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

252 When the diagnosis of myasthenia gravis has been established,
the optimal single oral dose of an anti- ChE agent can be determined
empirically. Baseline recordings are made for grip strength, vital
capacity, and a number of signs and symptoms that reflect the strength
of various muscle groups. The patient then is given an oral dose of
pyridostigmine (30-60 mg), neostigmine (7.5-15 mg), or ambenonium
(2.5-5 mg). The improvement in muscle strength and changes
in other signs and symptoms are noted at frequent intervals until there
is a return to the basal state. After an hour or longer in the basal state,
the drug is given again, with the dose increased to one and one- half
times the initial amount, and the same observations are repeated. This
sequence is continued, with increasing increments of one- half the initial
dose, until an optimal response is obtained.
The duration of action of these drugs is such that the interval
between oral doses required to maintain muscle strength usually is
2-4 hours for neostigmine, 3-6 hours for pyridostigmine, or 3-8 hours
for ambenonium. However, the dose required may vary from day to
day; physical or emotional stress, intercurrent infections, and menstruation
usually necessitate an increase in the frequency or size of
the dose. Unpredictable exacerbations and remissions of the myasthenic
state may require adjustment of dosage. Pyridostigmine is
available in sustained- release tablets containing a total of 180 mg, of
which 60 mg is released immediately and 120 mg over several
hours; this preparation is of value in maintaining patients for
6–8-hour periods, but should be limited to use at bedtime.
Muscarinic cardiovascular and GI side effects of anti- ChE agents
generally can be controlled by atropine or other anticholinergic drugs
(Chapter 9). However, these anticholinergic drugs mask many side
effects of an excessive dose of an anti- ChE agent. In most patients,
tolerance develops eventually to the muscarinic effects. Several
drugs, including curariform agents and certain antibiotics and general
anesthetics, interfere with neuromuscular transmission (Chapter 11);
their administration to patients with myasthenia gravis requires
proper adjustment of anti- ChE dosage and other precautions.
Other therapeutic measures are essential elements in the management
of this disease. Glucocorticoids promote clinical improvement
in a high percentage of patients. However, when treatment with
steroids is continued over prolonged periods, a high incidence of
side effects may result (Chapter 42). Gradual lowering of maintenance
doses and alternate- day regimens of short- acting steroids are
used to minimize side effects. Initiation of steroid treatment augments
muscle weakness; however, as the patient improves with continued
administration of steroids, doses of anti- ChE drugs can be
reduced (Drachman, 1994). Other immunosuppressive agents such
as azathioprine and cyclosporine also have been beneficial in more
advanced cases (Chapter 35).
Thymectomy should be considered in myasthenia associated
with a thymoma or when the disease is not controlled adequately by
anti- ChE agents and steroids. The relative risks and benefits of the surgical
procedure versus anti- ChE and glucocorticoid treatment require
careful assessment. Since the thymus contains myoid cells with nicotinic
receptors (Schluep et al., 1987), and a predominance of patients
have thymic abnormalities, the thymus may be responsible for the initial
pathogenesis. It also is the source of autoreactive T- helper cells.
In keeping with the presumed autoimmune etiology of myasthenia
gravis, plasmapheresis and immune therapy have proven beneficial
in patients who have remained disabled in the face of other
treatments (Drachman, 1994, 1996). Improvement in muscle
SECTION II
NEUROPHARMACOLOGY
strength correlates with the reduction of the titer of antibody directed
against the nicotinic ACh receptor.
Prophylaxis in Cholinesterase Inhibitor Poisoning. Studies in
experimental animals have shown that pretreatment with pyridostigmine
reduces the incapacitation and mortality associated with nerve
agent poisoning, particularly for agents such as soman that show rapid
aging. The first large- scale administration of pyridostigmine to
humans occurred in 1990 in anticipation of nerve- agent attack in the
first Persian Gulf War. At an oral dose of 30 mg every 8 hours, the
incidence of side effects was around 1%, but fewer than 0.1% of the
subjects had responses sufficient to warrant discontinuing the drug in
the setting of military action (Keeler et al., 1991). Long- term followup
indicates that veterans of the Persian Gulf War who received pyridostigmine
showed a low incidence of a neurologic syndrome, now
termed the Persian Gulf War syndrome. It is characterized by impaired
cognition, ataxia, confusion, myoneuropathy, adenopathy, weakness,
and incontinence (Haley et al., 1997; Institute of Medicine, 2003).
While pyridostigmine has been implicated by some as the causative
agent, the absence of similar neuropathies in pyridostigmine- treated
myasthenic patients makes it far more likely that a combination of
agents, including combusted organophosphates and insect repellents
in addition to pyridostigmine, contributed to this persisting syndrome.
It also is difficult to distinguish residual chemical toxicity from posttraumatic
stress experienced after combat action. Pyridostigmine is
FDA- approved for prophylaxis against soman, an organophosphate
that rapidly “ages” following inhibition of cholinesterases.
Intoxication by Anticholinergic Drugs. In addition to atropine and
other muscarinic agents, many other drugs, such as the phenothiazines,
antihistamines, and tricyclic antidepressants, have central and
peripheral anticholinergic activity. Physostigmine is potentially useful
in reversing the central anticholinergic syndrome produced by
overdosage or an unusual reaction to these drugs (Nilsson, 1982). The
effectiveness of physostigmine in reversing the anticholinergic effects
of these agents has been clearly documented. However, other toxic
effects of the tricyclic antidepressants and phenothiazines (Chapters 15
and 16), such as intraventricular conduction deficits and ventricular
arrhythmias, are not reversed by physostigmine. In addition,
physostigmine may precipitate seizures; hence, its usually small
potential benefit must be weighed against this risk. The initial intravenous
or intramuscular dose of physostigmine is 2 mg, with additional
doses given as necessary. Physostigmine, a tertiary amine,
crosses the blood- brain barrier, in contrast to the quaternary anti-
AChE drugs. The use of anti- ChE agents to reverse the effects of competitive
neuromuscular blocking agents is discussed in Chapter 11.
Alzheimer’s Disease. A deficiency of intact cholinergic
neurons, particularly those extending from subcortical
areas such as the nucleus basalis of Meynert, has been
observed in patients with progressive dementia of the
Alzheimer type (Chapter 22). Using a rationale similar
to that in other CNS degenerative diseases, therapy for
enhancing concentrations of cholinergic neurotransmitters
in the CNS was investigated.
In 1993, the FDA approved tacrine (tetrahydroaminoacridine)
for use in mild to moderate
Alzheimer’s disease, but a high incidence of enhanced