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

Table 11–1
Clinical Responses and Monitoring of Phase I and Phase II Neuromuscular Blockade
by Succinylcholine Infusion
RESPONSE PHASE I PHASE II
End-plate membrane potential Depolarized to –55 mV Repolarization toward –80 mV
Onset Immediate Slow transition
Dose-dependence Lower Usually higher or follows
prolonged infusion
Recovery Rapid More prolonged
Train of four and tetanic stimulation No fade Fade a
Acetylcholinesterase inhibition Augments Reverses or antagonizes
Muscle response Fasciculations → flaccid paralysis Flaccid paralysis
a
Post-tetanic potentiation follows fade.
depolarizing agent, giving rise to stimulation of the motor unit in an
antidromic fashion, the primary site of action of both competitive
and depolarizing blocking agents is the post-junctional membrane.
Presynaptic actions of the competitive agents may become significant
on repetitive high-frequency stimulation because pre-junctional
nicotinic receptors may be involved in the mobilization of ACh for
release from the nerve terminal (Bowman et al., 1990; Van der Kloot
and Molgo, 1994).
Many drugs and toxins block neuromuscular transmission by
other mechanisms, such as interference with the synthesis or release
of ACh (Chapter 8), but most of these agents are not employed clinically
for this purpose. One exception is botulinum toxin, which has
been administered locally into muscles of the orbit in the management
of ocular blepharospasm and strabismus and has been used to
control other muscle spasms and to facilitate facial muscle relaxation
(Chapters 8 and 64). This toxin also has been injected into the
lower esophageal sphincter to treat achalasia (Chapter 47). The sites
of action and interrelationship of several agents that serve as pharmacological
tools are shown in Figure 11–4.
Sequence and Characteristics of Paralysis. When an appropriate dose
of a competitive blocking agent is injected intravenously in human
beings, motor weakness progresses to a total flaccid paralysis. Small,
rapidly moving muscles such as those of the eyes, jaw, and larynx
relax before those of the limbs and trunk. Ultimately, the intercostal
muscles and finally the diaphragm are paralyzed, and respiration
then ceases. Recovery of muscles usually occurs in the reverse order
to that of their paralysis, and thus the diaphragm ordinarily is the
first muscle to regain function (Feldman and Fauvel, 1994; Viby-
Mogensen, 2005).
After a single intravenous dose of 10-30 mg of succinylcholine,
muscle fasciculations, particularly over the chest and
abdomen, occur briefly; then relaxation occurs within 1 minute,
becomes maximal within 2 minutes, and generally disappears within
5 minutes. Transient apnea usually occurs at the time of maximal
effect. Muscle relaxation of longer duration is achieved by continuous
intravenous infusion. After infusion is discontinued, the effects
of the drug usually disappear rapidly because of its efficient hydrolysis
by plasma and hepatic butyrylcholinesterase. Muscle soreness
may follow the administration of succinylcholine. Small prior doses
of competitive blocking agents have been employed to minimize fasciculations
and muscle pain caused by succinylcholine, but this procedure
is controversial because it increases the requirement for the
depolarizing drug.
During prolonged depolarization, muscle cells may lose significant
quantities of K + and gain Na + , Cl – , and Ca 2+ . In patients
with extensive injury to soft tissues, the efflux of K + following continued
administration of succinylcholine can be life-threatening.
The life-threatening complications of succinylcholine-induced
hyperkalemia are discussed later, but it is important to stress that
there are many conditions for which succinylcholine administration
is contraindicated or should be undertaken with great caution. The
change in the nature of the blockade produced by succinylcholine
(from phase I to phase II) presents an additional complication with
long-term infusions.
Central Nervous System. Tubocurarine and other quaternary
neuromuscular blocking agents are virtually
devoid of central effects following ordinary clinical
doses because of their inability to penetrate the bloodbrain
barrier. The most decisive experiment performed
to resolve whether curare significantly affects central
functions in the dose range used clinically was that of
Smith and associates (1947). Smith (an anesthesiologist)
daringly permitted himself to receive, intravenously,
two and one-half times the amount of
tubocurarine necessary for paralysis of all skeletal muscles.
Adequate respiratory exchange was maintained by
artificial respiration. At no time was there any evidence
of lapse of consciousness, clouding of sensorium, analgesia,
or disturbance of special senses. Despite adequate
artificially controlled respiration, Smith
experienced “shortness of breath” and the sensation of
choking due to the accumulation of unswallowed saliva
in the pharynx. The experience was decidedly unpleasant,