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a cholinergic drug (trade name Prostigmin) used to treat some ophthalmic conditions and to treat myasthenia gravis (同)Prostigmin

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/07/04 07:49:46」(JST)

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Neostigmine (Prostigmin, Vagostigmin) is a parasympathomimetic that acts as a reversible acetylcholinesterase inhibitor.

Synthesis

Neostigmine was first synthesized by Aeschlimann and Reinert in 1931.^[1]

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.^[2]

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.^[3] 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.

Clinical 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.

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.

Sometimes, hospitals use an intravenous version of neostigmine to delay the effects of envenomation through snakebite.^[4]

Though it is one of only two treatments available for myasthenia gravis, this drug is no longer available in the United States to anyone using the Medicare Part D program.

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.^[5]

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.^[6]

Spectral data

Neostigmine shows notable UV/VIS absorption at 261 nm, 267 nm, and 225 nm.^[7]

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.^[8]

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.

43. J.A. Aeschlimann, U.S. Patent 1,905,990 (1933).

References

^ Whitacre 2007, pp. 57.
^ Gilman, Goodman & Gilman 1980, pp. 103.
^ Howland, R. D., Mycek, M. J., Harvey, R. A., Champe, P. C., & Mycek, M. J. Pharmacology 3rd edition, Lippincott's Illustrated Reviews, 2008, pg. 51.
^ Potential Treatment For Snakebites Leads To A Paralyzing Test : Shots - Health News : NPR
^ Gilman, Goodman & Gilman 1980, pp. 114.
^ Gilman, Goodman & Gilman 1980, pp. 109.
^ Porst H; Kny L (May 1985). "[The structure of degradation products of neostigmine bromide]". Pharmazie. (in German) 40 (5): 325–8. PMID 4034636.
^ 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". Journal of Pharmacy and Pharmacology 45 (6): 559–562. doi:10.1111/j.2042-7158.1993.tb05598.x. PMID 8103105.

Bibliography

Gilman, A.G.; Goodman, L.S.; Gilman, A. (1980). Goodman & Gilman's The Pharmacological Basis of Therapeutics (6th ed.). New York: Macmillan Publishing Co., Inc.
Whitacre, David M. (2007). Reviews of Environmental Contamination and Toxicology. Springer. p. 57. ISBN 978-0-387-73162-9.

UpToDate Contents

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1. 急性偽性腸閉塞（オギルビー症候群） acute colonic pseudo obstruction ogilvies syndrome
2. 慢性偽性腸閉塞 chronic intestinal pseudo obstruction
3. Anesthesia for the patient with myasthenia gravis
4. 重症筋無力症の治療 treatment of myasthenia gravis
5. 重症患者における神経筋遮断剤の使用 use of neuromuscular blocking medications in critically ill patients

English Journal

Methylnaltrexone for Treatment of Acute Colonic Pseudo-obstruction.

Weinstock LB, Chang AC.Source*Department of Clinical Medicine and Surgery, Washington University School of Medicine †Specialists in Gastroenterologist, LLC, St. Louis, MO.
Journal of clinical gastroenterology.J Clin Gastroenterol.2011 Nov;45(10):883-4.
Acute colonic pseudo-obstruction (ACPO) or Ogilvie syndrome is an idiopathic syndrome of dilation of the colon without mechanical obstruction that develops in hospitalized patients usually in the setting of significant medical and surgical conditions. Standard care therapy includes colonoscopic deco
PMID 21992933

{alpha}7 Nicotinic acetylcholine receptor agonist GTS-21 attenuates ventilator-induced tumour necrosis factor-{alpha} production and lung injury.

Kox M, Pompe JC, Peters E, Vaneker M, van der Laak JW, van der Hoeven JG, Scheffer GJ, Hoedemaekers CW, Pickkers P.SourceDepartment of Intensive Care Medicine.
British journal of anaesthesia.Br J Anaesth.2011 Oct;107(4):559-66. Epub 2011 Jul 18.
BACKGROUND: /st> Mechanical ventilation (MV) induces an inflammatory response that can lead to lung injury. The vagus nerve can limit the inflammatory response through the cholinergic anti-inflammatory pathway. We evaluated the effects of stimulation of the cholinergic anti-inflammatory pathway w
PMID 21771746

Japanese Journal

短時間で2回の開腹手術を受けたのち残存筋弛緩のため呼吸抑制が認められた腎不全の1症例

山崎豊,齋藤厚,高橋巨
麻酔 60(2), 199-202, 2011-02
NAID 40018714060

寛解期の重症筋無力症患者で出血性ショック後に夜間呼吸不全を繰り返した一症例

冨田麻衣子,井上明日香,加藤妙,福本正俊,有馬一,中野浩
日本集中治療医学会雑誌 = Journal of the Japanese Society of Intensive Care Medicine 17(4), 541-542, 2010-10-01
NAID 10027854370

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リンク元	「コリンエステラーゼ阻害薬」「エドロホニウム」「ネオスチグミン」

「コリンエステラーゼ阻害薬」

Neostigmine
Systematic (IUPAC) name
	3-{[(dimethylamino)carbonyl]oxy}-N,N,N-trimethylbenzenaminium
Clinical data
Trade names	Prostigmin
AHFS/Drugs.com	monograph
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 Registry Number	59-99-4
ATC code	N07AA01 S01EB06 QA03AB93
PubChem	CID: 4456
DrugBank	DB01400
ChemSpider	4301
UNII	3982TWQ96G
KEGG	D08261
ChEBI	CHEBI:7514
ChEMBL	CHEMBL54126
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 ; Key:ALWKGYPQUAPLQC-UHFFFAOYSA-N ;
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英: cholinesterase inhibitor cholinesterase inhibitors
同: 抗コリンエステラーゼ薬 anticholinesterase
関: アセチルコリン、アセチルコリン受容体、副交感神経