Pyridostigmine: Uses, Studies, Indications, Dosage and Side Effects

It is an acetylcholinesterase inhibitor that can treat myasthenia gravis by increasing acetylcholine in the postsynaptic endplate.

It can also affect ganglionic neurotransmission and improve sympathetic activation in the standing position.

Pyridostigmine is a small synthetic molecule (C9H13N2O2) that was patented in 1951 and is often known by the trade name of Mestinon. The final effect is a greater amount of acetylcholine available to bind to postsynaptic receptors.

Applications

Pretreatment with carbamate pyridostigmine is a well-established method to protect against nerve agent poisoning in armed forces in several nations.

The therapeutic injections of botulinum toxin are commonly performed in pediatric otolaryngology. The aerodigestive complications of botulinum toxin injections, although rare, can be serious. Oral pyridostigmine is effective in the symptomatic treatment of these complications.

It may improve orthostatic hypotension but not affect supine hypertension to the same extent as midodrine or droxidopa.

It has been used for the treatment of postural orthostatic tachycardia syndrome. The medication has also been effective in combination with other therapies for the same problem.

Pyridostigmine inhibits the acetylcholinesterase enzyme, which reduces the natural enzymatic metabolism of acetylcholine at the neuromuscular junction and increases the transmission of impulses from cholinergic neurons through the synaptic cleft.

After oral administration, pyridostigmine reaches a maximum plasma concentration around 1.7 hours and has a short half-life of 1-2 hours.

Because ganglionar neurotransmission is cholinergic, it facilitates sympathetic and parasympathetic function.

The attraction of this pharmacological approach is that it will be silent in conditions of low sympathetic tone, as in a supine position, but it will enhance the sympathetic activation that occurs when standing. Therefore, this drug has the potential to improve orthostatic blood pressure without worsening supine hypertension.

Pyridostigmine is promising for the treatment of various gastrointestinal symptoms in patients with systemic sclerosis , particularly in patients with refractory constipation . Although side effects may limit its use, most patients who experienced benefits chose to continue the therapy.

Studies of pyridostigmine

Two previous studies reported the beneficial effect of pyridostigmine as a treatment for orthostatic hypotension in patients with autonomic failure.

The effect of 60 mg of pyridostigmine on resting diastolic blood pressure was tested for the first time in an open-label study in 15 patients with autonomic failure.

Pyridostigmine significantly increased orthostatic blood pressure and reduced the drop in blood pressure associated with head tilt.

In a subsequent double-blind, randomized, 4-way crossover study, pyridostigmine increased vertical systolic blood pressure by only 4 mmHg compared with placebo; the combination with 5mg of midodrine was slightly more effective.

The improvement in orthostatic blood pressure in both studies was associated with a significant improvement in the orthostatic symptom without causing supine hypertension.

A recent study, however, did not produce the same results; pyridostigmine did not improve tolerance or orthostatic symptoms, because patients with autonomic failure were more affected by orthostatic hypotension than in previous studies.

This supports the notion that the response to pyridostigmine is proportional to the degree of residual sympathetic tone.

Pyridostigmine should be considered part of the therapy available for the treatment of patients with autonomous insufficiency.

As with other agents, therapy must be individualized because some patients may have only a modest response. It is probably more effective in patients with a certain degree of residual sympathetic tone.

Indications

Although pyridostigmine can be used for myasthenia gravis, it may improve orthostatic hypotension. It has been used in combination with midodrine and fludrocortisone to treat patients with orthostatic hypotension and orthostatic postural tachycardia syndrome. These indications are off label.

Dose

A typical initial dose for children and adolescents is 0.5mg to 1.0mg / kg / dose, given 3 times a day, with a maximum initial dose of 60mg / dose.

The usual maximum for children and adolescents is 7mg / kg / day, although some patients may need higher doses, such as confirmed cases of certain subtypes of congenital myasthenic syndrome.

The maximum of 7mg / kg / day should rarely be exceeded in juvenile myasthenia gravis, and the risk of cholinergic side effects increases as the dose increases.

For adolescents and adults, some recommend a maximum absolute dose of 300 mg / day, although patients exceed that level in certain cases.

For orthostatic hypotension and postural orthostatic tachycardia syndrome, low dose therapy at a dose of 60mg orally twice a day is usually recommended.

Side effects

Common side effects include gastrointestinal effects, such as diarrhea and abdominal cramps. The effects of pyridostigmine can be reduced when quinidine is used.

Its potency is typically mild, especially compared to certain forms of immunomodulation.

However, most patients tolerate medication well and some patients with mild symptoms can be adequately controlled with monotherapy with pyridostigmine, which is why it is usually the first therapy used in juvenile myasthenia gravis.

An exception to this approach involves positive cases of specific muscle kinase antibodies, which often do not respond well to this medication.

Many patients do not experience any side effects. Some will develop diarrhea and, less frequently, other cholinergic side effects. Occasionally, drowsiness will occur.