Chapter 13
- Pharmacology of Muscle Relaxants and Their Antagonists
- Mohamed Naguib
- Cynthia A. Lien
HISTORY AND CLINICAL USE
In 1942 Griffith and Johnson[1]
suggested that d-tubocurarine (dTc) is a safe drug
to use during surgery to provide skeletal muscle relaxation. One year later, Cullen
[2]
described its use in 131 patients who had received
general anesthesia for their surgery. In 1954, Beecher and Todd[3]
reported a sixfold increase in mortality in patients receiving dTc versus those who
had not received a relaxant. The increased mortality was due to a general lack of
understanding of the pharmacology of neuromuscular blockers and their antagonism.
The impact of residual neuromuscular blockade postoperatively was not appreciated,
guidelines for monitoring muscle strength had not been established, and the importance
of pharmacologically antagonizing residual blockade was not understood. Since then,
the understanding of neuromuscular blocker pharmacology has improved, and relaxants
have become an important component of many anesthetics and have facilitated the growth
of surgery into new areas with the use of innovative techniques.[4]
Succinylcholine, introduced by Thesleff[5]
and by Foldes and colleagues in 1952,[4]
changed
anesthetic practice drastically. Its rapid onset of effect and ultrashort duration
of action allowed for rapid tracheal intubation.
In 1967, Baird and Reid first reported on clinical administration
of the synthetic aminosteroid pancuronium.[6]
Though
similar to dTc, in terms of its duration of action, this compound had an improved
cardiovascular side effect profile. It lacked ganglionic-blocking and histamine-releasing
properties and was mildly vagolytic. The resulting increases in heart rate and blood
pressure were considered significant improvements over its predecessors. Unlike
dTc or any of the nondepolarizing neuromuscular blockers previously used, none of
which were metabolized, pancuronium underwent some hepatic metabolism through deacetylation
of the acetoxy groups.
Development of the intermediate-acting neuromuscular blockers
built on compound metabolism and resulted in the introduction of vecuronium,[7]
an aminosteroid, and atracurium,[8]
[9]
a benzylisoquinolinium, into practice in the 1980s. These relaxants had little or
no dependence on the kidney for elimination. The lack of cardiovascular effects
of vecuronium established a benchmark for safety to which newer relaxants are still
held.[7]
Degradation of atracurium by Hofmann elimination
removed any important influence of biologic disorders such as advanced age or organ
failure on the pattern of neuromuscular blockade.
Mivacurium, the first short-acting nondepolarizing neuromuscular
blocker, was introduced into clinical practice in the 1990s,[10]
as was rocuronium,[11]
an intermediate-acting nondepolarizing
blocker with a rapid onset of effect. Mivacurium, like the intermediate-acting compounds,
is extensively metabolized. It is, however, metabolized by butyrylcholinesterase,
the same enzyme that is responsible for the metabolism of succinylcholine. In terms
of facilitating rapid endotracheal intubation, rocuronium is the first nondepolarizing
neuromuscular blocker considered to be a replacement for succinylcholine.
Other neuromuscular blockers have been introduced into clinical
practice since the use of dTc was first advocated. These blockers include pipecuronium,
doxacurium, cisatracurium, and rapacuronium. Although all do not remain in use,
each represented an advance or improvement in at least one aspect over its predecessors.
Still other neuromuscular blockers, TAAC3[12]
and
430A,[13]
are undergoing investigation.
Neuromuscular blockers should be administered only to anesthetized
individuals to provide relaxation of skeletal muscles. They should not be administered
to stop patient movement because they have no analgesic or amnestic properties.
Awareness during surgery[14]
and in the intensive
care unit (ICU)[15]
has been described in multiple
publications. Neuromuscular blockers are valuable adjuncts to general anesthetics
and should be used as such. As stated by Cullen and Larson, "muscle relaxants given
inappropriately may provide the surgeon with optimal [operating] conditions in ...
a patient [who] is paralyzed but not anesthetized—a state that [is] wholly
unacceptable for the patient."[16]
Additionally,
"muscle relaxants used to cover up deficiencies in total anesthetic management ...
represent an ... inappropriate use of the valuable adjuncts to anesthesia." To administer
relaxants for maintenance of neuromuscular blockade intraoperatively, the patient's
depth of neuromuscular block must be monitored and the depth of anesthesia continuously
assessed.
The use of neuromuscular blockers in the operating room is quite
common and has been important in the growth and development of anesthesia and surgery.
As stated by Foldes and coauthors,[4]
"... [the]
first use of ... muscle relaxants ... not only revolutionized the practice of anesthesia
but also started the modern era of surgery and made possible the explosive development
of cardiothoracic, neurologic and organ transplant surgery." Certainly, neuromuscular
blockers are now routinely used to facilitate endotracheal intubation and are commonly
used to maintain neuromuscular blockade through any number of different surgical
procedures. This chapter will review the pharmacology and clinical use of neuromuscular
blockers, as well as anticholinesterases, in the operating room. Diseases of the
neuromuscular system are also discussed as regards their influence on the actions
of neuromuscular blockers. Finally, the economics of providing neuromuscular blockade
is also considered.
