DRUG EFFECTS ON POSTJUNCTIONAL RECEPTORS

Classic Actions of Nondepolarizing Muscle Relaxants

Neurotransmission occurs when the action potential releases acetylcholine and binds to the receptor. All non-depolarizing relaxants impair or block neurotransmission by competitively preventing the binding of acetylcholine to its receptor. The final outcome (i.e., block or transmission) depends on the relative concentrations of the chemicals and their comparative affinities for the receptor. Figure 22-6 shows a system exposed to acetylcholine and tubocurarine. One receptor has attracted two acetylcholine molecules and opened its channel, where current will flow to depolarize that segment of membrane. Another has attracted one tubocurarine molecule; its channel will not open, and no current will flow, even if one acetylcholine molecule binds to the other site. The third receptor has acetylcholine on one α-subunit and nothing on the other. What will happen depends on which of the molecules binds. If acetylcholine binds, the channel will open, and the membrane will be depolarized; if tubocurarine binds, the channel will stay closed, and the membrane will not be depolarized. At other times, one or two tubocurarine molecules may attach to the receptor, in which case the receptor is not available to agonists; no current flow is recorded. In the presence of moderate concentrations of tubocurarine, the amount of current flowing through the entire end plate at any instant is

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Normally, acetylcholinesterase enzyme destroys acetylcholine and removes it from the competition for a receptor, so that tubocurarine has a better chance of inhibiting transmission. If, however, an inhibitor of the acetylcholinesterase such as neostigmine is added, the cholinesterase cannot destroy acetylcholine. The concentration of agonist in the cleft remains high, and this high concentration shifts the competition between acetylcholine and tubocurarine in favor of the former, improving the chance of two acetylcholine molecules binding to a receptor even though tubocurarine is still in the environment. Cholinesterase inhibitors overcome the neuromuscular paralysis produced by nondepolarizing relaxants by this mechanism. The channel opens only when acetylcholine attaches to both recognition sites. A single molecule of antagonist, however, is adequate to prevent the depolarization of that receptor. This modifies the competition by biasing it strongly in favor of the antagonist. Mathematically, if the concentration of tubocurarine is doubled, the concentration of acetylcholine must be increased fourfold if acetylcholine is to remain competitive. Paralysis produced by high concentrations of antagonist is more difficult to reverse than those produced by low concentrations. After large doses of nondepolarizing relaxants, reversal drugs may be ineffective until the concentration of the relaxant in the perijunctional area decreases to a lower level by redistribution or elimination of the drug.