Chapter 9: Neuromuscular Blocking Agents

HISTORY OF DEVELOPMENT

Neuromuscular blocking agents (NMBAs) were first “discovered” by the native Indian populations of South America and were used for hunting game. They called their plant-based concoction “ourari,” which was later interpreted as “curare” by the early European explorers. The use of neuromuscular relaxants in medicine, however, would have to wait until the mid-1800s, when Dr Louis Sayres of New York attempted to treat the spasms associated with tetanus with a rudimentary curare preparation (Chapter 10). The first successful use of curare during surgery was described by Dr Arthur Lawen in 1912; however, it would take an additional 30 years of further refinement in anesthesia methodology, notably improved tracheal intubation techniques, before Drs Harold Griffith and Enid Johnson demonstrated successful and safe use of curare in surgery and anesthesia. After their groundbreaking work, research into NMBAs led to the development and purification of several different neuromuscular agents. Of the modern neuromuscular agents still in clinical use, succinylcholine was first synthesized in 1906, but its clinical effect was not recognized until 1949. Pancuronium was manufactured in 1964, and further research to lessen its side-effect profile led to the development of vecuronium in 1979. More recently, mivacurium and rocuronium became available for clinical use in the early 1990s.

Further research into compounds with more rapid metabolism and elimination resulted in the introduction into practice in the 1980s of vecuronium,¹ an aminosteroid, and atracurium,^2,3 a benzylisoquinolinium compound. These relaxants had little or no dependence on the kidney for elimination, and vecuronium lacked cardiovascular effects.¹ The degradation of atracurium via Hofmann elimination removed any important influence of advanced age or organ failure on the profile of the drug and greatly increased its acceptance in the clinical setting, despite its hemodynamic side-effect profile. In an attempt to decrease the histamine release associated with atracurium, one of its isomers, cisatracurium, was isolated in the mid-1990s and became widely popular in anesthesia practice.

NORMAL NEUROMUSCULAR TRANSMISSION

NMBAs act to prevent effective transmission of nerve impulses across the neuromuscular junction, the synapse interposed between the presynaptic nerve terminal and the postsynaptic muscle membrane. Under normal conditions, when a nerve impulse is transmitted along the axon and reaches the nerve terminal, it causes release of stored acetylcholine from the nerve terminal (readily releasable vesicle pool). The acetylcholine (released as quanta, each quantum containing approximately 5000 acetylcholine molecules per vesicle) then diffuses across the synaptic cleft and interacts with nicotinic acetylcholine receptors on the postsynaptic (muscle) membrane. When enough of these receptors are activated (all-or-none rule), an action potential ensues leading to muscle contraction. The adult acetylcholine receptor (Figure 9–1) consists of 2 identical α subunits, and 1 β, δ, and ε subunits each, arranged in a rosette pattern (α₂βδε). In fetal acetylcholine receptors, the ε subunit is replaced by a γ subunit (α₂βδγ) (Figure ...