H3n

Figure 22.12 • Mechanism of inactivation of sodium channels. The hinged-lid mechanism. The intracellular loop connecting domains III and IV of the sodium channel is depicted as forming a hinged lid with the critical phenylalanine (F1489) within the IFM motif shown occluding the mouth of the pore during the inactivation process. The circles represent the transmembrane helices. (Reprinted from Catterall, W. A.: Ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron, 26:13-25, 2000, with permission from Elsevier.)

Figure 22.12 • Mechanism of inactivation of sodium channels. The hinged-lid mechanism. The intracellular loop connecting domains III and IV of the sodium channel is depicted as forming a hinged lid with the critical phenylalanine (F1489) within the IFM motif shown occluding the mouth of the pore during the inactivation process. The circles represent the transmembrane helices. (Reprinted from Catterall, W. A.: Ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron, 26:13-25, 2000, with permission from Elsevier.)

Extracellular

Extracellular

Intracellular

Figure 22.13 • Proposed mechanism of action of the local anesthetics: (A) Hydrophobic pathway into the nerve cell, (B) Hydrophobic pathway to the binding site, (C) Hydrophilic pathway from the inside of the nerve cell to the binding site. (Adapted with permission from Hille, B.: Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction. J. Gen. Physiol. 69:497-515, 1977 and Strichartz, G., et al.: Fundamental properties of local anesthetics. II. Measured octanol: buffer partition coefficients and pKa values of clinically used drugs. Anesth. Analg. 71:158-170, 1990.)

Intracellular

Figure 22.13 • Proposed mechanism of action of the local anesthetics: (A) Hydrophobic pathway into the nerve cell, (B) Hydrophobic pathway to the binding site, (C) Hydrophilic pathway from the inside of the nerve cell to the binding site. (Adapted with permission from Hille, B.: Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction. J. Gen. Physiol. 69:497-515, 1977 and Strichartz, G., et al.: Fundamental properties of local anesthetics. II. Measured octanol: buffer partition coefficients and pKa values of clinically used drugs. Anesth. Analg. 71:158-170, 1990.)

Mechanism of Action of Local Anesthetics

The mechanism of action of the local anesthetics is believed to be via their sodium channel blocking effects. The local anesthetic drug binds to the channel in an area just beyond the selectivity filter or P region (Fig. 22.13). When the local anesthetic binds, it blocks sodium ion passage into the cell and thus blocks the formation and propagation of the action potential. This blocks the transmittance of the message of "pain" or even "touch" from getting to the brain. The ability of a local anesthetic to block action potentials depends on the ability of the drug to penetrate the tissue surrounding the targeted nerve as well as the ability of the drug to access the binding site on the sodium channel.

Local anesthetics do not access the binding site by entering into the sodium channel from the exterior of the neuron. The molecules are too big to pass by the selectivity filter. When local anesthetics are synthesized with a permanent charge, such as compound QX-314 below, they are unable to access the binding site unless they are applied directly to the interior of the neuron.63 (For more information on QX-314 see "Future Directions," at the end of this chapter.)

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