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:

Clinical trials

There have been no clinical trials. This product was approved in 1982, prior to the era of clinical trials.

Indications

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

Off-label uses

Contraindications

Pyridostigmine use is contraindicated in patients with mechanical urinary or intestinal obstruction.

Goals and duration of treatment

The aim is control of muscle weakness, and treatment is required on a long-term basis. For optimal control, it may be necessary to combine regular tablets with time-span (prolonged-action) tablets. Pyridostigmine is less effective in Lambert-Eaton myasthenic syndrome.

Treatment with pyridostigmine has been reported to be quite effective in 3 siblings with GMPPB mutations causing congenital myasthenic syndromes overlapping with muscular dystrophy. Functional motor scales were regularly performed over a period of 40 months to monitor the effects of treatment (06). Improvement was remarkable and steady for 12 months; a moderate decrease was subsequently detected but functional motor status remained better than at start of the treatment. Development of scoliosis was prevented in one of the siblings, and start ofpyridostigmine treatment at an early age is recommended.

Dosing

The dosing for regular tablets (60 mg) of pyridostigmine is ½ to 4 tablets every 4 hours. Dosing for the 180 mg "time-span" tablets is 1 to 3 tablets once or twice daily.

The daily dose for children is 7 mg/kg given as a syrup (12 mg/mL) in divided doses.

The pyridostigmine dose escalation protocol for newly diagnosed outpatients with myasthenia gravis as recommended by the Association of British Neurologists is as follows (26):

These guidelines follow a path between evidence-based practice where available and established best practice where evidence is unavailable. Because of considerable individual variations, no fixed schedule can be recommended for general use. The optimal effective dose schedule should be determined for each patient.

Special considerations

Anesthesia. See myasthenia gravis topic. Prophylactic pyridostigmine, used for troops under threat of organophosphate exposure, can prolong recovery from neuromuscular block by succinylcholine. Pyridostigmine is used to reverse curarization of anesthesia, but significant residual neuromuscular block after vecuronium or rocuronium is not eliminated even by large doses of pyridostigmine. However, pyridostigmine, at a dose of 0.1 mg/kg, effectively reversed rocuronium-induced neuromuscular blockade in teenage patients with Duchenne muscular dystrophy undergoing surgery for correction of scoliosis (21).

Continuation of daily pyridostigmine is recommended in patients with myasthenia gravis undergoing surgery in addition to anesthetic precautions such as avoidance of neuromuscular blocking agents and careful monitoring of the patient (05).

Pregnancy. According to best practice guidelines from a U.K. multispecialty working group on myasthenia in pregnancy, use of pyridostigmine in pregnancy is safe (23). Pyridostigmine does not cross the placenta, and there are no reports of fetal malformations. Breastfed infants of mothers taking pyridostigmine ingest less than 0.1% of the maternal dose, and the American Academy of Pediatrics considers pyridostigmine to be compatible with breastfeeding (08).

Pediatric. Safety and effectiveness in this group has not been established. Pyridostigmine syrup is used in children.

Geriatric. Lower doses are required in the elderly because of slower clearance.

Interactions

No interactions are listed.

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.

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.