Antimyasthenic – Cholinergic
Action And Clinical Pharmacology: Pyridostigmine is a cholinergic agent which acts primarily by the inhibition of cholinesterase. It enhances cholinergic action by facilitating the transmission of impulses across neuromuscular junctions. It also has a direct cholinomimetic effect on skeletal muscle and possibly on autonomic ganglion cells and neurons of the CNS. Because of its quaternary ammonium structure, moderate doses of pyridostigmine do not cross the blood-brain barrier to produce CNS effects. Extremely high doses, however, produce CNS stimulation followed by CNS depression, in addition to a depolarizing neuromuscular blockade.
Pyridostigmine is an analog of neostigmine. However, it differs from neostigmine in certain clinically significant respects; for example, pyridostigmine is more effectively absorbed from the alimentary tract than is neostigmine; with equipotent doses, pyridostigmine has a slower onset and longer duration of action, and produces fewer gastrointestinal side effects than neostigmine. After oral administration, Mestinon generally has an onset of action of 20 minutes and a duration of action of approximately 6 hours; as for Mestinon-SR, it has an onset of action of 30 to 60 minutes and a duration of action of 6 to 12 hours.
Indications And Clinical Uses: For the symptomatic treatment of myasthenia gravis. In acute myasthenic crises where difficulty in breathing and swallowing is present, the parenteral form should be used. The patient can be transferred to the oral form as soon as it can be tolerated.
Contra-Indications: In patients with known hypersensitivy to anticholinesterase agents. Because of the presence of the bromide ion, this product should not be used in patients with a prior history of reaction to bromides. It is also contraindicated in patients with peritonitis or mechanical obstruction of the intestinal or urinary tract. tag_WarningWarnings
Manufacturers’ Warnings In Clinical States: Pyridostigmine should be used with caution in patients with epilepsy, bronchial asthma, bradycardia, recent coronary occlusion, vagotonia, hyperthyroidism, cardiac arrhythmias or peptic ulcer. Large oral doses of the drug should be avoided in patients with megacolon or decreased gastrointestinal motility. In these patients, the drug may accumulate and result in toxicity when gastrointestinal motility is restored.
Precautions: General: Although failure of patients to show clinical improvement may reflect underdosage, it can also be indicative of overdosage. It is important to differentiate between myasthenic crisis and cholinergic crisis caused by overdosage of pyridostigmine. Both conditions result in extreme muscle weakness but require radically different treatment (see Overdose: Symptoms and Treatment).
Information for the Patient: Complete restoration of muscle strength is rare in myasthenia gravis, and patients should be cautioned not to increase their dose, in an attempt to relieve their symptoms, without consulting their physician. The patient should be encouraged to keep a daily record of his or her condition to assist the physician in determining an optimal therapeutic regimen.
Drug Interactions: Atropine antagonizes the muscarinic effects of pyridostigmine and this interaction may be utilized to counteract the effects of pyridostigmine (see Overdose: Symptoms and Treatment).
Pyridostigmine does not antagonize, and in fact may prolong the phase I block of depolarizing muscle relaxants such as succinylcholine or decamethonium.
Certain antibiotics, especially neomycin, streptomycin and kanamycin, have a mild but definite nondepolarizing blocking action which may accentuate neuromuscular block. These antibiotics should be used in the myasthenic patient only where definitely indicated, and then careful adjustment should be made of adjunctive anticholinesterase dosage.
Local and some general anesthetics, antiarrhythmic agents and other drugs that interfere with neuromuscular transmission should be used cautiously, if at all, in patients with myasthenia gravis; the dose of pyridostigmine may have to be increased accordingly.
In severe myasthenia gravis, neostigmine has been used in combination with pyridostigmine to provide the benefits of short and long-term activity; because of the possibility of reduced intestinal motility and increased toxicity, this combination should be used only under strict medical supervision.
Carcinogenesis, Mutagenesis and Impairment of Fertility: Carcinogenicity and mutagenicity studies have not been performed with pyridostigmine.
A fertility and general reproductive performance study was performed in rats at dosages of 15 and 40 mg/kg/day. There were no adverse effects on pregnancy rate, average number of implantation sites, average number of embryos per dam, percent resorptions, duration of gestation, litter size, pup viability or pup growth.
Pregnancy: Teratogenic effects: Pregnancy category B: Reproductive studies have been performed in rats at dosages up to 40 mg/kg/day (2 times the maximum recommended human dose; 4.6 times the average recommended dose). These studies have revealed no evidence of impaired fertility or harm to the fetus due to pyridostigmine. There are, however, no adequate and well controlled studies in pregnant women. However, pyridostigmine, like other cholinesterase inhibitors, contains a quaternary ammonium and, therefore, would be expected to cross the placenta only to a limited extent. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nonteratogenic effects: Of newborn infants whose mothers have received anticholinesterase drugs for treatment of myasthenia gravis, 10 to 20% were observed to have transient muscular weakness.
Lactation: It is not known whether pyridostigmine is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions from pyridostigmine in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Children: See Dosage.
Adverse Reactions: Side effects are generally due to an exaggeration of pharmacological effects of which increased salivation and fasciculation are the most common. Abdominal cramps and diarrhea may also occur.
The following additional adverse reactions have been reported following the use of pyridostigmine:
Respiratory: increased bronchial secretions.
Gastrointestinal: nausea, vomiting, increased peristalsis.
Musculoskeletal: muscle cramps.
Dermatologic: urticaria, rash.
Miscellaneous: miosis, diaphoresis, weakness, allergic reactions.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: As is true of all anticholinesterase agents, overdosage of pyridostigmine can cause cholinergic crisis, which is characterized by increasing muscle weakness and which, through involvement of the muscles of respiration, may result in death. Myasthenic crisis, due to an increase in the severity of the disease, is also accompanied by extreme muscle weakness, and thus may be difficult to distinguish from cholinergic crisis on a symptomatic basis. However, such differentiation is extremely important, because increases in the dose of pyridostigmine or other drugs in this class in the presence of cholinergic crisis or of a refractory or “insensitive” state could have grave consequences. The two types of crises may be differentiated by the use of edrophonium chloride as well as by clinical judgment.
Treatment of the two conditions differs radically. Whereas the presence of myasthenic crisis requires more intensive anticholinesterase therapy, cholinergic crisis calls for the prompt withdrawal of all drugs of this type. The immediate use of atropine in cholinergic crisis is also recommended. A syringe containing 1 mg of atropine sulfate should be immediately available to be given in aliquots i.v. to counteract severe cholinergic reactions.
Atropine also may be used to abolish or minimize gastrointestinal side effects or other muscarinic reactions; but such use, by masking signs of overdosage, can lead to inadvertent induction of cholinergic crisis.
Dosage And Administration: The dosage, route and frequency of administration depend on the requirements and clinical response of the patients. The dosage schedule should be adjusted for each patient and changed as the need arises. Dosage requirements in patients with myasthenia gravis may vary from day to day, according to remissions and exacerbations of the disease and the physical and emotional stress suffered by the patient. Larger portions of the label daily dose may be given at times when the patient is more prone to fatigue (afternoon, mealtimes, etc.).
In the initial treatment of myasthenia gravis, oral pyridostigmine should be started at a dosage smaller than that required to produce maximum strength, and daily dosage gradually increased at intervals of 48 hours or more. Changes in oral dosage may take several days to show results. When a further increase in dosage produces no corresponding increase in muscle strength, dosage should be reduced to the previous level so that the patient receives the smallest dose necessary to produce maximum strength.
Note: For information on a diagnostic test for myasthenia gravis, and for the evaluation and stabilization of anticholinesterase therapy, see product monograph on Tensilon.
The immediate effect of a Mestinon-SR 180 mg tablet is about equal to that of a 60 mg conventional tablet; however, the duration of drug action, although varying in individual patients, averages 2 1/2 times that of a 60 mg dose. One to three 180 mg tablets, once or twice daily (180 mg to 1.08 g a day), will usually be sufficient to control symptoms; however, the needs of individual patients may vary markedly from this average. For optimal control, it may be necessary to use conventional tablets or syrup in conjunction with Mestinon-SR therapy. Mestinon-SR tablets are particularly useful for bedtime administration in patients who are very weak upon awakening.
Mestinon and Mestinon-SR tablets should be swallowed whole. Do not crush. However, in certain cases, Mestinon and Mestinon-SR tablets, can be cut in half; but Mestinon-SR tablets should not be crushed or quartered since this would destroy too much of the sustained release matrix.
Due to the slow-release mechanism of the tablet, the matrix may pass through the intestinal system intact. However, it should be noted that the medicinal ingredient has been released through the gastrointestinal tract over an 8 to 12 hour passing time and only the matrix is rejected.
Availability And Storage: Mestinon: Each white, flat compressed tablet, cross-scored on one side and embossed MESTINON 60-ICN on the other, contains: pyridostigmine bromide 60 mg. Nonmedicinal ingredients: lactose, silicone dioxide and stearic acid. Energy: 4.6 kJ (1.1 kcal). Gluten-, paraben-, sodium-, sulfite- and tartrazine-free. Bottles of 100.
Mestinon-SR: Each capsule-shaped, flattened on 2 sides with a single score on 1 face, light straw colored tablet, embossed ICN M180, contains: pyridostigmine bromide 180 mg. Nonmedicinal ingredients: calcium phosphate, carnauba wax, isopropyl alcohol and magnesium stearate. Energy: 2.3 kJ (0.5 kcal). Gluten-, lactose-, paraben-, sodium-, sulfite- and tartrazine-free. Bottles of 30.
Store in a dry place between 15 and 30°C, in a well-closed container with the desiccant enclosed.
Note: Because of the hygroscopic nature of the Mestinon and Mestinon-SR tablets, mottling may occur. This does not affect their efficacy.
MESTINON® MESTINON®-SR ICN Pyridostigmine Bromide Antimyasthenic – Cholinergic