Neostigmine

Neostigmine

Systematic (IUPAC) name
3-{[(dimethylamino)carbonyl]oxy}-N,N,N-trimethylbenzenaminium
Clinical data
Trade names	Prostigmin
AHFS/Drugs.com	monograph
Legal status	UK: POM (Prescription only)
Pharmacokinetic data
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
Identifiers
CAS Number	59-99-4 Y
ATC code	N07AA01 (WHO) S01EB06 QA03AB93 (WHO)
PubChem	CID: 4456
DrugBank	DB01400 Y
ChemSpider	4301 Y
UNII	3982TWQ96G Y
KEGG	D08261 Y
ChEBI	CHEBI:7514 Y
ChEMBL	CHEMBL54126 N
Chemical data
Formula	C12H19N2O2
Molecular mass	223.294 g/mol
SMILES O=C(Oc1cccc(c1)[N+](C)(C)C)N(C)C
InChI InChI=1S/C12H19N2O2/c1-13(2)12(15)16-11-8-6-7-10(9-11)14(3,4)5/h6-9H,1-5H3/q+1 Y Key:ALWKGYPQUAPLQC-UHFFFAOYSA-N Y
NY (what is this?)  (verify)

Neostigmine (Prostigmin, Vagostigmin) (from Greek neos, meaning "new," and "-stigmine," in reference to its parent molecule, physostigmine, on which it is based) is a parasympathomimetic compound that acts as a reversible acetylcholinesterase inhibitor. Given that it is a quaternary amine (unlike physostigmine, which is a tertiary amine), it penetrates the central nervous system poorly and has lower propensity to cause side effects there.

It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.

Medical uses

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.)

It can also be used for urinary retention resulting from general anesthesia and to treat curariform drug toxicity.)

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.

Side effects

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.

Neostigmine will cause slowing of the heart rate (bradycardia); for this reason it is usually given along with a parasympatholytic drug such as atropine or glycopyrrolate.

Gastrointestinal symptoms occur earliest after ingestion and include anorexia, nausea, vomiting, abdominal cramps, and diarrhea.

Pharmacology

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.

Spectral data

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.

Chemistry

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.

History

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.

See also

• Miotine