|Systematic (IUPAC) name|
|Bioavailability||Unclear, probably less than 5%|
|Metabolism||Slow hydrolysis by acetylcholinesterase and also by plasma esterases|
|Biological half-life||50–90 minutes|
|Excretion||Unchanged drug (up to 70%) and alcoholic metabolite (30%) are excreted in the urine|
|CAS Registry Number|
|ATC code||N07 S01 QA03|
|Molecular mass||223.294 g/mol|
- Synthesis 1
- Pharmacology 2
- Clinical uses 3
- Side effects 4
- Spectral data 5
- Chemistry 6
- See also 7
- Bibliography 8.1
Neostigmine was first synthesized by Aeschlimann and Reinert in 1931 and was patented by Aeschliman in 1933.
Neostigmine is made by first reacting 3-dimethylaminophenol with N-dimethylcarbamoyl chloride, which forms a dimethylcarbamate. Next, that product is alkylated using dimethylsulfate, which forms neostigmine.
By interfering with the breakdown of acetylcholine, neostigmine indirectly stimulates both nicotinic and muscarinic receptors. Unlike physostigmine, neostigmine has a quaternary nitrogen; hence, it is more polar and does not enter the CNS, but it does cross the placenta. Its effect on skeletal muscle is greater than that of physostigmine. Neostigmine has moderate duration of action – usually two to four hours. Neostigmine binds to the anionic and esteric site of cholinesterase. The drug blocks the active site of acetylcholinesterase so the enzyme can no longer break down the acetylcholine molecules before they reach the postsynaptic membrane receptors. This allows for the threshold to be reached so a new impulse can be triggered in the next neuron. In myasthenia gravis there are too few acetylcholine receptors so with the acetylcholinesterase blocked, acetylcholine can bind to the few receptors and trigger a muscular contraction.
It is used to improve muscle tone in people with myasthenia gravis and routinely in anesthesia to reverse the effects of non-depolarizing muscle relaxants such as rocuronium and vecuronium at the end of an operation, usually in a dose of 25 to 50 μg per kilogram. (Though it is one of only two treatments available for myasthenia gravis, neostigmine is no longer available in the United States to anyone using the Medicare Part D program.)
Another indication for use is the Ogilvie syndrome which is a pseudoobstruction of the colon in critically ill patients.)
Historically, it has been used as a test for early pregnancy. In a non-pregnant female whose menstrual period is delayed, administration of neostigmine can provoke menstrual bleeding. Modern tests which rely on detecting hCG in urine have rendered this application obsolete.)
Hospitals sometimes administer a solution containing neostigmine intravenously to delay the effects of envenomation through snakebite. Some promising research results have also been reported for administering the drug nasally as a snakebite treatment.
Neostigmine can induce generic ocular side effects including: headache, brow pain, blurred vision, phacodonesis, pericorneal injection, congestive iritis, various allergic reactions, and rarely, retinal detachment.
Gastrointestinal symptoms occur earliest after ingestion and include anorexia, nausea, vomiting, abdominal cramps, and diarrhea.
Neostigmine shows notable UV/VIS absorption at 261 nm, 267 nm, and 225 nm.
Neostigmine's 1H NMR Spectroscopy reveals shifts at: 7.8, 7.7, 7.4, 7.4, 3.8, and 3.1 parts per million. The higher shifts are due to the aromatic hydrogens. The lower shifts at 3.8ppm and 3.1ppm are due to the electronic withdrawing nature of the tertiary and quarterary nitrogen, respectively.
Neostigmine, N,N,N-trimethyl-meta-(dimethylcarbomoyloxy)-phenylammonium methylsulfonate, which can be viewed as a simplified analog of physostigmine, is made by reacting 3-dimethylaminophenol with N-dimethylcarbamoyl chloride, which forms the dimethylcarbamate, and its subsequent alkylation using dimethylsulfate forming the desired compound.
- Whitacre 2007, p. 57.
- Aeschliman, John A., U.S. Patent 1,905,990 (1933).
- Gilman, Goodman & Gilman 1980, p. 103.
- Howland, R. D., Mycek, M. J., Harvey, R. A., Champe, P. C., and Mycek, M. J., Pharmacology 3rd edition, Lippincott's Illustrated Reviews, 2008, pg. 51.
- Franklin, Deborah, "Potential Treatment For Snakebites Leads To A Paralyzing Test", NPR.org, July 31, 2013.
- "Universal antidote for snakebite: Experimental trial represents promising step", California Academy of Sciences via Science Daily, May 28, 2014.
- Gilman, Goodman & Gilman 1980, p. 114.
- Gilman, Goodman & Gilman 1980, p. 109.
- Porst H; Kny L (May 1985). "The structure of degradation products of neostigmine bromide".
- Ferdous, Abu J; Waigh, Roger D (1993). "Application of the WATR technique for water suppression in 1H NMR spectroscopy in determination of the kinetics of hydrolysis of neostigmine bromide in aqueous solution".
- Whitacre, David M. (2007). Reviews of Environmental Contamination and Toxicology.