DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

clinical responses to neuromuscular blocking agents
(e.g., bronchospasm, hypotension, excessive bronchial
and salivary secretion) appear to be caused by the
release of histamine. Succinylcholine, mivacurium, and
atracurium also cause histamine release, but to a lesser
extent unless administered rapidly. The ammonio
steroids, pancuronium, vecuronium, pipecuronium, and
rocuronium, have even less tendency to release histamine
after intradermal or systemic injection (Basta,
1992; Watkins, 1994). Histamine release typically is a
direct action of the muscle relaxant on the mast cell
rather than IgE-mediated anaphylaxis (Watkins, 1994).
Release of Cellular K + . Depolarizing agents can release
K + rapidly from intracellular sites; this may be a factor
in several of the clinical toxicities of these drugs (see
“Toxicology” later in the chapter).
Absorption, Distribution, and Elimination
Quaternary ammonium neuromuscular blocking agents
are very poorly absorbed from the GI tract, a fact well
known to the South American Indians, who ate with
impunity the flesh of game killed with curare-poisoned
arrows. Absorption is quite adequate from intramuscular
sites. Rapid onset is achieved with intravenous
administration. The more potent agents, of course, must
be given in lower concentrations, and diffusional
requirements slow their rate of onset.
When long-acting competitive blocking agents such as
D-tubocurarine and pancuronium are administered, blockade may
diminish after 30 minutes owing to redistribution of the drug, yet
residual blockade and plasma levels of the drug persist. Subsequent
doses show diminished redistribution. Long-acting agents may accumulate
with multiple doses.
The ammonio steroids contain ester groups that are
hydrolyzed in the liver. Typically, the metabolites have about onehalf
the activity of the parent compound and contribute to the total
relaxation profile. Ammonio steroids of intermediate duration of
action, such as vecuronium and rocuronium (Table 11–2), are cleared
more rapidly by the liver than is pancuronium. The more rapid decay
of neuromuscular blockade with compounds of intermediate duration
argues for sequential dosing of these agents rather than administering
a single dose of a long-duration neuromuscular blocking
agent. There is a modified γ-cyclodextrin available as an investigational
chelating agent specific for rocuronium and vecuronium (see
“Reversal of Effects by Chelation Therapy” later in the chapter).
Atracurium is converted to less active metabolites by plasma
esterases and spontaneous Hofmann elimination (Figure 11–3).
Cisatracurium is also subject to this spontaneous degradation.
Because of these alternative routes of metabolism, atracurium and
cisatracurium do not exhibit an increased t 1/2
in patients with
impaired renal function and therefore are good choices in this setting
(Hunter, 1994; Naguib and Lien, 2005).
The extremely brief duration of action of succinylcholine is
due largely to its rapid hydrolysis by the butyrylcholinesterase
synthesized by the liver and found in the plasma. Among the occasional
patients who exhibit prolonged apnea following the administration
of succinylcholine or mivacurium, most have an atypical
plasma cholinesterase or a deficiency of the enzyme owing to allelic
variations (Pantuck, 1993; Primo-Parmo et al., 1996), hepatic or
renal disease, or a nutritional disturbance; however, in some, the
enzymatic activity in plasma is normal (Whittaker, 1986).
Gantacurium is degraded by two chemical mechanisms, a
rapid cysteine adduction and a slower hydrolysis of the ester bond
adjacent to the chlorine. Both processes are purely chemical and
hence not dependent on enzymatic activities. The adduction process
has a t 1/2
of 1-2 minutes and is likely the basis for the ultrashort duration
of action of gantacurium. Administration of exogenous cysteine,
which may have excitotoxic side effects, can accelerate the antagonism
of gantacurium-induced neuromuscular blockade (Naguib and
Brull, 2009).
Clinical Pharmacology
Choice of Agent
Therapeutic selection of a neuromuscular blocking
agent should be based on achieving a pharmacokinetic
profile consistent with the duration of the interventional
procedure and minimizing cardiovascular compromise
or other side effects, with attention to drug-specific
modes of elimination in patients with renal or hepatic
failure (Table 11–2).
Two characteristics are useful in distinguishing side effects
and pharmacokinetic behavior of neuromuscular blocking agents. The
first relates to the duration of drug action: These agents are categorized
as long-, intermediate-, or short-acting. The persistent blockade
and difficulty in complete reversal after surgery with
D-tubocurarine, metocurine, doxacurium, and pancuronium led to the
development of vecuronium (NORCURON, others) and atracurium
(TRACRIUM, others), agents of intermediate duration; cisatracurium
(NIMBEX) is one of ten isomers of atracurium with three times its
potency. This was followed by the development of a short-acting
agent, mivacurium (not available in the U.S.). Often, the long-acting
agents are the more potent, requiring the use of low concentrations
(Table 11–3). The necessity of administering potent agents in low
concentrations delays their onset. Rocuronium (ZEMURON, others) is
an agent of intermediate duration but of rapid onset and lower
potency. Its rapid onset allows its use as an alternative to succinylcholine
in rapid-induction anesthesia and in relaxing the laryngeal
and jaw muscles to facilitate tracheal intubation (Bevan, 1994;
Naguib and Lien, 2005). Gantacurium, a mixed-onium chlorofumarate,
recently completed phase 2 clinical trials and is the first in a
new class of ultra-short acting, competitive neuromuscular blocking
agents designed to replace succinylcholine in rapid-induction anesthesia
(Naguib and Brull, 2009; Savarese, 2006).
The second useful classification is derived from the chemical
nature of the agents and includes the natural alkaloids or their congeners,
the ammonio steroids, the benzylisoquinolines, and the
asymmetric mixed-onium chlorofumarates (Table 11–2, Figure 11–3).
The natural alkaloid D-tubocurarine and the semisynthetic alkaloid
alcuronium are not approved for use in the U.S. Apart from a shorter
duration of action, newer agents exhibit greatly diminished frequency
of side effects, chief of which are ganglionic blockade, block
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CHAPTER 11
AGENTS ACTING AT THE NEUROMUSCULAR JUNCTION AND AUTONOMIC GANGLIA