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

Anti- ChE agents have been employed locally in the treatment
of a variety of other less common ophthalmologic conditions,
including accommodative esotropia and myasthenia gravis confined
to the extraocular and eyelid muscles. Adie (or tonic pupil)
syndrome results from dysfunction of the ciliary body, perhaps
because of local nerve degeneration. Low concentrations of
physostigmine are reported to decrease the blurred vision and pain
associated with this condition. In alternation with a mydriatic drug
such as atropine, short- acting anti- ChE agents have proven useful
for breaking adhesions between the iris and the lens or cornea. (For
a complete account of the use of anti- ChE agents in ocular therapy,
see Chapter 64).
Myasthenia Gravis. Myasthenia gravis is a neuromuscular
disease characterized by weakness and marked fatigability
of skeletal muscle (Drachman, 1994); exacerbations
and partial remissions occur frequently. The similarity
between the symptoms of myasthenia gravis and curare
poisoning in animals suggested to Jolly that physostigmine,
an agent known to antagonize curare, might be of
therapeutic value. Forty years elapsed before his suggestion
was given systematic trial.
The defect in myasthenia gravis is in synaptic transmission at
the neuromuscular junction. When a motor nerve of a normal subject
is stimulated at 25 Hz, electrical and mechanical responses are well
sustained. A suitable margin of safety exists for maintenance of neuromuscular
transmission. Initial responses in the myasthenic patient
may be normal, but they diminish rapidly, consistent with the rapid
muscle fatigue seen in patients.
The relative importance of prejunctional and postjunctional
defects in myasthenia gravis was a matter of considerable debate
until Patrick and Lindstrom found that rabbits immunized with
the nicotinic receptor purified from electric eels slowly developed
muscular weakness and respiratory difficulties that resembled the
symptoms of myasthenia gravis. The rabbits also exhibited decremental
responses following repetitive nerve stimulation, enhanced
sensitivity to curare, and following the administration of anti-
AChE agents, symptomatic and electrophysiological improvement
of neuromuscular transmission. This animal model prompted
intense investigation into whether the natural disease represented
an autoimmune response directed toward the ACh receptor. Antireceptor
antibodies are detectable in sera of 90% of patients with
the disease, although the clinical status of the patient does not correlate
precisely with antibody titers (Drachman, 1994; Lindstrom,
2000). Sequences and the structural location in the α1 subunit
constituting the main immunogenic region are well defined
(Lindstrom 2008).
The picture that emerges is that myasthenia gravis is caused
by an autoimmune response primarily to the ACh receptor at the
post- junctional end plate. These antibodies reduce the number of
receptors detectable either by snake α- neurotoxin- binding assays
(Fambrough et al., 1973) or by electrophysiological measurements
of ACh sensitivity (Drachman, 1994). Immune complexes along
with marked ultrastructural abnormalities appear in the synaptic cleft
and enhance receptor degradation through complement- mediated
lysis in the end plate. A related disease that also compromises
neuromuscular transmission is Lambert- Eaton syndrome. Here, antibodies
are directed against Ca 2+ channels that are necessary for presynaptic
release of ACh (Lang et al., 1998).
In a subset of ~10% of patients presenting with a myasthenic
syndrome, muscle weakness has a congenital rather than an autoimmune
basis. Characterization of biochemical and genetic bases of the
congenital condition has shown mutations to occur in the acetylcholine
receptor which affect ligand- binding and channel- opening kinetics and
durations (Engel et al., 2008; Sine and Engel, 2006). Other mutations
occur as a deficiency in the form of AChE that contains the collagenlike
tail unit. As expected, following administration of anti- ChE agents
(see following discussion), subjective improvement is not seen in most
congenital myasthenic patients, although some of the above channel
syndromes can be ameliorated pharmacologically.
Diagnosis. Although the diagnosis of autoimmune myasthenia gravis
usually can be made from the history, signs, and symptoms, its differentiation
from certain neurasthenic, infectious, endocrine, congenital,
neoplastic, and degenerative neuromuscular diseases can be
challenging. However, myasthenia gravis is the only condition in
which the aforementioned deficiencies can be improved dramatically
by anti- ChE medication. The edrophonium test for evaluation
of possible myasthenia gravis is performed by rapid intravenous
injection of 2 mg of edrophonium chloride, followed 45 seconds
later by an additional 8 mg if the first dose is without effect; a
positive response consists of brief improvement in strength, unaccompanied
by lingual fasciculation (which generally occurs in nonmyasthenic
patients).
An excessive dose of an anti- ChE drug results in a cholinergic
crisis. The condition is characterized by weakness resulting from
generalized depolarization of the motor end plate; other features
result from overstimulation of muscarinic receptors. The weakness
resulting from depolarization blockade may resemble myasthenic
weakness, which is manifest when anti- ChE medication is insufficient.
The distinction is of obvious practical importance, since the
former is treated by withholding, and the latter by administering, the
anti- ChE agent. When the edrophonium test is performed cautiously,
limiting the dose to 2 mg and with facilities for respiratory resuscitation
available, a further decrease in strength indicates cholinergic
crisis, while improvement signifies myasthenic weakness. Atropine
sulfate, 0.4-0.6 mg or more intravenously, should be given immediately
if a severe muscarinic reaction ensues (for complete details,
see Drachman, 1994; Osserman et al., 1972). Detection of antireceptor
antibodies in muscle biopsies or plasma is now widely
employed to establish the diagnosis.
Treatment. Pyridostigmine, neostigmine, and ambenonium
are the standard anti- ChE drugs used in the symptomatic
treatment of myasthenia gravis. All can
increase the response of myasthenic muscle to repetitive
nerve impulses, primarily by the preservation of
endogenous ACh. Following AChE inhibition, receptors
over a greater cross- sectional area of the end plate
presumably are exposed to concentrations of ACh that
are sufficient for channel opening and production of a
postsynaptic end-plate potential.
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CHAPTER 10
ANTICHOLINESTERASE AGENTS