is reached from the cytosol, implying that the drug must first penetrate the cell membrane (p. 206).
Local anesthetic activity is also shown by uncharged substances, suggesting a binding site in apolar regions of the channel protein or the surrounding lipid membrane.
Mechanism-specific adverse effects. Since local anesthetics block Na+ influx not only in sensory nerves but also in other excitable tissues, they are applied locally and measures are taken (p. 206) to impede their distribution into the body. Too rapid entry into the circulation would lead to unwanted systemic reactions such as:
• blockade of inhibitory CNS neurons, manifested by restlessness and seizures (countermeasure: injection of a benzodiazepine, p. 226); general paralysis with respiratory arrest after higher concentrations.
• blockade of cardiac impulse conduction, as evidenced by impaired AV conduction or cardiac arrest (coun-termeasure: injection of epineph-rine). Depression of excitatory processes in the heart, while undesired during local anesthesia, can be put to therapeutic use in cardiac arrhythmias (p. 134).
Forms of local anesthesia. Local anesthetics are applied via different routes, including infiltration of the tissue (infiltration anesthesia) or injection next to the nerve branch carrying fibers from the region to be anesthetized (conduction anesthesia of the nerve, spinal anesthesia of segmental dorsal roots), or by application to the surface of the skin or mucosa (surface anesthesia). In each case, the local anesthetic drug is required to diffuse to the nerves concerned from a depot placed in the tissue or on the skin.
High sensitivity of sensory nerves, low sensitivity of motor nerves. Impulse conduction in sensory nerves is inhibited at a concentration lower than that needed for motor fibers. This difference may be due to the higher impulse frequency and longer action potential duration in nociceptive, as opposed to motor, fibers.
Alternatively, it may be related to the thickness of sensory and motor nerves, as well as to the distance between nodes of Ranvier. In saltatory impulse conduction, only the nodal membrane is depolarized. Because depolarization can still occur after blockade of three or four nodal rings, the area exposed to a drug concentration sufficient to cause blockade must be larger for motor fibers (p. 205B).
This relationship explains why sen
B. Inhibition of impulse conduction in different types of nerve fibers myelinated A8-fibers are affected later and to a lesser degree than are stimuli conducted via unmyelinated C-fibers. Since autonomic postganglionic fibers lack a myelin sheath, they are particularly susceptible to blockade by local anesthetics. As a result, vasodilation ensues in the anesthetized region, because sympathetically driven vasomotor tone decreases. This local vasodilation is undesirable (see below).
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