Pyridostigmine …

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 03.12.2021
Released 02.23.1999
Expires For CME 03.12.2024

Pyridostigmine

Author: K K Jain MD†

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Pyridostigmine

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Introduction

Historical note and terminology

The beneficial effect of physostigmine, a cholinesterase inhibitor, on myasthenia gravis was first described by Mary Broadfoot Walker in 1934 (28). Physostigmine was soon replaced by prostigmine because of its side effects (29). Prostigmine remained the primary drug for myasthenia gravis until the 1950s when it was replaced by its analog, pyridostigmine. Pyridostigmine has a longer duration of action and fewer muscarinic side effects than does prostigmine. It is marketed for the treatment of myasthenia gravis. Even though data from well controlled clinical trials to support its clinical use are lacking, pyridostigmine is the most used first-line therapy for myasthenia gravis based on its use in practice for over 50 years (18). In 2003, the FDA approved pyridostigmine for use by the military for increasing troops' chances of surviving exposure to the nerve gas soman. Because no human trials have been done, the approval was based on reviewing effectiveness studies in animals.

Pharmacology

Pharmacodynamics. Pyridostigmine bromide is an orally active cholinesterase inhibitor. By preventing destruction of acetylcholine, it facilitates transmission of nerve impulses across the neuromuscular junction. The onset of action is in 10 to 30 minutes and the duration of action is 3 to 6 hours. Pyridostigmine differs from closely-related cholinesterase inhibitors used for the symptomatic treatment of Alzheimer disease such as donepezil in that it does not cross the blood-brain barrier, whereas donepezil does so, thus, limiting its action to the peripheral nervous system. Pyridostigmine, therefore, does not modulate immune response as elicited by centrally acting cholinesterase inhibitors because of the link between the central nervous system and terminal effector cells in the immune system (24).

Physostigmine produces a dose-dependent reduction in oxidative burst induced by polymorphonuclear neutrophils, independent of neuronal release of acetylcholine, which modulates immune function, but neostigmine lacks this effect (04).

Organophosphates exert their toxic effects by inhibiting acetylcholinesterase from terminating the action of acetylcholine at postsynaptic sites in cholinergic nerve terminals. Pyridostigmine pretreatment protects a critical fraction of acetylcholinesterase activity in the marmoset diaphragm, which is sufficient to allow the animal to breathe despite exposure to a dose of soman that is lethal in unprotected animals (12). In vitro pretreatment of human muscles with pyridostigmine bromide has been shown to protect up to 20% of muscle acetylcholinesterase and ameliorate some deleterious effects on endplate physiology induced by soman (19).

Animal experimental studies have shown that intravenous physostigmine is an effective treatment against sarin, an organophosphorus poison that causes irreversible inhibition of acetylcholinesterase in the nervous system. Strategies for prophylaxis against organophosphorus and nerve agent poisoning still include the administration of reversible cholinesterase inhibitors such as pyridostigmine, alone or in combination with other drugs. Pyridostigmine, as pretreatment for nerve agent poisoning, is in use by most of the armed forces in Western countries, but it barely crosses the blood-brain barrier and provides no protection against nerve agent–induced central injury.

Pharmacokinetics. Important points are as follows:

	• After a 60 mg oral dose of pyridostigmine bromide, oral availability is 11.5% to 18.9% as determined from the area under the curve ratio.
	• In healthy subjects, absorption proceeds at a slower rate than elimination. The mean half-life of the plasma level decline after oral dosing is 3 hours and 20 minutes, twice the length of terminal elimination half-life after intravenous infusion.
	• Patients with myasthenia gravis who receive continuous therapy with oral pyridostigmine have area under the curve values per unit dose corresponding to those in healthy subjects.
	• Prolonged duration of action of pyridostigmine in the elderly is due to its slow plasma clearance.
	• Pyridostigmine is excreted unchanged mainly by the kidneys, and lower doses may be required in patients with renal disease.

Indications

Pyridostigmine is indicated for treatment of myasthenia gravis. Pyridostigmine is also approved for treatment of poisoning by nerve gas soman.

Off-label uses

	• Prophylactic use in soldiers against possible exposure to poisonous nerve gases. Early treatment with pyridostigmine is useful for improving clinical symptoms and prognosis of congenital myotonia syndrome with episodic apnea caused by gene mutation of choline acetyltransferase (16).
	• Autonomic neuropathy associated with myasthenia gravis.
	• Autoimmune gastrointestinal dysmotility has been treated successfully with pyridostigmine.
	• REM-related reduction of obstructive sleep apnea after physostigmine may provide a treatment option if the effects are maintained in long-term studies.
	• Treatment of vincristine-induced bilateral ptosis.
	• Relief from episodic weakness in paramyotonia congenita (15).
	• A randomized controlled study in rats has shown that continuous pyridostigmine infusion improves muscle weakness after 7 days and 14 days of immobilization (11).
	• Pyridostigmine, combined with pyridoxine, has been used successfully for the treatment of children with vincristine-induced neuropathy (03).
	• Continuous infusion of physostigmine has been used successfully to reverse anticholinergic delirium in a child who unintentionally ingested olanzapine (13).
	• Pyridostigmine has been used for treatment of severe dysphagia and dyspnea as a complication of botulinum toxin treatment of head and neck dystonias (30). Pyridostigmine prevents the breakdown of acetylcholine at the neuromuscular junction, thus, making more neurotransmitters available for the muscles.
	• Treatment of dysphagia in Wallenberg syndrome (10).
	• A patient with stiff-person syndrome and evidence of presynaptic neuromuscular transmission defect responded to administration of pyridostigmine (17).
	• Prolonged beneficial response to treatment with high-dose pyridostigmine was reported in a patient with nemaline myopathy due to KLHL40 mutations (22).
	• A randomized open-label clinical trial provides class IV evidence that for patients with neurogenic orthostatic hypotension, long-term treatment with midodrine alone, pyridostigmine alone, or both midodrine and pyridostigmine is safe and has similar effects in improving orthostatic blood pressure drop up to 3 months (09).
	• Oral pyridostigmine is effective in the symptomatic treatment of aerodigestive complications of botulinum toxin injections (07).
	• Pyridostigmine has been used to facilitate motor recovery after snake bite and an allergic reaction to anti-snake venom (01).
	• Lack of improvement of myasthenia patients on long-term pyridostigmine therapy due to acetylcholine receptor deficiency can be ameliorated by the addition of the beta2-adrenergic agonist solbutamol, which enhances the neuromuscular junction synaptic structure (27).
	• Pyridoxine plus pyridostigmine therapy may be an effective option in the treatment of vincristine-induced peripheral neuropathy in pediatric patients with acute lymphoblastic leukemia (Aydin Köoer et al 2021).

Adverse effects

Skin rash due to leukocytoclastic vasculitis, a hypersensitivity reaction to medications, has been reported in a patient with myasthenia gravis after starting treatment with pyridostigmine (25). Adverse effects are mainly related to overdose and are muscarinic or nicotinic.

	• Muscarinic effects include nausea, vomiting, diarrhea, increased intestinal peristalsis, increased salivation, and increased bronchial secretions. These can be counteracted with atropine (0.4 to 0.6 mg orally 2 or 3 times).
	• Nicotinic side effects are muscle cramps and weakness.

Normally pyridostigmine does not penetrate the blood-brain barrier, and the effects are mainly on the peripheral nervous system. However, under conditions of stress, such as war, pyridostigmine may penetrate the blood-brain barrier and cause neurotoxicity.

Pyridostigmine, by cholinergic stimulation, decreases heart rate at rest and during exercise following sub-therapeutic doses with minimal side effects and without interfering with exercise tolerance and ventilation variables in healthy volunteers.

Release of reactive oxygen species from prophylactic use of pyridostigmine bromide in the Gulf War, which is known to cause neuronal damage, triggered the autoimmune reaction in Gulf War illness (20). Pyridostigmine was used during the Gulf War, but no sequelae related to it have been proven. However, blood biochemistry and oxidative stress biomarkers imply that long-term use of pyridostigmine might possibly change the basal metabolism and cause cellular damage with inflammatory changes, indicating a possible link to Gulf War illness (14).

In contrast to therapeutic use, diagnostic physostigmine administration in emergency department patients suspected of having antimuscarinic delirium is not associated with any significant complications.

References

01: Ahuja V, Chander A, Sawal N. The role of pyridostigmine in recovery from motor paralysis in a snakebite patient with an allergic reaction to anti-snake venom. Trop Doct 2020. [Epub ahead of print.] PMID 31902297
02: Aydin Köker S, Gözmen S, Demirağ B, et al. Effect of pyridoxine plus pyridostigmine treatment on vincristine-induced peripheral neuropathy in pediatric patients with acute lymphoblastic leukemia: a single-center experience. Neurol Sci 2021. Epub ahead of print. PMID 33439396
03: Akbayram S, Akgun C, Doğan M, Sayin R, Caksen H, Oner AF. Use of pyridoxine and pyridostigmine in children with vincristine-induced neuropathy. Indian J Pediatr 2010;77(6):681-3. PMID 20532679
04: Bitzinger DI, Zausig YA, Paech C, et al. Modulation of immune functions in polymorphonuclear neutrophils induced by physostigmine, but not neostigmine, independent of cholinergic neurons. Immunobiology 2013;218(8):1049-54. PMID 23434434
05: Blichfeldt-Lauridsen L, Hansen BD. Anesthesia and myasthenia gravis. Acta Anaesthesiol Scand 2012;56(1):17-22. PMID 22091897
06: Bobadilla-Quesada EJ, Natera-de Benito D, Carrera-García L, et al. Early and long-term effect of the treatment with pyridostigmine in patients with GMPPB-related congenital myasthenic syndrome. Neuromuscul Disord 2020;30(9):719-26. PMID 32819792
07: Boerner RM, Young DL, Gnagi SH, White DR, Halstead LA. Pyridostigmine for the reversal of severe adverse reactions to botulinum toxin in children. J Pediatr 2018;194:241-3. PMID 29275924
08: Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 9th edition. Philadelphia, PA: Lippincott Williams and Wilkins, 2011.
09: Byun JI, Moon J, Kim DY, et al. Efficacy of single or combined midodrine and pyridostigmine in orthostatic hypotension. Neurology 2017;89(10):1078-86. PMID 28794253
10: Eker A, Kaymakamzade B, Akpinar S. Treatment of Wallenberg's syndrome related dysphagia with pyridostigmine. Acta Neurol Belg 2017;117(1):329-31. PMID 27424039
11: Frick CG, Helming M, Martyn JA, Blobner M, Fink H. Continuous administration of pyridostigmine improves immobilization-induced neuromuscular weakness. Crit Care Med 2010;38(3):922-7. PMID 20009758
12: Haigh JR, Adler M, Apland JP, et al. Protection by pyridostigmine bromide of marmoset hemi-diaphragm acetylcholinesterase activity after soman exposure. Chem Biol Interact 2010;187(1-3):416-20. PMID 20144889
13: Hail SL, Obafemi A, Kleinschmidt KC. Successful management of olanzapine-induced anticholinergic agitation and delirium with a continuous intravenous infusion of physostigmine in a pediatric patient. Clin Toxicol (Phila) 2013;51(3):162-6. PMID 23473460
14: Karasova JZ, Hroch M, Pohanka M, et al. Pyridostigmine bromide and its relation to Gulf War illness. Toxin Reviews 2018. Available at: https://doi.org/10.1080/15569543.2018.1480496.
15: Khadilkar SV, Singh RK, Mansukhani KA, Urtizberea JA, Sternberg D. Relief from episodic weakness with pyridostigmine in paramyotonia congenita: a family study. Muscle Nerve 2010;41(1):133-7. PMID 19768756
16: Liu ZM, Fang F, Ding CH, et al. Clinical and genetic characteristics of congenital myasthenia syndrome with episodic apnea caused by CHAT gene mutation: a report of 2 cases. [Article in Chinese] Zhonghua Er Ke Za Zhi 2018;56(3):216-20. PMID 29518833
17: Lo YL, Tan YE. Presynaptic neuromuscular transmission defect in the stiff person syndrome. BMC Neurol 2016;16(1):249. PMID 27905901
18: Maggi L, Mantegazza R. Treatment of myasthenia gravis: focus on pyridostigmine. Clin Drug Investig 2011;31(10):691-701. PMID 21815707
19: Maselli RA, Henderson JD, Ng J, Follette D, Graves G, Wilson BW. Protection of human muscle acetylcholinesterase from soman by pyridostigmine bromide. Muscle Nerve 2011;43(4):591-5. PMID 21404290
20: Moss JI. Gulf War illnesses are autoimmune illnesses caused by reactive oxygen species which were caused by nerve agent prophylaxis. Med Hypotheses 2012;79(2):283-4. PMID 22632735
21: Muenster T, Forst J, Goerlitz P, Schmitt HJ. Reversal of rocuronium-induced neuromuscular blockade by pyridostigmine in patients with Duchenne muscular dystrophy. Paediatr Anaesth 2008;18(3):251-5. PMID 18230069
22: Natera-de Benito D, Nascimento A, Abicht A, et al. KLHL40-related nemaline myopathy with a sustained, positive response to treatment with acetylcholinesterase inhibitors. J Neurol 2016;263(3):517-23. PMID 26754003
23: Norwood F, Dhanjal M, Hill M, et al. Myasthenia in pregnancy: best practice guidelines from a U.K. multispecialty working group. J Neurol Neurosurg Psychiatry 2014;85(5):538-43.** PMID 23757420
24: Pohanka M. Inhibitors of acetylcholinesterase and butyrylcholinesterase meet immunity. Int J Mol Sci 2014;15(6):9809-25. PMID 24893223
25: Singh G, Hodgson T, Clarke DE. Leukocytoclastic vasculitis secondary to pyridostigmine (Mestinon): report of a possible first case. Perm J 2017;21.pii:15-240. PMID 28080955
26: Sussman J, Farrugia ME, Maddison P, Hill M, Leite MI, Hilton-Jones D. Myasthenia gravis: association of British Neurologists' management guidelines. Pract Neurol 2015;15(3):199-206. PMID 25977271
27: Vanhaesebrouck AE, Webster R, Maxwell S, et al. β2-Adrenergic receptor agonists ameliorate the adverse effect of long-term pyridostigmine on neuromuscular junction structure. Brain 2019;142(12):3713-27. ** PMID 31633155
28: Walker MB. Treatment of myasthenia gravis with physostigmine. Lancet 1934;1:1200-1.
29: Walker MB. Case showing the effect of prostigmine on myasthenia gravis. Proc Roy Soc Med 1935;28:759-61. PMID 19990268
30: Young DL, Halstead LA. Pyridostigmine for reversal of severe sequelae from botulinum toxin injection. J Voice 2014;28(6):830-4. PMID 25008379

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Pyridostigmine

Other Pertinent Drugs

cholinesterase inhibitors
donepezil
galantamine
neostigmine
physostigmine
- prostigmin

Also Relevant

Blood-brain barrier
Congenital myasthenic syndromes
Gulf War syndrome
Lambert-Eaton myasthenic syndrome
Myasthenia gravis
- Neurologic disorders related to chemical and biological warfare agents
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- Post-polio syndrome

Pyridostigmine …

Pyridostigmine

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

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	• Titrate up to find the lowest effective dose: initially 30 mg (½ tablet) 4 times daily for 2 to 4 days.
	• Then 60 mg (1 tablet) 4 times daily for 5 days and experiment with timing.
	• Then increase to 90 mg 4 times daily over 1 week, if required. The duration of action varies, and some patients require 5 divided daily doses.

Pyridostigmine

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Autoantibodies: mechanism and testing

Neurogenetics and genetic and genomic testing

Asymptomatic hyperCKemia

Limb-girdle muscular dystrophies

Metal neurotoxicity

Medications and substances causing headache

Multiple sclerosis: treatment of its symptoms

Chronic progressive external ophthalmoplegia

This is an article preview.
Start a Free Account
to access the full version.