Chemistry: Pyridostigmine is a synthetic quaternary ammonium
compound which is pharmacologically similar to neostigmine and
ambenonium. Pyridostigmine bromide occurs as a hygroscopic, white
or practically white, crystalline powder and is freely soluble in
water and in alcohol. The drug has a characteristic agreeable
odour and a bitter taste. The pH of commercially available
pyridostigmine bromide injection is adjusted to approximately 5
with citric acid (and sodium hydroxide if necessary).
Stability: Pyridostigmine bromide is unstable in alkaline
solutions. Extended-release tablets may become mottled because of
the hygroscopic nature of the drug, but this does not affect
their potency. Pyridostigmine bromide oral solution should be
protected from light.
Pyridostigmine is an anticholinesterase agent which inhibits the
hydrolysis of acetylcholine by competing with acetylcholine for
attachment to acetylcholinesterase. The pyridostigmine-enzyme
complex is hydrolysed at a much slower rate than the
acetylcholine enzyme complex. As a result, acetylcholine
accumulates at cholinergic synapses and its effects are prolonged
and exaggerated. Pyridostigmine therefore produces generalized
cholinergic responses including miosis, increased tonus of
intestinal and skeletal musculature, constriction of bronchi and
ureters, bradycardia, and stimulation of secretion by salivary
and sweat glands. In addition, pyridostigmine has a direct
cholinomimetic effect on skeletal muscle.
Because of its quaternary ammonium structure, moderate doses
of pyridostigmine do not cross the blood brain barrier to produce
CNS effects. Extremely high doses, however, produce CNS
stimulation followed by CNS depression, in addition to a
depolarizing neuromuscular blockade, and may result in
respiratory depression, paralysis, and death.
Absorption: Pyridostigmine bromide is poorly absorbed from the GI
tract. Extended release tablets reportedly release one third of
the total 180 mg dose immediately and the remainder over 8-12
hours; however release of the drug from this dosage form may be
erratic and unpredictable. Pyridostigmine has variable duration
of action in patients with myasthenia gravis, depending on the
physical or emotional stress suffered by the patient and the
severity of the disease. However, it generally has a shorter
duration of action than ambenomium and a slower onset and a
longer duration of action than neostigmine. After oral
administration, pyridostigmine generally has an onset of action
of 30-60 minutes and a duration of action of 3-6 hours. After IV
injection, muscle strength is increased in 2-5 minutes and the
improvement may continue for 2 hours in most patients. Following
IM administration, the drug has an onset of action within about
15 minutes.
Distribution: Pyridostigmine has been reported to cross the
placenta and to decrease fetal plasma cholinesterase activity
after large oral doses. Following oral administration of
radiolabeled pyridostigmine to animals, radioactivity was present
in most tissues except brain, intestinal wall, fat, and thymus.
Elimination: Pyridostigmine undergoes hydrolysis by
cholinesterase; the drug is also metabolized by microsomal
enzymes in the liver. Patients with severe myasthenia gravis seem
to metabolize and excrete pyridostigmine faster than patients
with a milder form of the disease; this may be one explanation
for the resistance anticholinesterase medication which occurs in
some severely ill patients. Pyridostigmine and its metabolites
are excreted in urine by tubular secretion. Although patients
with myasthenia gravis may show considerable individual variation
in urinary excretion patterns, pyridostigmine and 7 metabolites,
including the major metabolite 3-hydroxy-N-methylpyrinium, have
been detected in urine up to 72 hours after a single IV dose.
Myasthenia Gravis: Pyridostigmine is used mainly to increase
muscle strength in the symptomatic treatment of myasthenia
gravis. Because of its longer duration of action, smoother and
steadier effects, most clinicians prefer pyridostigmine to
neostigmine for oral therapy. I addition, pyridostigmine may be
more effective than neostigmine in relieving ptosis, diplopia,
dysarthria, and weakness of the bulbar muscles. Pyridostigmine is
not effective in patients who are resistant to other
anticholinesterase drugs.
In severe myasthenia gravis, neostigmine has been used in
conjunction with pyridostigmine to provide benefits of both short
and long term action; however, because of the possibility of
increased toxicity, this combination should be used only under
strict medical supervision. Ephedrine sulphate and/or potassium
chloride have also been given orally with pyridostigmine to
increase patient response. Approximately one third of myasthenic
patients experience a slight increase in strength when ephedrine
is added to anticholinesterase therapy; slightly fewer improve
with potassium.
Pyridostigmine is used parentally for symptomatic treatment
of acute exacerbations of myasthenia gravis and when oral therapy
is impractical. Some clinicians prefer neostigmine to
pyridostigmine for IM therapy since it has a shorter duration of
action and therefore dosage can be adjusted more frequently as
needed. Neostigmine is usually preferred for treatment of
neonatal myasthenia gravis, although pyridostigmine has been
used.
Surgery: Parental pyridostigmine is useful for reversal of the
effects of nondepolarizing neuromuscular blocking agents (eg.,
tubocurarine, metocurine, gallamine or pancuronium) after
surgery. When used for this purpose, pyridostigmine has been
reported to produce less oropharyngeal secretion, bradycardia,
and cardacarhythmia than neostigmine. Anticholinesterase drugs do
not antagonize the phase 1 block of depolarizing neuromuscular
blocking agents such as succinylcholine or decamethonium;
therefore, pyridostigmine should not be given in an attempt to
reverse the neuromuscular block produced by these agents. (See
drug interactions; Neuromuscular Blocking Agents).
Adverse effects: Adverse effects of pyridostigmine are chiefly
those of exaggerated response to parasympathetic stimulation and
include adverse muscarinic effects such as nausea, vomiting,
diarrhoea, increased peristalsis, miosis, excessive salivation
and sweating, increased bronchial secretions, abdominal cramps,
bradycardia, and bronchospasm. Weakness, muscle cramps,
fasciculation, and rarely, hypotension may occur.
Thrombophlebitis has been reported after IV administration.
Pyridostigmine reportedly fewer severe adverse muscarinic effects
than does neostigmine, but in high doses is more likely to
produce headache. As with other drugs containing bromide, skin
rash may occasionally occur during therapy; however, the rash
usually subsides promptly following discontinuance of
pyridostigmine bromide. Overdosage of pyridostigmine can cause
cholinergic crisis and death. (See acute toxicity;
Manifestations)
Adverse effects of pyridostigmine may be minimized by
precise dosage adjustment. Adverse muscarinic effects can be
reduced or eliminated by concomitant administration of atropine;
however, these symptoms may be the first indication of
pyridostigmine overdose, and masking them with atropine may
prevent early detection of cholinergic crisis.
Precautions and contra indications: Patients who are
hyperreactive to pyridostigmine experience a severe cholinergic
reaction to the drug. Therefore, atropine sulfate injection
should always be readily available as an antagonist for
muscarinic effects of pyridostigmine. Patients who are
hypersensitive to bromide may develop skin reactions such as
acneform rash during pyridostigmine bromide therapy; however,
these reactions usually disappear when the drug is discontinued.
Pyridostigmine chloride (an investigational drug) or ambenonium
chloride may be used for oral anticholinesterase therapy in
myasthenia gravis patients who are sensitive to bromides.
When pyridostigmine is used to treat myasthenia gravis, it
should be kept in mind that individual muscle groups may respond
differently to the same dose of anticholinesterase agent;
producing weakness in one muscle group while increasing strength
in another. The muscles of the neck and of chewing and swallowing
are usually the first muscles to be weakened by overdosage,
followed by the muscles of the shoulder girdle and upper
extremities, and finally the pelvic girdle and extraocular and
leg muscles. Vital capacity should be routinely checked whenever
dosage is increased, so that the dosage of the
anticholinesterase medication can be adjusted to ensure good
respiratory function. Adequate facilities for cardiopulmonary
resuscitation, cardiac monitoring, endotracheal intubation, and
assisting respiration should be available during dosage
adjustment.
Pyridostigmine should be used with caution in patients with
epilepsy, bronchial asthma, bradycardia, recent coronary
occlusion, vagotonia, hyperthyroidism, cardiac arrhythmias, or
peptic ulcer. Large oral doses of the drug should be avoided in
patients with megacolon or decreased GI motility. In these
patients, the drug may accumulate and result in toxicity when GI
motility is restored. Pyridostigmine bromide is contraindicated
in patients with mechanical obstruction of the intestinal or
urinary tracts and in patients who are known to be hypersensitive
to anticholinesterase agents.
Pregnancy: Few data are available regarding the effects of
cholinesterase inhibitors, including pyridostigmine, on the fetus
because of the rarity of maternal conditions requiring the use of
these drugs during pregnancy. Transient muscular weakness has
occurred in 10-20 % of neonates whose mothers received
anticholinesterase drugs for treatment of myasthenia gravis,
although similar symptoms have been reported in infants whose
mothers were not treated with these drugs. Anticholinesterase
drugs may cause uterine irritability and induce premature labour
when given IV to pregnant women near term. Use of pyridostigmine
in pregnant women requires that the possible benefits be weighed
against the potential risks.
Manifestations: pyridostigmine overdosage may induce cholinergic
crisis, which is characterized by nausea, vomiting, diarrhoea,
excessive salivation and sweating, increased bronchial
secretions, miosis, lacrimation, bradycardia or tachycardia,
cardiospasm, bronchospasm, hypotension, incoordination, blurred
vision, muscle cramps, weakness, fasciculation, and paralysis.
Extremely high doses may produce CNS symptoms of agitation and
restlessness. Death may result from cardiac arrest or respiratory
paralysis and pulmonary edema. In patients with myasthenia
gravis, in whom overdose is most likely to occur, fasciculation
and parasympathomimetic effects may be mild or absent, making
cholinergic crisis difficult to distinguish from myasthenic
crisis. The time of onset of weakness may indicate whether the
crisis is the result of overdosage or underdosage of (or
resistance to) anticholinesterase drugs. Weakness that begins
approximately 1 hour after drug administration suggests
overdosage, whilst weakness occurring 3 or more hors after drug
administration is more likely to be caused by underdosage or
resistance. Edrophonium can be used to distinguish cholinergic
crisis from myasthenic crisis. (See edrophonium chloride 36:56).
Treatment: In the treatment of pyridostigmine overdosage,
maintaining adequate respiration is of primary importance.
Tracheostomy, bronchial aspiration, and postural drainage may be
required to maintain an adequate airway; respiration can be
assisted mechanically or with oxygen, if necessary.
Pyridostigmine should be discontinued immediately and 1-4 mg of
atropine sulfate administered IV. Additional doses of atropine
may be given very 5-30 minutes as needed to control muscarinic
symptoms. Atropine overdosage should be avoided, as that, unlike
muscarinic effects, the skeletal muscle effects and consequent
respiratory paralysis which can occur following pyridostigmine
overdosage are not alleviated by atropine.
Neuromuscular blocking agents: Pyridostigmine does not
antagonize, and may in fact prolong, the phase 1 block of
depolarizing muscle relaxants such as succinycholine or
decamethonium. Fully established phase 2 (desensitization) block
can be reversed by pyridostigmine, but the individual variation
in transition time between phases 1 and 2 and difficulty in
accurately determining the stage of depolarizing neuromuscular
block at any given time often make anticholinesterase
administration ineffective or dangerous under these
circumstances. Parenteral pyridostigmine effectively antagonizes
the effect of nondepolarizing muscle relaxants (eg.,
tubocurarine, metocurine, gallamine, or pancuronium), and this
interaction is used to therapeutic advantage to reverse muscle
relaxation after surgery. (See uses, under surgery).
Other drugs: Atropine antagonizes the muscarinic effects of
pyridostigmine, and this interaction is utilized to counteract
the muscarinic symptoms of pyridostigmine toxicity.
Anticholinesterase agents are sometimes effective in reversing
neuromuscular block induced by aminoglycoside antibiotics.
However, aminoglycoside antibiotics, local and some general
anaesthetics, antiarrhythmic agents, and other drugs that
interfere with neuromuscular transmission should be used
cautiously, if at all, in patients with myasthenia gravis, and
the dose of pyridostigmine may have to be increased accordingly.
Theoretically, drugs such as dexpanthenol, which are converted to
pantothenic acid in vivo, may have additive effects with
pyridostigmine by increasing production of acetylcholine.
Pyridostigmine bromide is administered orally or by IM or very
slow IV injection. Oral dosage requirements of pyridostigmine
bromide are approximately 30 times those required for parenteral
therapy. Dosage, route, and frequency of administration depend on
the requirements and clinical response of the patient.
Myasthenia gravis: In patients with myasthenia gravis, dosage
requirements may vary from day to day, according to remissions
and exacerbations of the disease and the physical and emotional
stress suffered by the patient. Dosage should be adjusted so the
patient takes larger doses at the times of greatest fatigue (eg.,
30-45 minutes before meals to assist patients who have difficulty
eating). Complete restoration of muscle strength is rare in
myasthenia gravis, and patients should be cautioned not to
increase their dosage above the maximum response level in an
attempt to relieve all symptoms. Mild exacerbations may be
treated under medical supervision by increasing the dosage of
anticholinesterase medication, as long as the increase produces
symptomatic improvement. When anticholinesterase therapy has been
stabilized, patients can be taught to recognise adverse
muscarinic effects and modify their dosage of pyridostigmine
bromide accordingly, or take atropine if necessary. Oral
pyridostigmine bromide reportedly produces fewer adverse
muscarinic effects when it is administered with milk or food.
In the initial treatment of myasthenia gravis, oral
pyridostigmine bromide should be started at a dosage smaller than
that required to produce maximum muscle strength (usually 60 mg 3
times daily for adults), and dosage is gradually increased at
intervals of 48 hours or more. Children may be started on 7 mg/kg
or 200 mg/m2 daily, divided into 5 or 6 oral doses. Changes in
oral dosage may take several days to show results. When a further
increase in dosage produces no corresponding increase in muscle
strength, dosage should be reduced to previous level, so that the
patient receives the smallest dosage necessary to produce
maximum muscle strength. An Edrophonium test may be helpful in
adjusting the dosage. (See Edrophonium chloride 36:56). The usual
oral adult daily maintenance dosage of pyridostigmine bromide in
myasthenia gravis ranges from 60 mg to 1.5 g, with an average of
600 mg. Although the manufacturer states that adults may receive
180-540 mg of pyridostigmine bromide in extended-release tablets
once or twice daily (with at least 6 hours between doses), most
clinicians agree that this dosage form should be used only at
bedtime for patients who are very weak upon awakening.
Pyridostigmine oral solution is especially useful for children
and patients who have difficulty swallowing, and the solution may
be administered through a nasogastric tube, if necessary. Adults
have been given 25 mg of ephedrine sulfate 2-3 times daily and/or
1-2 g of potassium chloride 3-4 times daily in conjunction with
pyridostigmine therapy. (See uses: Myasthenia gravis)
In patients with myasthenia gravis who require parenteral
therapy, 2 mg or approximately 1/30 of the oral dose of
pyridostigmine bromide may be given by IM or very slow IV
injection every 2-3 hours. Large parenteral doses of
pyridostigmine bromide should be accompanied by 0.6-1.2 mg of
atropine sulfate IV to counteract the adverse muscarinic effects
of pyridostigmine, and the patient should be closely observed for
cholinergic reactions. Dosage of pyridostigmine bromide should be
reduced, or if possible, the drug discontinued if the patient is
placed on a ventilator or given corticosteroid therapy.
Myasthenic mothers may be given 1/30 of their usual oral dose by
IM or slow IV injection 1 hour before completion of second stage
labour to provide adequate strength during labour and to protect
the neonate. Neonatal myasthenia gravis may be treated with 5 mg
of pyridostigmine bromide taken orally every 4-6 hours. Because
of the self-limiting nature of the disease in neonates, the daily
dosage of anticholinesterase medication should be gradually
reduced until the drug can be withdrawn.
Myasthenic patients may become refractory to pyridostigmine
after prolonged treatment. Responsiveness may be restored,
especially when resistance may have been caused by overdosage, by
decreasing the dosage or withdrawing the drug for several days
under medical supervision. Large doses of corticosteroids or
corticotrophin have also been used in intensive care facilities
to increase responsiveness to anticholinesterase therapy,
although temporary worsening may occur.
Surgery: For reversal of nondepolarizing neuromuscular blocking
agents after surgery in adults, 10-20 mg (range 0.1-0.25 mg/kg)
of pyridostigmine bromide may be given IV, with or shortly after
0.6-1.2 mg atropine sulfate IV or 0.2-0.6 mg of glycopyrrolate IV
(about 0.2 mg glycopyrrolate for each 5 mg of pyridostigmine
bromide). The effect of each dose of pyridostigmine bromide on
respiration should be carefully observed before additional doses
are given, and assisted ventilation should always be employed.
The Patient should be closely observed to ensure that respiratory
depression does not recur. Full recovery usually occurs within
15-30 minutes, but may be delayed in the presence of extreme
debilitation, hypokalemia, carcinomatosis or with concomitant use
of certain broad spectrum antibiotics (eg., aminoglycosides) or
anaesthetic agents, notably ether. Satisfactory recovery of
respiration and neuromuscular transmission must be assured before
respiratory assistance is discontinued.
Pyridostigmine bromide
ORAL:
solution 60 mg/5 ml MestinonR Syrup (with alcohol) ICN
tablets 60 mg MestinonR (scored) ICN
tablets, extended release 180 mg MestinonR TimespanR scored) ICN
PARENTERAL:
Injection 5 mg/ml MestinonR (with parabens 0.2%) ICN;
RegonolR (with benzyl alcohol 1%)
Organon
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