同: neostigmine methylsulfate

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/06/17 08:14:00」(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.

Gastrointestial 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. 重症筋無力症の治療 treatment of myasthenia gravis
4. 全身麻酔の導入 induction of general anesthesia
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

Abnormal sympathetic hyper-reactivity in patients with myasthenia gravis: A prospective study.

Shukla G, Gupta S, Goyal V, Singh S, Srivastava A, Behari M.SourceDepartment of Neurology, All India Institute of Medical Sciences, New Delhi 110029, India. Electronic address: garimashukla@hotmail.com.
Clinical neurology and neurosurgery.Clin Neurol Neurosurg.2013 Feb;115(2):179-86. doi: 10.1016/j.clineuro.2012.05.013. Epub 2012 Jun 5.
INTRODUCTION: Patients with myasthenia gravis, especially those in crises, are not infrequently observed to demonstrate wide fluctuation in heart rate and blood pressure.OBJECTIVE: This study was conducted to assess autonomic function in patients with myasthenia gravis.METHODS: Patients with myasthe
PMID 22676958

Recovery of train-of-four ratio to 0.70 and 0.90 is delayed in type 2 diabetes with vecuronium-induced neuromuscular block.

Nitahara K, Sugi Y, Shigematsu K, Haraga I, Abe S, Higa K.SourceFrom the Department of Anesthesiology, Fukuoka University School of Medicine, Fukuoka, Japan.
European journal of anaesthesiology.Eur J Anaesthesiol.2013 Feb;30(2):80-4. doi: 10.1097/EJA.0b013e32835b9d9b.
CONTEXT: The recovery profile of train-of-four ratio to more than 0.70 in patients with diabetes mellitus has not been well investigated.OBJECTIVE: Our primary objective was to evaluate the spontaneous recovery profile of neuromuscular block by vecuronium until train-of-four ratio more than 0.90 in
PMID 23172246

A case of apparent re-dosing of atracurium during neostigmine reversal in a dog.

Garcia De Carellan A, Pelligand L.SourceVeterinary Clinical Sciences, Royal Veterinary College, Hatfield, Herts, UK. agarcia@rvc.ac.uk.
Veterinary anaesthesia and analgesia.Vet Anaesth Analg.2013 Jan 19. doi: 10.1111/vaa.12011. [Epub ahead of print]
PMID 23331619

Japanese Journal

機能的便通異常者の大腸内圧曲線

斎藤吉春,佐々木大輔,成田則正,石岡昭,川上澄
心身医学 21(3), 229-235, 1981-06-01
… 5 mg of prostigmin was given i. … The true effect of prostigmin appeared to begin about 15 minutes after the injection and end about 40 minutes after the injection. … For qualitative analysis, colonic motility index (CMI) was calculated from basal 15 minutes recordings and 30 minutes after an interval of 15 minutes from the injection of prostigmin. …
NAID 110001119599

腸管癒着症に関する研究第1篇腸管癒着症に関する文献的考察

大谷満
岡山大学温泉研究所報告 31, 40-53, 1963-01-25
… The stimulation of peristalsis by means of prostigmin and early feeding, however, appears to be effective in the prevention of adhesions, although its use in clinical cases has not been reported. …
NAID 120002310946

Mecholyl, Prostigmin及びLysozymeの負荷による腸管の病変発生に関する研究 : 特にこの際に於けるビタミンB2複合体欠乏の意義について

雪田成夫
弘前醫學 13(2), 299-319,*49, 1961-11
NAID 110004769446

Related Pictures

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★リンクテーブル★

リンク元	「ネオスチグミン」「プロスチグミン」

「ネオスチグミン」

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
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: neostigmine
ラ: neostigminum
同: プロスチグミン prostigmin
化: メチル硫酸ネオスチグミン、臭化ネオスチグミン
商: ワゴスチグミン(臭化ネオスチグミン)、アトワゴリバース。(点眼液)マイピリン、ミオピン
関: フィゾスチグミン

コリンエステラーゼ阻害薬
四級アミン

作用機序

コリンエステラーゼの活性化部位に存在する

薬理作用

動態

血液脳関門を通過しない

「プロスチグミン」

　　[★]

英: prostigmin
関: ネオスチグミン

[FOOTNOTEWhitacre200757-1] Whitacre 2007, pp. 57.

[FOOTNOTEGilmanGoodmanGilman1980103-2] Gilman, Goodman & Gilman 1980, pp. 103.

[3] 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.

[4] Potential Treatment For Snakebites Leads To A Paralyzing Test : Shots - Health News : NPR

[FOOTNOTEGilmanGoodmanGilman1980114-5] Gilman, Goodman & Gilman 1980, pp. 114.

[FOOTNOTEGilmanGoodmanGilman1980109-6] Gilman, Goodman & Gilman 1980, pp. 109.

[pmid4034636-7] Porst H; Kny L (May 1985). "[The structure of degradation products of neostigmine bromide]". Pharmazie. (in German) 40 (5): 325–8. PMID 4034636.

[pmid8103105-8] 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.

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