3. Channel blockade—Biologic toxins such as batrachotoxin, aconitine, veratridine, and some scorpion venoms bind to receptors within the channel and prevent inactivation. This results in prolonged influx of sodium through the channel and depolarization of the resting potential. The marine toxins tetrodotoxin (TTX) and saxitoxin have clinical effects that largely resemble those of local anesthetics (ie, block of conduction without a change in the resting potential). However, in contrast to the local anesthetics, the toxin binding site is located near the extracellular surface. The sensitivity of these channels to TTX varies, and subclassification based on this pharmacologic sensitivity has important physiologic and therapeutic implications. Six of the aforementioned channels are sensitive to nanomolar concentration of this biotoxin (TTX-S), while three are resistant (TTX-R). Of the latter, Nav1.8 and Nav1.9 appear to be exclusively expressed in dorsal root ganglia nociceptors, which raises the developmental possibility of targeting these specific neuronal subpopulations. Such fine-tuned analgesic therapy has the theoretical potential of providing effective analgesia, while limiting the significant adverse effects produced by nonspecific sodium channel blockers.
When progressively increasing concentrations of a local anesthetic are applied to a nerve fiber, the threshold for excitation increases, impulse conduction slows, the rate of rise of the action potential declines, action potential amplitude decreases, and, finally, the ability to generate an action potential is completely abolished. These progressive effects result from binding of the local anesthetic to more and more sodium channels. If the sodium current is blocked over a critical length of the nerve, propagation across the blocked area is no longer possible. In myelinated nerves, the critical length appears to be two to three nodes of Ranvier. At the minimum dose required to block propagation, the resting potential is not significantly altered.
The blockade of sodium channels by most local anesthetics is both voltage and time dependent: Channels in the rested state, which predominate at more negative membrane potentials, have a much lower affinity for local anesthetics than activated (open state) and inactivated channels, which predominate at more positive membrane potentials (see Figure 14–10). Therefore, the effect of a given drug concentration is more marked in rapidly firing axons than in resting fibers (Figure 26–3). Between successive action potentials, a portion of the sodium channels will recover from the local anesthetic block (see Figure 14–10). The recovery from drug-induced block is 10–1000 times slower than the recovery of channels from normal inactivation (as shown for the cardiac membrane in Figure 14–4). As a result, the refractory period is lengthened and the nerve conducts fewer action potentials.
Elevated extracellular calcium partially antagonizes the action of local anesthetics owing to the calcium-induced increase in the surface potential on the membrane (which favors the low-affinity rested state). Conversely, increases in extracellular potassium depolarize the membrane potential and favor the inactivated state, enhancing the effect of local anesthetics.