Classes of Drugs Used
Three classes of drugs, potassium channel-blocking drugs, acetylcholinesterase
inhibitors, and the γ-cyclodextrin derivatives, can be used clinically to reverse
nondepolarizer-induced paralysis.[82]
[83]
The best known of the potassium blocking drugs is 4-aminopyridine. Its actions
are predominantly prejunctional; it impedes the efflux of potassium from the nerve
ending. Because the efflux of potassium is the event that normally ends the action
potential of the nerve ending, this action prolongs the depolarization of the nerve.
Because the flux of calcium into the nerve continues for as long as the depolarization
lasts, drugs of this class indirectly increase the flux of calcium into the nerve
ending. The nerve releases more acetylcholine and for a longer time than usual,
conditions that are effective in antagonizing nondepolarizing relaxants. Because
they act prejunctionally, these drugs can antagonize a block produced by certain
antibiotics that act on the nerve ending, notably the polymyxins. Although 4-aminopyridine
and drugs like it can be used clinically, their use is severely restricted because
they are not specific. They affect the release of transmitters by all nerve endings,
including motor nerves, autonomic nerves, and central nervous system components.
Their use is accompanied by a variety of undesirable effects, and in practice, they
are used only in special circumstances. A most serious side effect of potassium
channel blockers is seizures.
The more commonly used antagonists of neuromuscular block (e.g.,
neostigmine, pyridostigmine, edrophonium) inhibit acetylcholinesterase by mechanisms
that are similar but not identical.[82]
Neostigmine
and pyridostigmine are attracted by an electrostatic interaction between the positively
charged nitrogen in the molecules and the negatively charged catalytic site of the
enzyme. This produces a carbamylated enzyme, which is not capable of further action
(i.e., the catalytic site is blocked and the enzyme is inhibited). Edrophonium has
neither an ester nor a carbamate group, but it is attracted and bound to the catalytic
site of the enzyme by the electrostatic attraction between the positively charged
nitrogen in the drug and the negatively charged acetylcholinesterase site of the
enzyme. Edrophonium also seems to have prejunctional effects, enhancing the release
of acetylcholine from the nerve terminal. This effect is therefore useful when deep
neuromuscular block needs reversal. Of the three commonly used anticholinesterases,
edrophonium shows by far the greatest selectivity between acetylcholinesterase and
butyrylcholinesterase, the serum esterase that hydrolyzes succinylcholine and mivacurium.
It greatly favors the former enzyme and therefore seems to be the most desirable
agent to reverse mivacurium. However, if the patient has normal serum esterase,
pharmacokinetic factors are the principal determinants of the duration of blockade,
and the activity of serum esterase or the lack of it plays only a minor role in the
recovery. There is little reason to prefer one or another reversal drug on these
grounds. Anticholinesterases are administered for prolonged periods in the treatment
of myasthenia gravis[3]
and as prophylaxis in cases
of nerve gas poisoning.[38]
Ironically, prolonged
administration of cholinesterase inhibitors can also lead to a myasthenia-like state
with muscle weakness.[84]
The cholinesterase inhibitors act preferentially at the neuromuscular
junction and act at other synapses that use the same transmitter, including muscarinic
receptors. An atropine-like drug should be administered with the cholinesterase
inhibitor to counter the effects of the acetylcholine that accumulates in the muscarinic
synapses of the gut, bronchi, and cardiovascular system. These three anticholinesterase
inhibitors do not affect synapses in the central nervous system because all are quaternary
ammonium ions, which do not easily penetrate the blood-brain barrier. A quaternary
ammonium derivative of atropine, such as glycopyrrolate, which does not diffuse through
the blood-brain barrier, frequently is used to
limit the anticholinergic effects to the periphery. Other cholinesterase inhibitors,
notably physostigmine and tacrine, are not quaternary ammonium compounds, and they
have profound effects in the central nervous system. These may be antagonized by
atropine but not by its quaternary ammonium analog derivatives. Unlike the other
cholinesterase inhibitors, physostigmine and tacrine are also potent inhibitors of
the enzyme phosphodiesterase, which plays an important role in the regulation of
transmitter release at many synapses in the central nervous system. This action
may be related to the reported efficacy of these two drugs in the treatment of Alzheimer's
dementia.
Cholinesterase inhibitors also have actions at the postjunctional
membrane independent of its effects on the enzyme. Several of these compounds contain
methyl groups on a positively charged nitrogen, and they can act as agonists on the
receptor channels, initiating ion flow and enhancing neuromuscular transmission.
Neostigmine, physostigmine, and certain organophosphates can increase the frequency
of MEPPs and increase the quantal content of end-plate potentials, but the importance
of the increased transmitter release to reversal of neuromuscular blockade is not
clear. Continuous exposure to the carbamate- or organophosphate-containing inhibitors
causes degeneration of prejunctional and postjunctional structures, apparently because
these structures accumulate toxic amounts of calcium. Calcium channel blockers such
as verapamil prevent the neural actions of these drugs. All the drugs of this class
also act in or on receptors to influence the kinetics of the open-close cycle and
to block the ion channel.[57]
[58]
The clinical significance of the drugs on reversal of nondepolarizers is not known.
A new approach to reversing residual neuromuscular block is by
direct binding of the relaxant by means of chemical interaction. Antidote drugs
that work by binding other drugs include protamine, citrate anticoagulation, lead
or copper chelators, and RNA molecules recombinantly engineered to bind drugs. Cyclodextrins
(i.e., small, cyclic polysaccharides) are one such compound synthesized from starch
by bacteria as early as 1891. The γ-cyclodextrin derivative ORG25969 binds
steroidal relaxants with very high affinity, resulting in inactive muscle relaxants.
The kidney then removes these complexes. Preliminary studies show promising results.
[83]
