Depolarizing Muscle Relaxants

In this drug class, only succinylcholine (succinyldicholine, suxamethonium, A) is of clinical importance. Structurally, it can be described as a double ACh molecule. Like ACh, succinylcholine acts as agonist at endplate nicotinic cholino-ceptors, yet it produces muscle relaxation. Unlike ACh, it is not hydrolyzed by acetylcholinesterase. However, it is a substrate of nonspecific plasma cholin-esterase (serum cholinesterase, p. 100). Succinylcholine is degraded more slowly than is ACh and therefore remains in the synaptic cleft for several minutes, causing an endplate depolarization of corresponding duration. This depolarization initially triggers a propagated action potential (AP) in the surrounding muscle cell membrane, leading to contraction of the muscle fiber. After its i.v. injection, fine muscle twitches (fascicu-lations) can be observed. A new AP can be elicited near the endplate only if the membrane has been allowed to repo-larize.

The AP is due to opening of voltage-gated Na-channel proteins, allowing Na+ ions to flow through the sarcolem-ma and to cause depolarization. After a few milliseconds, the Na channels close automatically ("inactivation"), the membrane potential returns to resting levels, and the AP is terminated. As long as the membrane potential remains incompletely repolarized, renewed opening of Na channels, hence a new AP, is impossible. In the case of released ACh, rapid breakdown by ACh esterase allows repolarization of the endplate and hence a return of Na channel excitability in the adjacent sarcolemma. With succinylcholine, however, there is a persistent depolarization of the endplate and adjoining membrane regions. Because the Na channels remain inactivated, an AP cannot be triggered in the adjacent membrane.

Because most skeletal muscle fibers are innervated only by a single endplate, activation of such fibers, with lengths up to 30 cm, entails propagation of the Lullmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.

AP through the entire cell. If the AP fails, the muscle fiber remains in a relaxed state.

The effect of a standard dose of suc-cinylcholine lasts only about 10 min. It is often given at the start of anesthesia to facilitate intubation of the patient. As expected, cholinesterase inhibitors are unable to counteract the effect of succi-nylcholine. In the few patients with a genetic deficiency in pseudocholineste-rase (= nonspecific cholinesterase), the succinylcholine effect is significantly prolonged.

Since persistent depolarization of endplates is associated with an efflux of K+ ions, hyperkalemia can result (risk of cardiac arrhythmias).

Only in a few muscle types (e.g., extraocular muscle) are muscle fibers supplied with multiple endplates. Here succinylcholine causes depolarization distributed over the entire fiber, which responds with a contracture. Intraocular pressure rises, which must be taken into account during eye surgery.

In skeletal muscle fibers whose motor nerve has been severed, ACh receptors spread in a few days over the entire cell membrane. In this case, succinyl-choline would evoke a persistent depolarization with contracture and hyper-kalemia. These effects are likely to occur in polytraumatized patients undergoing follow-up surgery.

Acetylcholine

Depolarising Muscle Relaxants
Depolarization

h3c ch3 n

0 h2c chj N

Depolarization

ACh Propagation of --action potential (AP)

ACh Propagation of --action potential (AP)

Skeletal muscle cell

1 Rapid ACh cleavage by acetylcholine esterases

Succinylcholine

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