Page 494 - Basic _ Clinical Pharmacology ( PDFDrive )

480 SECTION V Drugs That Act in the Central Nervous System

B. Depolarizing Relaxant Drugs nondepolarizing block (ie, a nonsustained twitch response to a
1. Phase I block (depolarizing)—Succinylcholine is the only tetanic stimulus) (Figure 27–6), with possible reversal by acetyl-
cholinesterase inhibitors.
clinically useful depolarizing blocking drug. Its neuromuscular
effects are like those of acetylcholine except that succinylcholine
produces a longer effect at the myoneural junction. Succinylcho-
line reacts with the nicotinic receptor to open the channel and ■ CLINICAL PHARMACOLOGY
cause depolarization of the motor end plate, and this in turn OF NEUROMUSCULAR BLOCKING
spreads to the adjacent membranes, causing transient contractions
of muscle motor units. Data from single-channel recordings indi- DRUGS
cate that depolarizing blockers can enter the channel to produce
a prolonged “flickering” of the ion conductance (Figure 27–7). Skeletal Muscle Paralysis
Because succinylcholine is not metabolized effectively at the Before the introduction of neuromuscular blocking drugs, pro-
synapse, the depolarized membranes remain depolarized and found skeletal muscle relaxation for intracavitary operations could
unresponsive to subsequent impulses (ie, a state of depolarizing be achieved only by producing levels of volatile (inhaled) anesthe-
blockade). Furthermore, because excitation-contraction coupling sia deep enough to produce profound depressant effects on the
requires end plate repolarization (“repriming”) and repetitive cardiovascular and respiratory systems. The adjunctive use of neu-
firing to maintain muscle tension, a flaccid paralysis results. In romuscular blocking drugs makes it possible to achieve adequate
contrast to the nondepolarizing drugs, this so-called phase I muscle relaxation for all types of surgical procedures without the
(depolarizing) block is augmented, not reversed, by cholinesterase cardiorespiratory depressant effects produced by deep anesthesia.
inhibitors.
The characteristics of a depolarizing neuromuscular blockade
are summarized in Table 27–2 and Figure 27–6. Assessment of Neuromuscular
Transmission
2. Phase II block (desensitizing)—With prolonged exposure
to succinylcholine, the initial end plate depolarization decreases Monitoring the effect of muscle relaxants during surgery (and
and the membrane becomes repolarized. Despite this repolariza- recovery following the administration of cholinesterase inhibi-
tion, the membrane cannot easily be depolarized again because tors) typically involves the use of a device that produces transder-
it is desensitized. The mechanism for this desensitizing phase is mal electrical stimulation of one of the peripheral nerves to the
unclear, but some evidence indicates that channel block may hand or facial muscles and recording of the evoked contractions
become more important than agonist action at the receptor in
phase II of succinylcholine’s neuromuscular blocking action. (ie, twitch responses). The motor responses to different patterns
Regardless of the mechanism, the channels behave as if they are of peripheral nerve stimulation can be recorded in the operat-
in a prolonged closed state (Figure 27–6). Later in phase II, the ing room during the procedure (Figure 27–6). The standard
characteristics of the blockade are nearly identical to those of a approach for monitoring the clinical effects of muscle relaxants

4 pA

25 ms

FIGURE 27–7 Action of succinylcholine on single-channel end plate receptor currents in frog muscle. Currents through a single AChR
channel were recorded using the patch clamp technique. The upper trace was recorded in the presence of a low concentration of succinylcho-
line; the downward deflections represent openings of the channel and passage of inward (depolarizing) current. The lower trace was recorded
in the presence of a much higher concentration of succinylcholine and shows prolonged “flickering” of the channel as it repetitively opens and
closes or is “plugged” by the drug. (Reproduced, with permission, from Marshall CG, Ogden DC, Colquhoun D: The actions of suxamethonium (succinyldicholine) as an
agonist and channel blocker at the nicotinic receptor of frog muscle. J Physiol [Lond] 1990;428:155.)