NEOSTIGMINE BROMIDE, NEOSTIGMINE METHYLSULFATE
Chemistry - Synthetic quaternary ammonium parasympathomimetic agents, neostigmine bromideand neostigmine methylsulfate both occur as odorless, bitter-tasting, white, crystalline powders thatare very soluble in water and soluble in alcohol. The melting point of neostigmine methylsulfate isfrom 144-149°. The pH of the commercially available neostigmine methylsulfate injection is from5-6.5.
Neostigmine methylsulfate injection is reportedly compatible with the commonly used IV replacement solutions and the following drugs: glycopyrrolate, pentobarbital sodium, and thiopentalsodium.
Uses, Indications - Neostigmine is indicated for rumen atony, initiating peristalsis, emptying thebladder and stimulating skeletal muscle contractions in cattle, horses, sheep and swine (Packageinsert; Stiglyn® 1:500 - P/M; Mallinckrodt). It has also been used in the diagnosis and treatment ofmyasthenia gravis and in treating non-depolarizing neuromuscular blocking agents (curare-type)overdoses in dogs.
Neostigmine is 15-25% bound to plasma proteins. It has not been detected in human milk norwould be expected to cross the placenta when given at usual doses.
In humans, the half-life of the drug is approximately one hour. It is metabolized in the liver andalso hydrolyzed by cholinesterases to 3-OH PTM which is weakly active. When administeredparenterally, approximately 80% of the drug is excreted in the urine within 24 hours, with 50%excreted unchanged.
Contraindications/Precautions - Neostigmine is contraindicated in patients with peritonitis, mechanical intestinal or urinary tract obstructions, late stages of pregnancy, in animals hypersensitive to this class of compounds or treated with other cholinesterase inhibitors.
Use neostigmine with caution in patients with epilepsy, peptic ulcer disease, bronchial asthma, cardiac arrhythmias, hyperthyroidism, vagotonia or megacolon.
Overdosage - Overdosage of neostigmine can induce a cholinergic crisis. Symptoms can includenausea, vomiting, diarrhea, excessive salivation and drooling, sweating (in animals with sweatglands), miosis, lacrimation, increased bronchial secretions, bradycardia or tachycardia, cardiospasm, bronchospasm, hypotension, muscle cramps and weakness, agitation, restlessness orparalysis. In patients with myasthenia gravis, it may be difficult to distinguish between a cholinergiccrisis and myasthenic crisis. A test dose of edrophonium, should differentiate between the two.
Cholinergic crisis is treated by temporarily ceasing neostigmine therapy and instituting treatmentwith atropine (doses are listed in the Atropine monograph). Maintain adequate respirations usingmechanical assistance if necessary.
Drugs that possess some neuromuscular blocking activity (e.g., aminoglycoside antibiotics, some antiarrhythmic and anesthetic drugs) may necessitate increased dosages of neostigmine intreating or diagnosing myasthenic patients.
Corticosteroids may decrease the anticholinesterase activity of neostigmine. After stoppingcorticosteroid therapy, neostigmine may cause increased anticholinesterase activity.
Neostigmine may prolong the Phase I block of depolarizing muscle relaxants (e.g., succinyl-choline, decamethonium). Neostigmine antagonizes the actions of non-depolarizing neuromuscular blocking agents (pancuronium, tubocurarine, gallamine, etc.).
Atropine will antagonize the muscarinic effects of neostigmine and is often used to reduceneostigmine's side effects. Use cautiously however, as atropine can mask the early symptoms ofcholinergic crisis.
Theoretically, dexpanthenol may have additive effects when used with neostigmine.
Storage, Stability, Compatibility
Neostigmine bromide tablets should be stored at room temperature in tight containers. Neostigmine methylsulfate injection should be stored at room temperature and protected from light; avoid freezing.Neostigmine methylsulfate injection is reportedly compatible with the commonly used IV replacement solutions and the following drugs: glycopyrrolate, pentobarbital sodium, and thiopentalsodium.
Pharmacology - NEOSTIGMINE BROMIDE, NEOSTIGMINE METHYLSULFATE
Neostigmine competes with acetylcholine for acetylcholinesterase. As theneostigmine-acetylcholinesterase complex is hydrolyzed at a slower rate than that of the acetylcholine-enzyme complex, acetylcholine will accumulate with a resultant exaggeration and prolongation of its effects. These effects can include increased tone of intestinal and skeletal musculature, stimulation of salivary and sweat glands, bronchoconstriction, ureter constriction, miosis andbradycardia. Neostigmine also has a direct cholinomimetic effect on skeletal muscle.Uses, Indications - Neostigmine is indicated for rumen atony, initiating peristalsis, emptying thebladder and stimulating skeletal muscle contractions in cattle, horses, sheep and swine (Packageinsert; Stiglyn® 1:500 - P/M; Mallinckrodt). It has also been used in the diagnosis and treatment ofmyasthenia gravis and in treating non-depolarizing neuromuscular blocking agents (curare-type)overdoses in dogs.
Pharmacokinetics - NEOSTIGMINE BROMIDE, NEOSTIGMINE METHYLSULFATE
Information on the pharmacokinetics of neostigmine in veterinary species wasnot located. In humans, neostigmine bromide is poorly absorbed after oral administration with only1-2% of the dose absorbed. Neostigmine effects on peristaltic activity in humans begin within 10-30 minutes after parenteral administration and can persist for up to 4 hours.Neostigmine is 15-25% bound to plasma proteins. It has not been detected in human milk norwould be expected to cross the placenta when given at usual doses.
In humans, the half-life of the drug is approximately one hour. It is metabolized in the liver andalso hydrolyzed by cholinesterases to 3-OH PTM which is weakly active. When administeredparenterally, approximately 80% of the drug is excreted in the urine within 24 hours, with 50%excreted unchanged.
Contraindications/Precautions - Neostigmine is contraindicated in patients with peritonitis, mechanical intestinal or urinary tract obstructions, late stages of pregnancy, in animals hypersensitive to this class of compounds or treated with other cholinesterase inhibitors.
Use neostigmine with caution in patients with epilepsy, peptic ulcer disease, bronchial asthma, cardiac arrhythmias, hyperthyroidism, vagotonia or megacolon.
Adverse Effects, Warnings
Adverse effects of neostigmine are dose-related and cholinergic innature. See overdosage section below.Overdosage - Overdosage of neostigmine can induce a cholinergic crisis. Symptoms can includenausea, vomiting, diarrhea, excessive salivation and drooling, sweating (in animals with sweatglands), miosis, lacrimation, increased bronchial secretions, bradycardia or tachycardia, cardiospasm, bronchospasm, hypotension, muscle cramps and weakness, agitation, restlessness orparalysis. In patients with myasthenia gravis, it may be difficult to distinguish between a cholinergiccrisis and myasthenic crisis. A test dose of edrophonium, should differentiate between the two.
Cholinergic crisis is treated by temporarily ceasing neostigmine therapy and instituting treatmentwith atropine (doses are listed in the Atropine monograph). Maintain adequate respirations usingmechanical assistance if necessary.
Drug Interactions
Anticholinesterase therapy may be antagonized by administration of parenteral magnesium therapy, as it can have a direct depressant effect on skeletal muscle.Drugs that possess some neuromuscular blocking activity (e.g., aminoglycoside antibiotics, some antiarrhythmic and anesthetic drugs) may necessitate increased dosages of neostigmine intreating or diagnosing myasthenic patients.
Corticosteroids may decrease the anticholinesterase activity of neostigmine. After stoppingcorticosteroid therapy, neostigmine may cause increased anticholinesterase activity.
Neostigmine may prolong the Phase I block of depolarizing muscle relaxants (e.g., succinyl-choline, decamethonium). Neostigmine antagonizes the actions of non-depolarizing neuromuscular blocking agents (pancuronium, tubocurarine, gallamine, etc.).
Atropine will antagonize the muscarinic effects of neostigmine and is often used to reduceneostigmine's side effects. Use cautiously however, as atropine can mask the early symptoms ofcholinergic crisis.
Theoretically, dexpanthenol may have additive effects when used with neostigmine.