Depolarizing Blocker Succinylcholine

Succinylcholine chloride (Anectine) is the only depolar-izing-type blocker that is in widespread clinical use. It produces neuromuscular block by overstimulation, so that the end plate is unable to respond to further stimulation. Structurally, succinylcholine is equivalent to two ACh molecules joined back to back. The resulting 10-carbon atom spacing between the two quaternary ammonium heads is important for activation of the two binding sites on the AChR. Because the succinylcholine molecule is "thin," binding to the two sites does not ster-ically occlude the open channel, and cations are allowed to flow and depolarize the end plate.

Neuromuscular block with succinylcholine occurs by two sequential events. An initial depolarization of the end plate produces muscle action potentials and fasciculation. Maintained depolarization past the threshold for firing produces Na+ channel inactivation, so that muscle action potentials cannot be generated. This is called phase I, or depolarization block. In the continued presence of succinylcholine, the membrane becomes repolarized, Na+ channel inactivation is reversed, and muscle membrane excitability is restored. Nonetheless, the neuromuscular block persists because of desensitization of the AChR. This is known as phase II, or desensitization block.

Although the mechanism for phase II block is not completely understood, a series of allosteric transitions in the AChR is suspected. One model to describe this has the AChR in equilibrium among four conformations: resting, active, inactive, and desensitized. Agonists stabilize the active and desensitized states, whereas antagonists tend to stabilize the resting and possibly the desensitized state.

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