Muscle relaxation: Mechanism

In the resting state, the electrical potential of the inside of a nerve cell is negative with respect with the outside. When the action potential depolarizes the nerve terminal, an influx of calcium diffuse into the cell via channels. Theentry of calcium facilitates the release of acetylcholine (ACh). These ACh molecules then diffuse across the synaptic cleft andbind to the nicotinic cholinergic receptorsat the motor end-plate. Thisdepolarizes the end-plate generating an action potential propagating the activation of sodium channels throughout the muscle fiber.

Neuromuscular blocking agents work at the neuromuscular junction. There are two types, depolarizing and nondepolarizing.Depolarizing muscle relaxants acts as ACh receptoragonists. They bind to the ACh receptors and generate an action potential. However, because they are not metabolized by acetylcholinesterase, the binding of this drug to the receptor is prolonged resulting in an extended depolarization of the muscle end-plate. As the muscle relaxant continues to bind to the ACh receptor, the end plate cannot repolarize, resulting in aphase I block. The ACh receptor can also undergo conformational and ionic changes after a period of time, resulting in aphase II block.

Nondepolarizing muscle relaxants act as competitiveantagonists. They bind to the ACh receptors but unable to induce ion channel openings. They prevent ACh from binding and thus end plate potentials do not develop.

When there is a compensatory increase in the number of ACh receptors extrajunctional isoforms of the receptor such as in certain disease states, there is an increased sensitivity to depolarizing relaxants and resistance to nondepolarizers. In states where there are fewer ACh receptors, the opposite occurs where there is resistance to the depolarizers and increased sensitivity to the nondepolarizers.

Neuromuscular Activation

• Influx of Ca++ in nerve terminals leads to release of ACh
• ACh binds nicotinic receptors at motor endplate and causes depolarization / Na+ entry
• Action potential caused by Na+ depolarizes muscle fibers