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

268 reduced renal function (pancuronium). Great care
should be taken when administering neuromuscular
blockers to dehydrated or severely ill patients.
SECTION II
NEUROPHARMACOLOGY
The depolarizing agents can release K + rapidly from intracellular
sites; this may be a factor in production of the prolonged apnea
in patients who receive these drugs while in electrolyte imbalance.
Succinylcholine-induced hyperkalemia is a life-threatening complication
of that drug (Yentis, 1990). For example, such alterations in
the distribution of K + are of particular concern in patients with congestive
heart failure who are receiving digoxin or diuretics. For the
same reason, caution should be used or depolarizing blocking agents
should be avoided in patients with extensive soft-tissue trauma or
burns. A higher dose of a competitive blocking agent often is indicated
in these patients. In addition, succinylcholine administration is
contraindicated or should be given with great caution in patients with
nontraumatic rhabdomyolysis, ocular lacerations, spinal cord injuries
with paraplegia or quadriplegia, or muscular dystrophies.
Succinylcholine no longer is indicated for children ≤8 years of age
unless emergency intubation or securing an airway is necessary.
Hyperkalemia, rhabdomyolysis, and cardiac arrest have been
reported. A subclinical dystrophy is frequently associated with these
adverse responses. Neonates may also have an enhanced sensitivity
to competitive neuromuscular blocking agents.
Malignant Hyperthermia. Malignant hyperthermia is a potentially
life-threatening event triggered by the administration of certain anesthetics
and neuromuscular blocking agents. The clinical features
include contracture, rigidity, and heat production from skeletal muscle
resulting in severe hyperthermia (increases of up to 1°C/5 min),
accelerated muscle metabolism, metabolic acidosis, and tachycardia.
Uncontrolled release of Ca 2+ from the sarcoplasmic reticulum of
skeletal muscle is the initiating event. Although the halogenated
hydrocarbon anesthetics (e.g., halothane, isoflurane, and sevoflurane)
and succinylcholine alone have been reported to precipitate the
response, most of the incidents arise from the combination of depolarizing
blocking agent and anesthetic. Susceptibility to malignant
hyperthermia, an autosomal dominant trait, is associated with certain
congenital myopathies such as central core disease. In the majority
of cases, however, no clinical signs are visible in the absence of anesthetic
intervention.
Determination of susceptibility is made with an in vitro contracture
test on a fresh biopsy of skeletal muscle, where contractures
in the presence of halothane and caffeine are measured. In over 50%
of affected families, a linkage is found between the phenotype as
measured by the contracture test and a mutation in the gene encoding
the skeletal muscle ryanodine receptor (RYR-1). Over 30 mutations
in a region of the gene that encodes the cytoplasmic face of the
receptor have been described. Other loci have been identified on the
L-type Ca 2+ channel (voltage-gated dihydropyridine receptor) and
on other associated proteins or channel subunits. The large number
of mutations in the RYR-1 gene, combined with genetic and metabolic
heterogeneity of the condition, have precluded reliable genotypic
determination of susceptibility to malignant hyperthermia
(Rosenberg et al., 2007).
Treatment entails intravenous administration of dantrolene
(DANTRIUM, others), which blocks Ca 2+ release from the sarcoplasmic
reticulum of skeletal muscle (see “Control of Muscle Spasms and
Rigidity” earlier in the chapter). Rapid cooling, inhalation of 100%
oxygen, and control of acidosis should be considered adjunct therapy
in malignant hyperthermia. Declining fatality rates for malignant
hyperthermia relate to anesthesiologists’ awareness of the
condition and the efficacy of dantrolene.
Patients with central core disease, so named because of the
presence of myofibrillar cores seen on biopsy of slow-twitch muscle
fibers, show muscle weakness in infancy and delayed motor development.
These individuals are highly susceptible to malignant hyperthermia
with the combination of an anesthetic and a depolarizing
neuromuscular blocker. Central core disease has five allelic variants
of RYR-1 in common with malignant hyperthermia. Patients with
other muscle syndromes or dystonias also have an increased frequency
of contracture and hyperthermia in the anesthesia setting.
Succinylcholine in susceptible individuals also induces trismusmasseter
spasm, an increase in jaw muscle tone, which may complicate
endotracheal tube insertion and airway management (van der
Spek et al., 1990). This condition has been correlated with a mutation
in the gene encoding the α subunit of the voltage-sensitive Na +
channel (Vita et al., 1995). This increase in jaw muscle tone can be
an early sign of the onset of malignant hyperthermia, and when
observed along with rigidity in other muscles, is a signal that anesthesia
should be halted and treatment of malignant hyperthermia
begun (Gronert et al., 2005).
Respiratory Paralysis. Treatment of respiratory paralysis arising
from an adverse reaction or overdose of a neuromuscular blocking
agent should be by positive-pressure artificial respiration with oxygen
and maintenance of a patent airway until recovery of normal respiration
is ensured. With the competitive blocking agents, this may
be hastened by the administration of neostigmine methylsulfate (0.5-
2 mg IV) or edrophonium (10 mg IV, repeated as required up to a
total of 40 mg) (Watkins, 1994).
Interventional Strategies for Other Toxic Effects. Neostigmine
effectively antagonizes only the skeletal muscular blocking action
of the competitive blocking agents and may aggravate such side
effects as hypotension or induce bronchospasm. In such circumstances,
sympathomimetic amines may be given to support the
blood pressure. Atropine or glycopyrrolate is administered to counteract
muscarinic stimulation. Antihistamines are definitely beneficial
to counteract the responses that follow the release of histamine,
particularly when administered before the neuromuscular blocking
agent.
Reversal of Effects by Chelation Therapy. There is now an investigational
chelating agent specific for rocuronium and vecuronium,
sugammadex (BRIDION), a modified γ-cyclodextrin. Administration of
sugammadex at doses >2 mg/kg is able to reverse neuromuscular
blockade from rocuronium within 3 minutes. The majority of sugammadex
and its complex with rocuronium is eliminated in the urine.
In patients with impaired renal function, sugammadex clearance is
markedly reduced and this agent should be avoided. Theoretically,
neuromuscular blockade can reoccur if rocuronium or vecuronium
become displaced from the sugammadex complex, necessitating
careful monitoring and repeat dosing if necessary. Sugammadex is
approved for clinical use in Europe but not yet in the U.S. (Naguib
and Brull, 2009). Side effects include dysgeusia and rare self-limiting
hypersensitivity.