Introduction
Myasthenia gravis is an autoimmune disease involving dysfunction at the neuromuscular junction, most commonly due to autoantibodies directed against the acetylcholine receptor (AChR), which results in muscle tone loss, muscle weakness, and fatigue. Acetylcholinesterase inhibitors have been the symptomatic treatment of choice in myasthenia gravis since the 1930s with the early use of physostigmine and neostigmine. By inhibiting the breakdown of acetylcholine in the neuromuscular junction, they increase signalling and relieve symptoms. Pyridostigmine is the current drug of choice, with superior pharmacokinetics and reduced side effects compared to neostigmine. In addition to treating myasthenia gravis, pyridostigmine is used to reverse neuromuscular blocks, relieve symptoms in congenital myasthenic syndromes, and protect against certain nerve agents, notably during the Gulf War.
Uses
Pyridostigmine is a cholinesterase inhibitor used for symptomatic treatment of myasthenia gravis and congenital myasthenic syndromes and to reverse neuromuscular blockade by nondepolarizing muscle relaxants.
Pyridostigmine is indicated for the treatment of myasthenia gravis. When administered intravenously, it is indicated for the reversal or antagonism of the neuromuscular blocking effects of nondepolarizing muscle relaxants.
Pyridostigmine has also been used as a prophylactic agent against irreversible organophosphorus acetylcholinesterase inhibitors, primarily in a military capacity.
Associated Conditions
Pharmacodynamics
Pyridostigmine bromide, designated as 3-hydroxy-1-methyl-pyridinium bromide dimethyl-carbamate, is an orally active reversible cholinesterase inhibitor similar to neostigmine but with a milder adverse effect profile and a longer duration of action. Pyridostigmine may, specifically in the case of excessive administration, result in a cholinergic crisis, with symptoms mimicking a myasthenic crisis. Administration of atropine is recommended in the case of a true cholinergic crisis or to counteract muscarinic/nicotinic effects such as bradycardia and excessive bronchial secretions.
Mechanism of Action
Myasthenia gravis is an autoimmune disease involving dysfunction at the neuromuscular junction most commonly due to autoantibodies directed against the acetylcholine receptor (AChR), but also against other targets such as the muscle-specific kinase (MUSK), lipoprotein-related protein 4 (LRP4), or agrin. In the case of AChR antibodies, AChRs are directly bound and cross-linked, impairing acetylcholine binding and contributing through various mechanisms to receptor degradation. The lack of acetylcholine signalling leads to muscle tone loss, muscle weakness, and fatigue.
Pyridostigmine is a reversible acetylcholinesterase inhibitor that increases extracellular acetylcholine levels in the neuromuscular junction by impairing its breakdown by acetylcholinesterase. The increased acetylcholine leads to increased neural transmission across the junction, which drastically improves myasthenia gravis symptoms.
In addition to its use in myasthenia gravis and in reversing neuromuscular blocks, pyridostigmine is also a common first-line treatment in congenital myasthenic syndromes (CMS), of which there are multiple subtypes caused by mutations in more than 30 distinct genes. CMS present similarly to myasthenia gravis, albeit due to distinct underlying causes, and often benefit from pyridostigmine. However, in some subgroups, treatment with pyridostigmine is detrimental; detailed genetic testing is required before starting therapy.
Absorption
Pyridostigmine administered orally is poorly absorbed in the GI tract, with an oral bioavailability of only 10-20%. However, this may in part be due to some metabolism by both the blood and liver. Approximately 1-2 hours following a single oral dose of 60 mg, the Cmax was determined to be 40-60 μg/L. Pyridostigmine follows approximately linear kinetics, with a direct correlation between the dose and plasma AUC. Pyridostigmine taken orally with food results in a flatter peak to the plasma concentration vs. time curve. The peak plasma concentrations are reached ~90 minutes later than in fasted subjects but with no change in bioavailability or AUC.
Volume of Distribution
Pyridostigmine administered intravenously in healthy, myasthenic, and surgical patients has a range of distribution volumes, between 0.53 and 1.76 L/kg.
Protein Binding
Neither pyridostigmine nor any of its detectable plasma metabolites are appreciably protein-bound.
Route of Elimination
Pyridostigmine is primarily renally eliminated. Roughly 90% of an intravenous dose is recovered in the urine within 24 hours, with unchanged pyridostigmine and its main metabolite HNM recovered in an approximately 4:1 ratio.
Half Life
Pyridostigmine administered intravenously in healthy, myasthenic, and surgical patients has a range of elimination half-lives, between 0.38 and 1.86 hours.
Clearance
Pyridostigmine administered intravenously in healthy, myasthenic, and surgical patients has a range of clearance values, between 0.29 and 1.0 L/h/kg.
Toxicity
Toxicity information regarding pyridostigmine is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as bradycardia, excessive bronchial secretions, and cholinergic crisis. Symptomatic and supportive measures are recommended.
Food Interactions
- Take with food. Food decreases irritation.
Dosage
Newborn Infants: The dosage requirements of Pyridostigmine range from 5-10 mg orally every four hours, given 30-60 minutes before feeding. Treatment is not usually required beyond eight weeks of age except in the rare conditions of congenital and familial infantile myasthenia.
Older Children: Children under 6 years old should receive an initial dose of half a tablet (30 mg) of Pyridostigmine, children 6-12 years old should receive one tablet (60 mg). Dosage should be increased gradually, in increments of 15-30 mg daily, until maximum improvement is obtained. Total daily requirements are usually in the range of 30-360 mg by mouth.
