to produce a more intense motor blockade. This action further below). One consequence of the surmountable nature of the post-weakens neuromuscular transmission and diminishes the ability synaptic blockade produced by nondepolarizing muscle relaxants is of the acetylcholinesterase inhibitors (eg, neostigmine, edropho-the fact that tetanic stimulation (rapid delivery of electrical stimuli nium, pyridostigmine) to antagonize the effect of nondepolar-to a peripheral nerve) releases a large quantity of acetylcholine izing muscle relaxants. and is followed by transient posttetanic facilitation of the twitch
Nondepolarizing relaxants can also block prejunctional sodium strength (ie, relief of blockade). An important clinical consequence channels. As a result of this action, muscle relaxants interfere with of this principle is the reversal of residual blockade by cholinesterase the mobilization of acetylcholine at the nerve ending and cause fade inhibitors. The characteristics of a nondepolarizing neuromuscular of evoked nerve twitch contractions (Figure 27–6, and described blockade are summarized in Table 27–2 and Figure 27–6.
TABLE 27–2 Comparison of a typical nondepolarizing muscle relaxant (rocuronium) and a depolarizing muscle relaxant (succinylcholine).
1It is not known whether this interaction is additive or synergistic (superadditive). 2The amplitude is decreased, but the response is sustained. 3The rate depends on the dose and on the completeness of neuromuscular blockade.
B. Depolarizing Relaxant Drugs 1.
Phase I block (depolarizing)—Succinylcholine is the only clinically useful depolarizing blocking drug. Its neuromuscular effects are like those of acetylcholine except that succinylcholine produces a longer effect at the myoneural junction. Succinylcholine reacts with the nicotinic receptor to open the channel and cause depolarization of the motor end plate, and this in turn spreads to the adjacent membranes, causing transient contractions of muscle motor units. Data from single-channel recordings indicate that depolarizing blockers can enter the channel to produce a prolonged “flickering” of the ion conductance (Figure 27–7). Because succinylcholine is not metabolized effectively at the synapse, the depolarized membranes remain depolarized and unresponsive to subsequent impulses (ie, a state of depolarizing blockade). Furthermore, because excitation-contraction coupling requires end plate repolarization (“repriming”) and repetitive firing to maintain muscle tension, a flaccid paralysis results. In contrast to the nondepolarizing drugs, this so-called phase I (depolarizing) block is augmented, not reversed, by cholinesterase inhibitors.
The characteristics of a depolarizing neuromuscular blockade are summarized in Table 27–2 and Figure 27–6.
2.
Phase II block (desensitizing)—With prolonged exposure to succinylcholine, the initial end plate depolarization decreases and the membrane becomes repolarized. Despite this repolarization, the membrane cannot easily be depolarized again because it is desensitized. The mechanism for this desensitizing phase is unclear, but some evidence indicates that channel block may become more important than agonist action at the receptor in phase II of succinylcholine’s neuromuscular blocking action. Regardless of the mechanism, the channels behave as if they are in a prolonged closed state (Figure 27–6). Later in phase II, the characteristics of the blockade are nearly identical to those of a nondepolarizing block (ie, a nonsustained twitch response to a tetanic stimulus) (Figure 27–6), with possible reversal by acetylcholinesterase inhibitors.