Pyridostigmine Bromide

●  Brand Name: Mestinon (US)

●  Indications: Pyridostigmine is an acetylcholinesterase inhibitor that has been used for many years to treat neuromuscular disorder myasthenia gravis. It is also employed to protect against the effects of certain nerve agents in chemical warfare. It can be used off-label for POTS and those with ME/CFS or long-covid who have autonomic dysfunction.

●  Contraindications: Not recommended for those with mechanical obstruction of the intestinal or urinary tract, patients with known hypersensitivity to anticholinesterase agents.

●  Mechanism of Action: Pyridostigmine works by inhibiting acetylcholinesterase, increasing acetylcholine levels at the neuromuscular junction, which can enhance parasympathetic tone and/or improve sympathetic vasoconstriction. This helps lower upright heart rate and has been investigated for treating neurally mediated hypotension (NMH) and postural tachycardia syndrome (POTS).

●  Side Effects: Common side effects are nervousness, muscle cramps or twitching, nausea, vomiting, or diarrhea, stomach cramps, increased saliva, anxiety, and watering eyes. Serious side effects include skin rash, seizures, difficulty breathing, slurred speech, confusion, or irregular heartbeat. It can also increase bronchial secretions in asthmatics and should be used with caution in these patients. Mestinon pills are gluten-free, but contain lactose, while the syrup is dairy-free.

●  Expected Benefits: In a small randomized crossover study, POTS patients taking 30 mg of pyridostigmine reported symptom relief within four hours, along with a reduction in standing heart rates. A retrospective study of 300 POTS patients found that about half experienced improvement in orthostatic symptoms with pyridostigmine use. It may also benefit cognitive function and muscle strength by maintaining higher acetylcholine levels, improving cognitive clarity and exercise tolerance. This makes it potentially helpful for patients with autonomic dysfunction, including those with ME/CFS or Long COVID. Pyridostigmine is generally well tolerated but can increase colonic motility, so it should be avoided in patients prone to diarrhea though can be helpful in patients with constipation.

●  Dosage: For adolescents and adults with POTS, pyridostigmine is typically prescribed using 60 mg pills or the 60 mg/5 mL oral solution with doses of 30 to 60 mg up to three times daily. Dosage titration example (Day 1-3: 30 mg once daily, Day 4-7: 30 mg twice daily, Day 8-10: 60 mg in the morning, 30 mg in the afternoon, Day 11 onward: 60 mg twice daily). Advised to take medication with food or milk to minimize gastric irritation. Some patients may achieve good results with lower doses (30 mg once or twice daily or even starting dose of 15 mg) and may not need an increase if tolerated well. Occasional patients benefit from a third dose during the day (morning, mid-day, bed-time), and one adolescent found that 45 mg in the morning, 30 mg at noon and 15 mg at bedtime was ideal for her. Some patients with chronic fatigue syndrome have been reported to do better on small doses of just 12.5-30 mg once daily.

●  Reproductive and Pregnancy Considerations: should be avoided during pregnancy due to potential risks to the fetus. Its safety during pregnancy has not been established, and there is a risk of uterine irritability and premature labor if anticholinesterase agents are administered intravenously near term. Pyridostigmine is classified as Category B indicating that animal studies did not show risks, but human studies are lacking. It is not known whether pyridostigmine is excreted in breast milk, and safety during lactation is also not established, so caution is advised for nursing women.

Citations

AHFS drug information 2021. Snow EK, ed. Pyridostigmine bromide. Bethesda, MD: American Society of Health-System Pharmacists; 2021. Bausch. Mestinon® (pyridostigmine bromide) solution, tablets, and Timespan® extended-release tablets prescribing information. Bridgewater, NJ; 2019 Oct. Defense Supply Center. Pyridostigmine bromide tablets prescribing information. Philadelphia, PA; 2003 Feb.116. Keeler

Joseph, P., Pari, R., Miller, S., Warren, A., Stovall, M. C., Squires, J., Chang, C. J., Xiao, W., Waxman, A. B., & Systrom, D. M. (2022). Neurovascular Dysregulation and Acute Exercise Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Placebo-Controlled Trial of Pyridostigmine. Chest, 162(5), 1116–1126. https://doi.org/10.1016/j.chest.2022.04.146

Kanjwal, K., Karabin, B., Sheikh, M., Elmer, L., Kanjwal, Y., Saeed, B., & Grubb, B. P. (2011). Pyridostigmine in the treatment of postural orthostatic tachycardia: a single-center experience. Pacing and clinical electrophysiology : PACE, 34(6), 750–755. https://doi.org/10.1111/j.1540- 8159.2011.03047.x

Raj, S. R., Black, B. K., Biaggioni, I., Harris, P. A., & Robertson, D. (2005). Acetylcholinesterase inhibition improves tachycardia in postural tachycardia syndrome. Circulation, 111(21), 2734–2740. https://doi.org/10.1161/CIRCULATIONAHA.104.497594