VA Class:AU300
Pyridostigmine is a reversible anticholinesterase agent.
Pyridostigmine is used to improve muscle strength in the symptomatic treatment of myasthenia gravis. Following oral administration of a conventional (immediate-release) preparation of pyridostigmine, the onset of effect occurs within about 15-30 minutes and the duration is about 3-4 hours.127, 206 Experts state that pyridostigmine should be part of the initial treatment in most patients with myasthenia gravis.125, 128 Although symptomatic improvement can usually be achieved with an anticholinesterase agent, additional treatment with corticosteroids or other immunosuppressive agents may be required.127, 128, 206
Pyridostigmine has been used parenterally for symptomatic treatment of acute exacerbations of myasthenia gravis and when oral therapy was impractical. However, the injectable preparation previously indicated for this use is no longer commercially available in the US, and the currently available parenteral injection is not FDA-labeled for this use.124
Reversal of Neuromuscular Blockade
Pyridostigmine bromide injection is used for reversal of the effects of nondepolarizing neuromuscular blocking agents (e.g., atracurium, cisatracurium, pancuronium, rocuronium, vecuronium) after surgery. An anticholinergic agent such as atropine sulfate or glycopyrrolate should be used in conjunction with pyridostigmine to minimize adverse muscarinic effects of the drug (e.g., bradycardia, bradyarrhythmias, increased secretions, bronchoconstriction).124, 220, 221
Incomplete neuromuscular recovery after surgery can cause prolonged weakness of the upper airway muscles resulting in airway obstruction, hypoxemia, and postoperative respiratory complications.126, 220, 221, 222, 223 Anticholinesterase agents such as pyridostigmine are used to reverse the effects of nondepolarizing neuromuscular blocking agents and reduce the risk of residual neuromuscular blockade.124, 126, 220 Pyridostigmine has been reported to produce less oropharyngeal secretion, bradycardia, and cardiac arrhythmia than neostigmine.
Anticholinesterase agents do not antagonize the phase I block of depolarizing neuromuscular blocking agents such as succinylcholine; therefore, pyridostigmine should not be used to reverse the effects of these agents. (See Drug Interactions: Neuromuscular Blocking Agents.)
Chemical Warfare Agent Poisoning
Pyridostigmine bromide is used in military combat personnel for preexposure prophylaxis against the lethal effects of soman nerve agent poisoning.111, 116 Pyridostigmine is used in conjunction with standard treatment of nerve agent poisoning (i.e., atropine and pralidoxime chloride) and other protective measures such as specifically designed masks, hoods, and overgarments.111 Use of pyridostigmine alone will not be protective against the effects of soman; efficacy of pyridostigmine is dependent on the rapid administration of atropine and pralidoxime following exposure to the nerve agent.111 Pyridostigmine is administered orally prior to an expected exposure to soman (i.e., when under the threat of a nerve agent attack); the drug must be discontinued immediately at the first indication of nerve agent poisoning.111 In addition, pyridostigmine should not be taken after exposure to soman.111 If pyridostigmine is taken immediately before exposure or at the same time as soman poisoning, the drug is not likely to be effective and may exacerbate the effects of a sublethal exposure to soman.111
The most toxic of the known chemical warfare agents are the nerve agents.112, 113, 114 Most nerve agents are liquid at room temperature (although most are volatile at ambient temperatures, the term nerve gas is a misnomer); nerve agents are readily absorbed after inhalation of aerosols (e.g., following an explosion), ingestion, or dermal contact.112, 113, 114 Nerve agents (e.g., sarin, soman, tabun, VX [metylphosphonothionic acid]) are chemically similar to the organophosphate pesticides and exert their biologic effects by inhibiting acetylcholinesterase enzymes.112, 113, 114 Nerve agents alter cholinergic synaptic transmission at neuroeffector junctions (muscarinic effects), at skeletal myoneural junctions and autonomic ganglia (nicotinic effects), and in the CNS.112, 114 (See Uses: Chemical Warfare Agent Poisoning, in Pralidoxime 92:12.)
Pyridostigmine was approved for preexposure prophylaxis against effects of soman under FDA's animal efficacy rule that allows use of animal data of effectiveness for certain conditions when a drug cannot be ethically tested in humans.111 Studies in animals indicate that administration of pyridostigmine prior to exposure to soman reduces lethality of soman provided that atropine and pralidoxime are given immediately after exposure to the nerve agent.111 Administration of pyridostigmine in conjunction with atropine and pralidoxime increases survival after lethal exposures to soman above that provided by atropine and pralidoxime alone.116
Pyridostigmine bromide is administered orally (as conventional tablets, extended-release tablets, or oral solution) or by IV injection.123, 124 The drug also has been administered by IM injection,125 but the manufacturer of the currently available injectable preparation states that the injection is for IV use only.124
When used as a neuromuscular reversal agent, pyridostigmine should be administered only by trained clinicians experienced in the use of such agents.124 Patients must be well ventilated and have a patent airway prior to administration of pyridostigmine and until complete recovery of normal respiration.124 Continuous monitoring of neuromuscular function is recommended to ensure adequate reversal from the neuromuscular block.124 To exclude with certainty the possibility of residual paralysis, an objective (quantitative) method of monitoring such as peripheral nerve stimulation should be used in conjunction with other clinical assessments (e.g., observation of skeletal muscle tone, respiratory measurements).124, 220, 222, 223, 224, 230 Adequate recovery of neuromuscular function generally is defined as a train-of-four (TOF) ratio of 0.9 in addition to the patient's ability to maintain satisfactory ventilation and a patent airway.124, 220
When pyridostigmine is administered as conventional dosage forms for the symptomatic treatment of myasthenia gravis, the dosage should be adjusted so that larger doses are taken at times of greatest fatigue (e.g., 30-45 minutes before meals to assist patients who have difficulty eating).
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.
In patients with myasthenia gravis, dosage requirements of pyridostigmine bromide may vary on a daily basis according to remissions and exacerbations of the disease and the patient's physical and emotional condition. Dosage and frequency of administration should be individualized.123, 128 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 pyridostigmine, as long as the increase produces symptomatic improvement.
In the initial treatment of myasthenia gravis in adults, oral pyridostigmine bromide should be started at a low dosage (usually 60 mg 3 times daily as conventional tablets or oral solution), and increased gradually at intervals of 48 hours or more to provide maximum relief of symptoms. 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.
Pyridostigmine bromide extended-release tablets (Mestinon® Timespan®) are designed to slowly release the drug for a prolonged duration of action.123 The immediate effect of a 180-mg extended-release tablet is similar to that of a 60-mg conventional tablet, but the duration of effect is about 2.5 times longer.123 Although the manufacturer states that adults may receive 180-540 mg of pyridostigmine bromide as extended-release tablets once or twice daily (with at least 6 hours between doses), this dosage form is generally used only at bedtime in patients who awaken at night or in the early morning with impairing weakness.127, 206
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 the previous level, so that the patient receives the smallest dosage necessary to produce maximum strength.
In adults with myasthenia gravis requiring parenteral therapy, approximately 1/30 of the usual oral dose of pyridostigmine bromide has been given by IM or very slow IV injection. However, the currently available parenteral preparation (Regonol®) is not FDA-labeled for the treatment of myasthenia gravis.124
Neonatal myasthenia gravis† has been treated with an oral pyridostigmine bromide dosage of 5 mg every 4-6 hours (given as an immediate-release formulation) or, if parenteral therapy is necessary, an IV or IM dosage of 0.05-0.15 mg/kg (maximum single dose of 10 mg) every 4-6 hours.125 In children† with myasthenia gravis, some clinicians have suggested an oral dosage of 7 mg/kg daily (given as an immediate-release formulation and divided into 5 or 6 doses)129 or, if parenteral therapy is necessary, an IV or IM dosage of 0.05-0.15 mg/kg (maximum single dose of 10 mg) every 4-6 hours.125
Reversal of Neuromuscular Blockade
For reversal of the effects of nondepolarizing neuromuscular blocking agents in adults, doses of 0.1-0.25 mg/kg (approximately 10-20 mg) of pyridostigmine bromide may be given IV, shortly after or simultaneously with 0.6-1.2 mg of atropine sulfate IV (or an equipotent dose of glycopyrrolate).124 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's muscle twitch response to peripheral nerve stimulation should be monitored, and pyridostigmine bromide should be administered after spontaneous recovery of neuromuscular function has begun.124 (See Dosage and Administration: Administration.) Satisfactory reversal is evident by adequate voluntary respiration, respiratory measurements, and use of a peripheral nerve stimulator device.124 The patient must be well-ventilated and a patent airway and manual or mechanical ventilation should be maintained until complete recovery of normal respiration is assured.124 Recurrence of paralysis is unlikely after satisfactory reversal of the effects of nondepolarizing neuromuscular blocking agents has been attained.124 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 (e.g., aminoglycosides) or anesthetic agents. Satisfactory recovery of respiration and neuromuscular transmission must be assured before respiratory assistance is discontinued.
Chemical Warfare Agent Poisoning
For preexposure prophylaxis against the lethal effects of soman nerve agent poisoning, the recommended dosage of pyridostigmine bromide is 30 mg orally every 8 hours.111 Administration of pyridostigmine bromide should be started several hours prior to anticipated exposure to the nerve agent.111 At the first sign of nerve agent poisoning, pyridostigmine should be discontinued and treatment with atropine and pralidoxime instituted immediately.111
The effects of continued administration of pyridostigmine for longer than 14 consecutive days for this indication have not been definitively established.111 Administration of the drug for longer than 14 consecutive days should be evaluated in the context of the likelihood of exposure to soman.111
Since pyridostigmine is excreted predominantly by the kidneys, the manufacturer of Mestinon® states that lower dosages of pyridostigmine bromide may be required in patients with renal disease. In such patients, the dosage should be titrated carefully to produce the desired effect.
Adverse effects of pyridostigmine are generally due to an exaggerated response to parasympathetic stimulation and include adverse muscarinic effects such as nausea, vomiting, diarrhea, increased peristalsis, miosis, excessive salivation and sweating, increased bronchial secretions, abdominal cramps, bradycardia, and bronchospasm. Weakness, muscle cramps, fasciculation, and, rarely, hypotension may also occur. Thrombophlebitis has been reported after IV administration. Pyridostigmine reportedly produces 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.
The most frequently reported adverse effects associated with pyridostigmine administration in 41,650 soldiers (the 18th Airborne Corps) who received the drug at the onset of hostilities of Operation Desert Storm (Jan 1991) were GI and urinary tract symptoms.116 Adverse GI effects (increased flatus, loose stools, abdominal cramps, nausea) occurred in 50% or more of soldiers; urinary urgency and frequency occurred in 5-30% of soldiers; headache, rhinorrhea, diaphoresis, or tingling of the extremities was reported in less than 5% of soldiers.116 Other adverse effects reported in these soldiers include bad dreams, worsening of acute bronchitis, slurred speech, rash, vertigo, asthma exacerbation, hypertension, or bleeding episode.116 Approximately 1% of soldiers experiencing an adverse effect sought medical attention; less than 0.1% of soldiers discontinued the drug on medical advice.116 While most soldiers were aware that pyridostigmine altered their normal physiology, these changes did not interfere with their daily lives.116 Soldiers taking pyridostigmine under combat conditions reportedly were able to perform at full effectiveness.116
The possible association between chronic illness in Persian Gulf War veterans (Jan 1991 war) and pyridostigmine has been evaluated.119 Data from a 1996-1997 survey in 700 reserve male veterans indicated that use of pyridostigmine during the Gulf War was associated with a decline in self-reported health status after the war.119 Reactions to vaccines and other medications also were associated with a decline in self-reported health status.119 Results from this survey and other data suggest that pyridostigmine alone or in combination with other factors such as stress or other toxic exposures may play a role in some of the symptoms experienced by many Gulf War veterans.119
Precautions and Contraindications
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 the muscarinic effects of pyridostigmine. Patients who are hypersensitive to bromides may develop skin reactions such as acneiform rash during pyridostigmine bromide therapy; however, these reactions usually disappear when the drug is discontinued.
When pyridostigmine is used to treat myasthenia gravis, individual muscle groups may respond differently and the drug may produce 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 weakened by overdosage, followed by the muscles of the shoulder girdle and upper extremities, and finally the pelvic girdle and extraocular and leg muscles.
When pyridostigmine is used for preexposure prophylaxis against the lethal effects of soman, efficacy of pyridostigmine depends on the rapid use of atropine and pralidoxime following exposure to the nerve agent.111 Use of pyridostigmine alone will not be protective against the effects of soman.111 The primary means of protection against exposure to nerve agents is wearing protective garments including masks, hoods, and overgarments specifically designed for this use.111 Individuals should not solely rely on pyridostigmine, atropine, and pralidoxime to provide complete protection against the effects of soman.111 Pyridostigmine should not be administered after exposure to soman.111 If pyridostigmine is taken immediately before exposure (e.g., when the attack alarm is given), at the same time as soman poisoning, or after such exposure, the drug is not likely to be effective and may exacerbate the effects of a sublethal exposure to soman.111
If military personnel receiving pyridostigmine experience serious adverse effects such as difficult breathing, severe dizziness, or loss of consciousness, they should be advised to temporarily discontinue the drug and immediately seek medical care.111
Caution should be observed when pyridostigmine is used in patients with renal impairment.111 Since pyridostigmine is excreted predominantly by the kidneys, lower dosages of the drug may be required in patients with renal disease.123 In such patients, the dosage should be titrated carefully to produce the desired effect.123
Pyridostigmine should be used with caution in patients with bronchial asthma, chronic obstructive pulmonary disease, bradycardia, or cardiac arrhythmias. In addition, pyridostigmine should be used with caution in patients receiving concomitant therapy with a β-adrenergic blocking agent for the treatment of hypertension or glaucoma.111
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.
The manufacturers state that safety and efficacy of pyridostigmine bromide have not been established pediatric patients.111, 123, 124 However, the drug has been used for the treatment of juvenile myasthenia gravis†.128, 129
Regonol® injection contains benzyl alcohol as a preservative.124 Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates.103, 104, 105, 106, 107, 108 Toxicity appears to have resulted from administration of large amounts (i.e., 100-400 mg/kg daily) of benzyl alcohol in these neonates.103, 104, 105, 106, 107, 108 Although use of drugs preserved with benzyl alcohol should be avoided in neonates whenever possible,103, 105 the American Academy of Pediatrics states that the presence of small amounts of the preservative in a commercially available injection should not proscribe its use when indicated in neonates.103 The manufacturer recommends that clinicians administering the drug should take into account the total daily metabolic load of benzyl alcohol from all sources.124
Clinical studies of pyridostigmine did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger individuals.111 Drug dosage should be selected carefully in geriatric individuals taking into consideration the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly.111 Because patients with renal impairment may be at increased risk of pyridostigmine-induced toxicity and geriatric individuals may have decreased renal function, the pyridostigmine bromide dosage should be selected carefully in patients in this age group.111 It may be advisable to monitor renal function in geriatric patients.111
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 the treatment of myasthenia gravis, although similar symptoms have also been reported in infants whose mothers were not treated with these drugs. Some experts state that oral pyridostigmine is the first-line treatment of choice for pregnant women with myasthenia gravis.128 However, anticholinesterase drugs may cause uterine irritability and induce premature labor 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.
Since it is not known whether pyridostigmine is distributed into milk, the drug should be used with caution in nursing women.111
Pyridostigmine does not antagonize, and may in fact prolong, the phase I block of depolarizing neuromuscular blocking agents such as succinylcholine. Fully established phase II (desensitization) block can be reversed by pyridostigmine, but the individual variation in transition time between phases I and II 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 neuromuscular blocking agents (e.g., atracurium, cisatracurium, pancuronium, rocuronium, vecuronium), and this interaction is used to therapeutic advantage to reverse muscle relaxation after surgery. (See Uses: Reversal of Neuromuscular Blockade.)
When pyridostigmine is used for nerve agent prophylaxis in soldiers, particular caution is advised if a depolarizing neuromuscular blocking agent (i.e., succinylcholine) is administered during surgery since the degree of neuromuscular blockage may be enhanced by pyridostigmine.111, 117 Conversely, doses of nondepolarizing neuromuscular blocking agents (e.g., pancuronium) may need to be increased in soldiers who have received pyridostigmine.111
Beta-Adrenergic Blocking Agents
Pyridostigmine should be used with caution in patients receiving concomitant therapy with a β-adrenergic blocking agent.111, 118 Military personnel receiving therapy with a β-adrenergic blocking agent are likely to be receiving such therapy for the treatment of hypertension or glaucoma; the prescribing information for military combat use of pyridostigmine advises that the drug be used with caution in patients receiving concomitant therapy with a β-adrenergic blocking agent for the treatment of hypertension or glaucoma.111 While no difference in heart rate, plasma catecholamine concentrations, or resting blood pressure was observed in military personnel receiving a β-adrenergic blocker for the treatment of mild to moderate hypertension and pyridostigmine bromide 30 mg every 8 hours for 5 doses relative to those receiving a β-adrenergic blocker and placebo, the effect of pyridostigmine in patients receiving a β-adrenergic blocker who have borderline heart failure or atrioventricular conduction disturbances has not been determined.118
Pyridostigmine may produce additive effects (i.e., cause or exacerbate problems with night vision) in patients receiving ophthalmic anticholinesterases (e.g., physostigmine) for the treatment of glaucoma.111
Bradycardia associated with the administration of opiate agonists may exacerbate pyridostigmine-induced bradycardia.111
The potential exists that pyridostigmine and mefloquine may have additive effects on the GI tract since the most frequently reported adverse effect of each drug is loose stools.111 Additive effects on atrial rate have been reported when pyridostigmine and mefloquine were used concomitantly.111
Atropine antagonizes the muscarinic effects of pyridostigmine, and this interaction is utilized to counteract the muscarinic symptoms of pyridostigmine toxicity. However, atropine may mask manifestations of pyridostigmine overdose if used concomitantly, possibly increasing the risk of inadvertent induction of cholinergic crisis.123 (See Acute Toxicity: Manifestations.)
Anticholinesterase agents are sometimes effective in reversing neuromuscular block induced by aminoglycoside antibiotics. However, aminoglycoside antibiotics, local and some general anesthetics, antiarrhythmic agents, and other drugs that interfere with neuromuscular transmission should be used cautiously, if at all, in patients receiving pyridostigmine.
Pyridostigmine overdosage may induce cholinergic crisis, which is characterized by nausea, vomiting, diarrhea, 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, restlessness, confusion, visual hallucinations, and paranoid delusions. Electrolyte abnormalities, possibly resulting from high serum bromide concentrations, also have been reported. 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 adverse 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, while weakness occurring 3 or more hours after drug administration is more likely to be caused by underdosage or resistance.
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 every 5-30 minutes as needed to control muscarinic symptoms. Atropine overdosage should be avoided, as tenacious secretions and bronchial plugs may result. It should be kept in mind that, unlike muscarinic effects, the skeletal muscle effects and consequent respiratory paralysis which can occur following pyridostigmine overdosage are not alleviated by atropine.
Pyridostigmine is an anticholinesterase agent that inhibits the hydrolysis of acetylcholine by competing with acetylcholine for attachment to acetylcholinesterase. The pyridostigmine-enzyme complex is hydrolyzed 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.
Pyridostigmine is a reversible inhibitor of acetylcholinesterase; nerve agents irreversibly inhibit acetylcholinesterase.111, 117, 118, 120, 121 Toxicity of nerve agents, including soman, results from irreversible inhibition of acetylcholinesterase at nicotinic receptors (resulting in muscle fasciculation, weakness, and paralysis), muscarinic receptors (resulting in excessive respiratory secretions and bronchoconstriction), and at cholinergic receptors in the CNS (resulting in loss of consciousness, seizures, and respiratory depression).111, 121, 122 Although the mechanism of action of pyridostigmine in nerve agent poisoning has not been definitely established, the effect of the drug is presumed to result from reversible binding of pyridostigmine to a critical number of acetylcholinesterase active sites in the peripheral nervous system, blocking access of the nerve agent to the active site, and thereby protecting the enzyme from irreversible inhibition by the nerve agent.111, 117, 118 Following nerve agent exposure, pyridostigmine is hydrolyzed from acetylcholinesterase and also can be displaced by administration of pralidoxime; these actions regenerate functional acetylcholinesterase enzyme.120, 121 Reversal of pyridostigmine-induced inhibition of acetylcholinesterase results in release of sufficient enzyme to sustain life.111, 117, 118, 120, 121 Administration of pyridostigmine bromide in a dosage of 30 mg every 8 hours results in binding of 20-40% of acetylcholinesterase.117, 120, 121 Between 20-40% cholinesterase inhibition is considered adequate to protect against nerve agents.121 Pyridostigmine is administered prior to an expected exposure to a nerve agent and discontinued immediately at the first indication of nerve agent poisoning.111 Based on the mechanism of action of pyridostigmine, administration of the drug immediately before or during exposure to soman is not expected to be beneficial.111
Pralidoxime chloride is used concomitantly with atropine as standard treatment of nerve agent poisoning.114, 121 To be effective, pralidoxime must be administered before aging (the average time required for irreversible binding) of the inhibited enzyme occurs; once aging is completed, cholinesterase cannot be reactivated by administration of pralidoxime.114, 121 (See Pharmacology in Pralidoxime 92:12.) Aging occurs at different rates for different nerve agents.122 Soman has an aging half-life of 2-6 minutes in humans.121, 122 In contrast, the aging half-life for tabun, sarin, or VX is about 14, 3-5, or 48 hours, respectively.121 Because of the rapid aging of the soman-acetylcholinesterase complex, it is unlikely that pralidoxime would be administered early enough to reactivate cholinesterase in victims exposed to this nerve agent.121 However, acetylcholinesterase that is bound to pyridostigmine prior to exposure to the nerve agent can be reactivated by pralidoxime.120, 121 Pyridostigmine is approved by FDA for preexposure prophylaxis against the lethal effects of soman nerve agent poisoning; the effect of pyridostigmine against other nerve agents remains to be established.111, 116 In animal studies, administration of pyridostigmine conferred benefit against soman or tabun nerve agents, but not against sarin or VX.111, 121
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.
Pyridostigmine bromide is poorly absorbed from the GI tract. The bioavailability of orally administered pyridostigmine bromide is 10-20%.111, 115 Extended-release tablets reportedly release one-third of the total 180-mg dose immediately after ingestion and the remainder over 8-12 hours; however, release of the drug from this dosage form may be erratic and unpredictable. Pyridostigmine has a variable duration of action in patients with myasthenia gravis, depending on the physical and emotional stress suffered by the patient and the severity of the disease. However, it generally has a slower onset and a longer duration of action than neostigmine. After oral administration of conventional (immediate-release) tablets, pyridostigmine generally has an onset of action of 30-45 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 2-3 hours in most patients. Following IM administration, the drug has an onset of action within about 15 minutes.
Following oral administration of a single 30-mg dose of pyridostigmine bromide in fasting individuals, peak plasma concentration is achieved in 2.2 hours.111 Following oral administration of immediate-release pyridostigmine bromide 30 mg every 8 hours for 21 days, steady-state trough plasma concentrations average about 25% of the peak plasma concentration following a single oral 30-mg dose.111 The pharmacokinetics of pyridostigmine bromide are linear over a dose range of 30-60 mg.111 Pharmacodynamic parameters of pyridostigmine have been determined using red blood cell acetylcholinesterase activity.115 This pharmacodynamic end point was selected because red blood cell acetylcholinesterase activity has been shown to correlate with survival in nerve agent exposure in some animal models.115 The maximal effect of pyridostigmine bromide 30 mg on red blood cell acetylcholinesterase occurs shortly after the peak plasma concentration of pyridostigmine and returns to baseline within 8 hours.115
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. A volume of distribution of approximately 19 L has been reported.111 Information on protein binding is not available.111
The elimination half-life of pyridostigmine is 1.05-1.86 or 3 hours following IV administration or oral administration of conventional tablets, respectively, in patients with normal renal function.100, 101, 102, 110, 111 A prolonged elimination half-life of approximately 6.3 hours has been reported in anephric patients.102
Pyridostigmine undergoes hydrolysis by cholinesterases; the drug also is 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 to anticholinesterase medication which occurs in some severely ill patients. Approximately 80-90% of a dose of pyridostigmine is excreted unchanged by the kidneys;100, 101, 102 the drug and its metabolites are excreted in urine by tubular secretion and glomerular filtration. Following IV administration, total body clearance of pyridostigmine is about 8.5-9.7 mL/minute per kg.100, 101, 102, 110 In anephric patients, clearance was decreased to 0.21 mL/minute per kg.102 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 -methylpyridinium, have been detected in urine up to 72 hours after a single IV dose.
Pyridostigmine is a synthetic quaternary ammonium compound that is pharmacologically similar to neostigmine. 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 odor 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). The injectable preparation of pyridostigmine bromide currently commercially available in the US (Regonol®) contains benzyl alcohol as a preservative.124
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.123
Pyridostigmine bromide 60-mg tablets, extended-release tablets, and oral solution should be stored at 25°C (but may be exposed to temperatures of 15-30°C).123 The injectable preparation should be stored at 25°C (but may be exposed to temperatures of 15-30°C) and should be protected from light.124
Pyridostigmine bromide 30-mg immediate-release tablets for military use should be stored at 2-8°C and protected from light.111 Pyridostigmine bromide tablets for military use that have been removed from the refrigerator for longer than 3 months should not be used; military personnel should be advised to discard the contents of individual unit packages 3 months after issue.111
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Solution | 60 mg/5 mL | Mestinon® Oral Solution | |
Tablets, immediate-release | 60 mg* | Mestinon® (scored) | Bausch | |
Pyridostigmine Bromide Tablets | ||||
Tablets, extended-release | 180 mg* | Mestinon® Timespan® (scored) | Bausch | |
Pyridostigmine Bromide Extended-release Tablets | ||||
Parenteral | Injection | 5 mg/mL |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
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