Mestinon

Uses

Mestinon is useful in the treatment of myasthenia gravis

Mestinon is also used to associated treatment for these conditions: Congenital Myasthenic Syndrome, Constipation, Myasthenia Gravis, Neuromuscular Blockade, Postpoliomyelitis Syndrome, Orthostatic syncope, Soman nerve gas poisoning

How Mestinon works

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.

Mestinon 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.

Dosage

Mestinon dosage

The size and frequency of the dosage must be adjusted to the needs of the individual patient. The average dose is 10 tablets (600 mg) spaced to provide maximum relief when maximum strength is needed. In severe cases as many as 25 tablets (1500 mg) a day may be required, while in mild cases one to six tablets a day may sufhce. The interval between doses should be at least 6 hours.

Side Effects

The side effects of Mestinon are most commonly related to overdose and generally are of two varieties, muscarinic and nicotinic. Muscarinic side effects are nausea, vomiting, diarrhea, abdominal cramps, increased peristalsis movement, increased salivation, increased bronchial secretions, miosis and diaphoresis. Nicotinic side effects are comprised chiefly of muscle cramps, fasciculation and weakness. Muscarinic side effects can usually be counteracted by atropine. As with any compound containing the bromide radical, a skin rash may be seen in an occasional patients. Such reactions usually subside promptly upon discontinuance of the medication.

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.

Precaution

Mestinon is mainly excreted unchanged by the kidney. Therefore, lower doses may be required in patients with renal disease, and treatment should be based on titration of drug dosage to effect.

Interaction

A potential interaction between the antimalarial drug mefloquine and pyridostigmine bromide exists through a possible additive effect on the gastrointestinal tract. Theoretically, drugs such as dexpanthenol, which are converted to pantothenic acid in vivo, may have additive effects with pyridostigmine by increasing production of acetylcholine.

Food Interaction

• Take with food. Food decreases irritation.

Mestinon Drug Interaction

Unknown: aspirin, diphenhydramine, mycophenolate mofetil, ubiquinone, duloxetine, apixaban, omega-3 polyunsaturated fatty acids, fluticasone nasal, linaclotide, pregabalin, metoprolol, metoprolol, bifidobacterium infantis / lactobacillus acidophilus, levothyroxine, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol, ondansetron, cetirizine

Mestinon Disease Interaction

Major: bradycardia, bronchospasm, coronary artery disease, parkinsonism, PUD, seizuresModerate: hyperthyroidism

Volume of Distribution

Mestinon administered intravenously in healthy, myasthenic, and surgical patients has a range of distribution volumes, between 0.53 and 1.76 L/kg.

Elimination Route

Mestinon 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 C_max was determined to be 40-60 μg/L. Mestinon follows approximately linear kinetics, with a direct correlation between the dose and plasma AUC. Mestinon 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.

Half Life

Mestinon administered intravenously in healthy, myasthenic, and surgical patients has a range of elimination half-lives, between 0.38 and 1.86 hours.

Clearance

Mestinon administered intravenously in healthy, myasthenic, and surgical patients has a range of clearance values, between 0.29 and 1.0 L/h/kg.

Elimination Route

Mestinon 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.

Pregnancy & Breastfeeding use

Pregnancy Category C. Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus.

Contraindication

Mestinon is contraindicated in mechanical intestinal or urinary obstruction, and particular caution should be used in its administration to patients with bronchial asthma. Care should be observed in the use of atropine for counteracting side effects.

Special Warning

Renal Impairment: Lower initial dose may be needed, titrate to desired effect.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Acute Overdose

Symptoms may include diarrhea; fainting; increased production of saliva; increased sweating; muscle weakness; nausea; small pupils; stomach cramps; trouble breathing; vision changes; vomiting; weakness.

Storage Condition

Store in cool and dry place, protected from light. Keep out of children’s reach.

Innovators Monograph

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