KEY POINTS
- The neuromuscular junction provides a rich array of receptors and substrates
for drug action. Several drugs used clinically have multiple sites of action. The
muscle relaxants are not exceptions to the rule that most drugs have more than one
site or mechanism of action. The major actions seem to occur by the mechanisms and
at the sites described for decades: agonistic and antagonistic actions at postjunctional
receptors for depolarizing and nondepolarizing relaxants, respectively. This description
of neuromuscular drug action is a simplistic one. Neuromuscular transmission is
impeded by nondepolarizers because they prevent access of acetylcholine to its recognition
site on the postjunctional receptor.
- If the concentration of nondepolarizer is increased, another, noncompetitive
action—block of the ion channel—is superimposed. The paralysis is also
potentiated by the prejunctional actions of the relaxant, preventing the release
of acetylcholine. The latter can be documented as fade that occurs with increased
frequency of stimulation. A more accurate description of the relaxant effects recognizes
that the neuromuscular junction is a complex and dynamic system, in which the phenomena
produced by drugs are composites of actions that vary with drug, dose, activity in
the junction and muscle, time after administration, the presence of anesthetics or
other drugs, and the age and condition of the patient.
- Inhibition of the postjunctional acetylcholinesterase by anticholinesterases
increases concentration of acetylcholine, which can compete and displace the nondepolarizer-reversing
paralysis. These anticholinesterases also have other effects, including those on
nerve terminals and on the receptor, by means of an allosteric mechanism. Cyclodextrins
are reversal compounds that detoxify the effects of steroidal muscle relaxants only
by directly binding to them.
- Depolarizing compounds initially react with the acetylcholine recognition
site and, like the transmitter, open ion channels and depolarize the end-plate membrane.
Unlike the transmitter, they are not subject to hydrolysis by acetylcholinesterase
and so remain in the junction. Soon after administration of the drug, some receptors
are desensitized and, although occupied by an agonist, do not open to allow current
to flow to depolarize the area.
- If the depolarizing relaxant is applied in high concentration and allowed
to remain at the junction for a long time, other effects occur. These include entry
of the drug into the channel to obstruct it or to pass through it into the cytoplasm.
Depolarizing relaxants also have effects on prejunctional structures, and the combination
of prejunctional and postjunctional effects plus secondary ones on muscle and nerve
homeostasis results in the complicated phenomenon known as phase
II blockade.
- Intense research in the area of neuromuscular transmission continues at
a rapid pace. The newer observations on receptors, ion channels, membranes, and
prejunctional functions reveal a much broader range of sites and mechanisms of action
for agonists and antagonists.
- Some of the other drugs used clinically (e.g., botulinum toxin) have effects
on the nerve and therefore indirectly on muscle.[35]
Nondepolarizing relaxants administered even for 12 hours or prolonged periods can
have effects on postsynaptic receptor simulating denervation.[85]
[86]
In recognizing these sites and mechanisms,
we begin to bring our theoretical knowledge closer to explaining the phenomena observed
when these drugs are administered to living humans.
- Most recent work seems to be focused on the postjunctional membrane and
the control of acetylcholine receptor expression in normal and diseased states.
The presence or absence of the mature and immature isoforms seems to complicate matters
further. In certain pathologic states (e.g., sepsis, burns, immobilization, chronic
use of relaxants), upregulation of acetylcholine receptors occurs, usually with expression
of the immature isoform. The altered functional and pharmacologic characteristics
of these receptors results in increased sensitivity with hyperkalemia to succinylcholine
and resistance to nondepolarizers.
- An area of increasing attention is the control of the expression of mature
versus immature receptors and the role of the immature isoform of the receptor in
the muscle weakness associated with the diseases enumerated. The immature isoform
expression is probably related to aberrant growth factor signaling. Mutations in
the acetylcholine receptor, which result in prolonged open-channel time, similar
to that seen with the immature receptor, even the presence of normal receptor numbers,
can lead to a myasthenia-like state.[37]
The weakness
is usually related to the prolonged open-channel time. It is possible that the synaptic
area expression of the immature receptor, which has a prolonged open-channel time,
may simulate a myasthenia-like state.
- Attenuated growth factor (e.g., insulin) signaling may also cause apoptosis
in muscle. Loss of muscle mass due to apoptosis may compound the muscle weakness
of critical illness related to expression of immature isoform receptors. In the
future, it may be possible to manipulate the signaling mechanism to alter the expression
of the receptor isoforms, attenuate apoptosis, and improve muscle function. Alternatively,
these goals could be achieved by gene therapy.
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