Discuss the pharmacology of drugs which target the voltage gated sodium channels.
In most excitable cells, activation of voltage gated sodium channels is responsible for the “upstroke” in membrane potential during phase 0 of the cardiac action potential as well as the action potentials in skeletal muscle and nerve axons. The voltage gated sodium channel is therefore an important drug target. Local anaesthetics block action potential generation by blocking sodium channels. In nature, there are also several toxins that block the sodium channels of excitable tissue, but there are various toxins that modify sodium channel gating facilitating activation. There are also many antiepileptic drugs that affect the membrane excitability by targeting voltage gated sodium channels. Some of these drugs will be described in this essay.
The molecular structure of voltage-gated sodium channels has three subunits in the brain (αβ1β2) and two subunits in the heart and skeletal muscle (αβ1). However, expression of the α subunit alone seems to produce functional sodium channels suggesting that it has the structural features necessary for voltage gating and ion selectivity. The α subunit has four homologous domains each with six transmembrane segments. The domains are folded in the membrane to give four-fold symmetry around a central pore. There are two major phosphorylation sites. The intracellular loop between domains I and II is the site for PKC and cAMP-dependent protein kinases which reduce the channel activation. Inactivation can be slowed by the phosphorylation of the intracellular loop between domains III IV (near IFM motif).
Voltage-gated channels can exist in three functional states: resting (closed during normal resting potential), activated (open state briefly during initial depolarisation) and inactivated (blocked state). Various drugs can have their actions by either enhancing the inactivation of the channel, by blocking inactivation or reducing the potential...