Semin Neurol. 2004;24(1) 

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Anticholinesterase Drugs

Acetylcholinesterase inhibitors are typically the first line treatment of MG. These medications boost the amount of acetylcholine available for neuromuscular transmission by impairing the breakdown of acetylcholine at the synaptic cleft. Pyridostigmine (Mestinon) is the main acetylcholinesterase inhibitor used. Other agents, such as neostigmine (Prostigmin), are available but are rarely used. A generic form of pyridostigmine became available only recently in the fall of 2003. Pyridostigmine provides only symptomatic treatment, but in some patients is the only therapy needed. The effects of pyridostigmine may be noticed 15 to 30 minutes after taking a dose. Beneficial effects last for 3 to 4 hours. However, pyridostigmine can often be dosed successfully four or even only three times a day. Pyridostigmine comes as 60-mg pills. These are double-scored, permitting easy dosing in 15-mg increments. The typical starting dose is 30 mg three times a day. Many patients can be well controlled on 60 mg three to four times a day. Pyridostigmine can be increased in 30-mg dose increments and can be safely dosed at 120 mg four times a day. However, if at a dose of 60 to 90 mg four times a day a patient has significant weakness, then the MG is not under good control and an immunomodulating treatment should be added (see below).

A slow-release form of pyridostigmine (Mestinon Timespan) is available. This is a 180-mg pill meant to have a delayed absorption and therefore a longer time of action. This is not a good choice for daytime use because absorption is variable and it can be difficult to regulate the total pyridostigmine dose. Some patients take this preparation at night to avoid significant weakness in the morning. Most patients do not have significant weakness in the morning and taking a regular release pyridostigmine dose after awakening is sufficient. In a small number of patients who do have severe weakness upon awakening, a bedtime dose of Mestinon Timespan can be helpful.

At high doses, pyridostigmine can cause muscle weakness through effects on nicotinic acetylcholine receptors. However, in the current era of MG management, in which immunomodulating therapies are often utilized, the doses of pyridostigmine used are not (or should not be) high enough to cause weakness. In the past, patients sometimes developed so-called "cholinergic crisis" that was difficult to distinguish from deterioration from MG itself. As stated above, if a patient does not respond to moderate doses of pyridostigmine, other treatments should be added. Limb and bulbar weakness typically show a good response to pyridostigmine, but ocular symptoms such as ptosis and, particularly, diplopia may not respond as well.

At standard doses of pyridostigmine, rather than weakness, patients may experience fasciculations. Other common adverse effects of pyridostigmine are from muscarinic effects and include abdominal cramps and diarrhea. These symptoms, which may limit the use of pyridostigmine, can often be mitigated by anticholinergic medications. Hyoscyamine sulfate 0.125 mg can be taken as needed or prophylactically with each dose of pyridostigmine.

Pyridostigmine can be given intravenously if oral medications cannot be taken. This usually is only during hospitalization for myasthenic crisis. The intravenous dose is one-thirtieth the oral dose and dosing frequency is the same. When an MG patient is in crisis, pyridostigmine may be beneficial,[1] but our practice is to hold cholinesterase inhibitors and treat aggressively with immunomodulating therapies (see below). When the patient is off the ventilator and is improving as a result of the other therapeutic interventions and bed rest, resume oral pyridostigmine. Pyridostigmine is probably not a key deciding factor in getting the patient through the episode of crisis. In addition, it may increase bronchial secretions and precipitate cardiac arrhythmias.[2] Attempt to titrate immunomodulating therapy to a point where the patient has reached maximal improvement, not masked by the effects of pyridostigmine.

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