Clinical Uses
Myasthenia gravis is an
autoimmune disease in which antibodies recognize nicotinic cholinoreceptors on
skeletal muscle. This decreases the number of functional receptors and
consequently decreases the sensitivity of the muscle to ACh. Muscle weakness
and rapid fatigue of muscles during use are characteristics of the disease.
Anticholinesterase agents help to alleviate the weak-ness by elevating and
prolonging the concentration of ACh in the synaptic cleft, producing a greater
activation of the remaining nicotinic receptors. By contrast, thymectomy,
plasmapheresis, and corticosteroid administration are treatments directed at
decreasing the au-toimmune response.
Anticholinesterase agents
play a key role in the di-agnosis and therapy of myasthenia gravis, because
they increase muscle strength. During diagnosis, the patient’s muscle strength
is examined before and immediately af-ter the intravenous injection of
edrophonium chloride. In myasthenics, an increase in muscle strength is
ob-tained for a few minutes.
The pronounced weakness that
may result from in-adequate therapy of myasthenia gravis (myasthenic crisis)
can be distinguished from that due to anti-cholinesterase overdose (cholinergic
crisis) by the use of edrophonium. In cholinergic crisis, edrophonium will
briefly cause a further weakening of muscles, whereas improvement in muscle
strength is seen in the myasthenic patient whose anticholinesterase therapy is
inadequate. Means for artificial respiration should be available when patients
are being tested for cholinergic crisis.
Pyridostigmine and
neostigmine are the major anti-cholinesterase agents used in the therapy of
myasthenia gravis, but ambenonium can be used when these drugs are unsuitable.
When it is feasible, these agents are given orally. Pyridostigmine has a
slightly longer duration of action than neostigmine, with smoother dos-ing, and
it causes fewer muscarinic side effects. Ambenonium may act somewhat longer
than pyri-dostigmine, but it produces more side effects and tends to
accumulate.
Anticholinesterase agents can
be employed in the treat-ment of adynamic ileus and atony of the urinary
blad-der, both of which may result from surgery. Neostigmine is most commonly
used, and it can be administered sub-cutaneously or intramuscularly in these
conditions. Cholinesterase inhibitors are, of course, contraindicated if
mechanical obstruction of the intestine or urinary tract is known to be
present. myasthenic patient whose anticholinesterase therapy is inadequate.
Means for artificial respiration should be available when patients are being
tested for cholinergic crisis.
Pyridostigmine and
neostigmine are the major anti-cholinesterase agents used in the therapy of
myasthenia gravis, but ambenonium can be used when these drugs are unsuitable.
When it is feasible, these agents are given orally. Pyridostigmine has a
slightly longer duration of action than neostigmine, with smoother dos-ing, and
it causes fewer muscarinic side effects. Ambenonium may act somewhat longer
than pyri-dostigmine, but it produces more side effects and tends to
accumulate.
Anticholinesterase agents can
be employed in the treat-ment of adynamic ileus and atony of the urinary
blad-der, both of which may result from surgery. Neostigmine is most commonly
used, and it can be administered sub-cutaneously or intramuscularly in these
conditions. Cholinesterase inhibitors are, of course, contraindicated if
mechanical obstruction of the intestine or urinary tract is known to be
present.
A number of drugs in addition
to atropine and scopol-amine have antimuscarinic properties. These include
tri-cyclic antidepressants, phenothiazines, and antihista-mines. Physostigmine
has been used in the treatment of acute toxicity produced by these compounds.
However, physostigmine can produce cardiac arrhyth-mias and other serious toxic
effects of its own, and therefore, it should be considered as an antidote only
in life-threatening cases of anticholinergic drug overdose.
Alzheimer’s disease is a
slowly developing neurodegen-erative disease that produces a progress loss of
memory and cognitive function, that is, dementia. These func-tional changes
appear to result primarily from the loss of cholinergic transmission in the
neocortex. The four cholinesterase inhibitors that have been approved for use
in the palliative treatment of Alzheimer’s disease are tacrine, donepezil,
rivastigmine, and galanthamine. These agents can cross the blood-brain barrier
to pro-duce a reversible inhibition of AChE in the CNS. These compounds produce
modest but significant improve-ment in the cognitive function of patients with
mild to moderate Alzheimer’s disease, but they do not delay progression of the
disease. Donepezil, rivastigmine, and galanthamine are as effective as tacrine
in increasing cognitive performance but do not share tacrine’s hepa-totoxic
effects.
Long-lasting AChE inhibitors,
such as demecarium (Humorsol ),
echothiophate, and physostigmine are also effective in treating open-angle
glaucoma, although they have now been largely replaced by less toxic drugs.
Topical application of long-acting cholinesterase in-hibitors to the eye not
only presents the risk of systemic effects, but they can cause cataracts; this
is a primary rea-son for reluctance to use these drugs even in resistant cases
of glaucoma. Pilocarpine should be used rather than AChE inhibitors for
treating angle-closure glaucoma.
Drug treatment of strabismus (turning of one or both eyes
from the normal position) is largely limited to cer-tain cases of accommodative
esotropia (inward devia-tion).
Long-acting anticholinesterase agents, such as echothiophate or demecarium, are
employed to poten-tiate accommodation by blocking ACh hydrolysis at the ciliary
muscle and decreasing the activity of extraocular muscles of convergence. This
results in reduced accom-modative convergence. The same side effects and
pre-cautions mentioned for the use of these drugs in glau-coma apply to the
therapy of strabismus.
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