4.2.5.2 Cholinergic Antagonists: Neuromuscular Blocking Agents
Neuromuscular blocking agents are widely used in surgery. They are capable of relax-
ing the abdominal muscles without the use of deep anesthesia, and make surgery much
easier for both the surgeon and the patient. There are two major categories of such
agents: (1) competitive neuromuscular agents, which occupy the same site as ACh; and
(2)depolarizing neuromuscular blocking agents, which mimic the action of ACh but
persist at the receptor.
Competitive neuromuscular agents.These agents were developed through the study
of curare, the arrow poison of South American Indians. Crude curare contains a number
of isoquinoline and indole alkaloids, the best known of which is tubocurarine (3.10), a
tertiary–quaternary amine in which the distance between the two cations is rigidly fixed
at about 1.4 nm (the “curarizing distance”). A similarly rigid, large molecule is the syn-
thetic steroid derivative pancuronium (4.25), a bisquaternary derivative with an N+–N+
distance of 1.1 nm. Two acetylcholine molecules built into a rigid framework are clearly
discernible. With curarization, the neuromuscular junction becomes insensitive to ACh
and the motor nerve impulse, and the endplate potential falls dramatically. Numerous
bulky analogs have been developed.
Depolarizing neuromuscular blocking agents. These were discovered through mim-
icking the N+–N+distance described above with aliphatic compounds. Decamethonium
(1.2), in an extended conformation, approximates this distance, and is the prototype of
the depolarizing blocking agents. This drug binds normally to the AChR and triggers
NEUROTRANSMITTERS AND THEIR RECEPTORS 215