Pyridostigmine is a medication that has been approved by the U.S. Food and Drug Administration (FDA) under the brand name Mestinon to treat muscle weakness in myasthenia gravis. Pyridostigmine is produced by many manufacturers and is available in many generic formulations. It is used off-label to treat muscle weakness caused by Lambert-Eaton myasthenic syndrome (LEMS).

How pyridostigmine works

To move muscles, a nerve signal is sent from the brain as an electrical signal down the nerve fibers to the muscles. When the nerve fiber reaches the muscle, a point called the neuromuscular junction, the electrical signal is changed into a chemical signal as the nerve cell ending secretes a neurotransmitter (cell-signaling molecule) called acetylcholine. Acetylcholine binds to its receptor found on the muscle and the muscle contracts in response. When the nerve signal has been sent, an enzyme (acetylcholinesterase) breaks down the acetylcholine, which resets the neuromuscular junction so that it is ready to receive the next nerve signal.

In LEMS, the immune system mistakenly attacks and damages the nerve cell endings. As a result, the nerve cell cannot send a strong signal to the muscles, which causes the muscles to weaken and atrophy (shrink).

Pyridostigmine contains a small molecule that binds to acetylcholinesterase and inhibits the enzyme. With the enzyme inhibited, acetylcholine stays in the neuromuscular junction longer, which strengthens the signal that the muscle perceives from the nerve cell. This can decrease muscle weakness, in a sense, amplifying the signal received from the nerve cell.

For most LEMS patients, pyridostigmine alone is enough to treat symptoms and the treatment often is used in combination with Firdapse (amifampridine), a potassium channel blocker that increases the release of acetylcholine at the neuromuscular junction, or guanidine. Guanidine also blocks potassium channels, but is associated with increased risk of side effects, such as damage to kidneys and bone marrow.

Pyridostigmine in clinical trials

A double-blind crossover study was conducted comparing Firdapse to pyridostigmine in nine LEMS patients. Patients received either Firdapse or Mestinon, then switched to the other treatment. They then received both treatments. The results of the trial were published in the journal American Society for Clinical Pharmacology & Therapeutics. They showed that Firdapse improved muscle strength, and no change was observed in muscle strength with pyridostigmine alone. The authors also found there was no additive effect in combining the treatments, meaning that adding pyridostigmine to the Firdapse treatment regime did not cause additional improvement in muscle strength compared to Firdapse alone.

A small trial of low-dose guanidine in combination with pyridostigmine was carried out in nine LEMS patients to assess long-term safety and effectiveness. Guanidine dosage was kept below 1,000 mg per day for all patients. The combination therapy was used for three to 102 months (with the average being 34 months). The results were published in the journal Muscle & Nerve. Clinical status was improved in all patients. Guanidine therapy had to be discontinued due to severe gastrointestinal symptoms in three patients, but no serious side reactions (such as bone marrow or kidney damage) were detected. The authors concluded that low-dose guanidine may be used safely long-term in combination with pyridostigmine to treat the symptoms of LEMS.

Other information

Pyridostigmine can cause side effects, including diarrhea, abdominal pain or cramps, and nausea.


Last updated: July 20, 2019


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