Nervous system voltage-gated sodium channels

LAs block nerve conduction when applied locally to nervous tissue by a voltage- and frequency-dependent inhibition of sodium currents (see Voltage-gated Sodium Channels Structure and Function1). Due to this mechanism, they preferentially block hyperexcitable cells and interfere comparatively less with normal physiological sensory and motor function. However, they are not selective for pain-relevant sodium channel subtypes so that they have a relatively high risk of adverse effects associated with the central nervous and cardiovascular systems when administered systemically. Known LAs are not active when administered orally. 

Carbamazepine is both an important anticonvulsant in therapeutic doses and a powerful proconvulsant in overdose. The therapeutic anticonvulsant mechanism is primarily related to blockade of presynaptic voltage-gated sodium channels. Blockade of the sodium channels is believed to inhibit the release of synaptic glutamate and possibly other neurotransmitters. Carbamazepine is also a powerful inhibitor of the muscurinic and nicotinic acetylcholine receptors, N-methyl-D-aspartate (NMDA) receptors and the central nervous system (CNS) adenosine receptors. In addition, carbamazepine is structurally related to the cyclic antidepressant impramine and in massive overdose may affect cardiac sodium channels. 

Various isoforms of voltage-gated sodium channels exist. They are encoded by nine genes in the human genome as reviewed by Catterall [248]. Nayl. 1, Nayl. 2, Nayl. 3, and Nayl.6 are primary sodium channels of the central nervous system, whereas Navl.7, Nayl.8, Nayl.9 are primarily expressed in peripheral neurons. Nayl.4 and Nayl.5 are primarily expressed in skeletal and heart muscle, respectively. 

Tarnawa, L, Bolcskei, H., Kocsis, P, 2007. Blockers of voltage-gated sodium channels for the treatment of central nervous system diseases. Recent Pat. CNS Drug Discov. 2 (1), 57—78. 

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