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Revision as of 13:45, 24 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{drugbox}} taken from revid 456592363 of page Neostigmine for the Chem/Drugbox validation project (updated: 'ChEMBL').  Latest revision as of 20:09, 30 August 2024 edit 174.66.87.253 (talk) Sort cats. 
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{{Short description|Anti-full body paralysis drug treatment}}
{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}}
{{Use dmy dates|date=January 2020}}
{{Drugbox {{Drugbox
| Verifiedfields = changed | Verifiedfields = changed
| verifiedrevid = 401609488 | verifiedrevid = 462259406
| image = Neostigmine.svg
| IUPAC_name = 3-{oxy}-''N,N,N''-trimethylbenzenaminium
| image = Neostigmine.png | image2 = Neostigmine ball-and-stick.png


<!--Clinical data--> <!--Clinical data-->
| tradename = Prostigmin | tradename = Bloxiverz, Prostigmin, Vagostigmin, others
| Drugs.com = {{drugs.com|monograph|neostigmine-bromide}} | Drugs.com = {{drugs.com|monograph|neostigmine-methylsulfate}}
| DailyMedID = Neostigmine
| pregnancy_category =
| pregnancy_AU = B2
| legal_status =
| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Neostigmine Use During Pregnancy | website=Drugs.com | date=3 January 2020 | url=https://www.drugs.com/pregnancy/neostigmine.html | access-date=21 January 2020}}</ref>
| routes_of_administration =
| pregnancy_category=
| routes_of_administration = ], ], ], ]
| class = ]
| ATC_prefix = N07
| ATC_suffix = AA01
| ATC_supplemental = {{ATC|S01|EB06}} {{ATCvet|A03|AB93}}

<!-- Legal status -->
| legal_AU = S4
| legal_AU_comment =
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
| legal_BR_comment =
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA_comment =
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = POM
| legal_UK_comment =
| legal_US = Rx-only
| legal_US_comment = <ref>{{cite web | title=Bloxiverz- neostigmine methylsulfate injection | website=DailyMed | date=3 March 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1fb5c812-1e63-4bd9-a68e-7f9dc5e7a33a | access-date=15 July 2022}}</ref>
| legal_EU =
| legal_EU_comment =
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment =
| legal_status = <!-- For countries not listed above -->


<!--Pharmacokinetic data--> <!--Pharmacokinetic data-->
Line 18: Line 46:
| elimination_half-life = 50–90 minutes | elimination_half-life = 50–90 minutes
| excretion = Unchanged drug (up to 70%) and alcoholic metabolite (30%) are excreted in the urine | excretion = Unchanged drug (up to 70%) and alcoholic metabolite (30%) are excreted in the urine
| onset = Within 10-20 min (injection),<ref name=AHFS2016/> with 4 hrs (by mouth) {{cn|date=December 2022}}
| duration_of_action = up to 4 hrs<ref name=AHFS2016/>


<!--Identifiers--> <!--Identifiers-->
| index2_label = as methylsulfate
| CASNo_Ref = {{cascite|correct|CAS}}
| index3_label = as bromide <!-- pending Infobox update -->
| CAS_number_Ref = {{cascite|correct|??}} | CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 59-99-4 | CAS_number = 59-99-4
| ATC_prefix = N07
| ATC_suffix = AA01
| ATC_supplemental = {{ATC|S01|EB06}} {{ATCvet|A03|AB93}}
| PubChem = 4456 | PubChem = 4456
| DrugBank_Ref = {{drugbankcite|changed|drugbank}} | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01400 | DrugBank = DB01400
| DrugBank2 = DBSALT000128
| DrugBank3 = DBSALT001191 <!-- pending Infobox update -->
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 4301 | ChemSpiderID = 4301
| UNII_Ref = {{fdacite|correct|FDA}} | UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 3982TWQ96G | UNII = 3982TWQ96G
| KEGG_Ref = {{keggcite|changed|kegg}} | KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08261 | KEGG = D08261
| KEGG2 = D00998
| ChEBI_Ref = {{ebicite|changed|EBI}}
| KEGG3 = D00995 <!-- pending Infobox update -->
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 7514 | ChEBI = 7514
| ChEMBL_Ref = {{ebicite|changed|EBI}} | ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = <!-- blanked - oldvalue: 54126 --> | ChEMBL = 54126

| C=12 | H=19 | N=2 | O=2
<!--Chemical data-->
| molecular_weight = 223.294 g/mol
| IUPAC_name = 3-{oxy}-''N,N,N''-trimethylbenzenaminium
| smiles = O=C(Oc1cccc(c1)(C)(C)C)N(C)C
| C=12 | H=19 | N=2 | O=2 | charge = +
| InChI = 1/C12H19N2O2/c1-13(2)12(15)16-11-8-6-7-10(9-11)14(3,4)5/h6-9H,1-5H3/q+1
| SMILES = CN(C)C(=O)OC1=CC=CC(=C1)(C)(C)C
| InChIKey = ALWKGYPQUAPLQC-UHFFFAOYAL
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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 | StdInChI = 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
Line 49: Line 81:
| StdInChIKey = ALWKGYPQUAPLQC-UHFFFAOYSA-N | StdInChIKey = ALWKGYPQUAPLQC-UHFFFAOYSA-N
}} }}

<!-- Definition and medical uses -->
'''Neostigmine''', sold under the brand name '''Bloxiverz''', among others, is a ] used to treat ], ], and ] without the presence of a blockage.<ref name=AHFS2016/><ref name=WHO2008>{{cite book | title = WHO Model Formulary 2008 | year = 2009 | isbn = 9789241547659 | vauthors = ((World Health Organization)) | veditors = Stuart MC, Kouimtzi M, Hill SR | hdl = 10665/44053 | author-link = World Health Organization | publisher = World Health Organization |page=428 | hdl-access=free }}</ref> It is also used in anaesthesia to end the effects of non-depolarising ].<ref name=AHFS2016/> It is given by injection either ], ], or ].<ref name=AHFS2016/> After injection effects are generally greatest within 30 minutes and last up to 4 hours.<ref name=AHFS2016>{{cite web|title=Neostigmine Bromide|url=https://www.drugs.com/monograph/neostigmine-bromide.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161221012812/https://www.drugs.com/monograph/neostigmine-bromide.html|archive-date=21 December 2016}}</ref><ref>{{cite web | title=Neostigmine Methylsulfate Monograph for Professionals | website=Drugs.com | date=19 September 2019 | publisher=The American Society of Health-System Pharmacists | url=https://www.drugs.com/monograph/neostigmine-methylsulfate.html | access-date=20 January 2020}}</ref>

<!-- Side effects and mechanisms -->
Common side effects include nausea, increased saliva, crampy abdominal pain, and ].<ref name=AHFS2016/> More severe side effects include ], weakness, and ].<ref name=AHFS2016/> It is unclear if use in ] is safe for the baby.<ref name=AHFS2016/> Neostigmine is in the ] family of medications.<ref name=AHFS2016/> It works by blocking the action of ] and therefore increases the levels of ].<ref name=AHFS2016/>

<!-- History, society and culture -->
Neostigmine was patented in 1931.<ref name=Fis2006>{{cite book| vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery|date=2006|publisher=John Wiley & Sons|isbn=9783527607495|page=540|url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA540|language=en|url-status=live|archive-url=https://web.archive.org/web/20161220143859/https://books.google.ca/books?id=FjKfqkaKkAAC&pg=PA540|archive-date=2016-12-20}}</ref> It is on the ].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> The term is from Greek ''neos'', meaning "new", and "-stigmine", in reference to its parent molecule, ], on which it is based.<ref>{{Cite web|title = neostigmine: definition of neostigmine in Oxford dictionary (American English) (US)|url = http://www.oxforddictionaries.com/us/definition/american_english/neostigmine|website = www.oxforddictionaries.com|access-date = 2015-12-17|url-status = dead|archive-url = https://web.archive.org/web/20151222160649/http://www.oxforddictionaries.com/us/definition/american_english/neostigmine|archive-date = 2015-12-22}}</ref> It is available as a ].<ref>{{cite web | title=Competitive Generic Therapy Approvals | website=U.S. ] (FDA) | date=29 June 2023 | url=https://www.fda.gov/drugs/generic-drugs/competitive-generic-therapy-approvals | access-date=29 June 2023 | archive-date=29 June 2023 | archive-url=https://web.archive.org/web/20230629233651/https://www.fda.gov/drugs/generic-drugs/competitive-generic-therapy-approvals | url-status=live }}</ref>

== Medical uses ==
It is used to improve muscle tone in people with ], and also to reverse the effects of non-] ]s such as ] and ] at the end of an operation.<ref name = "Neely_2022">{{cite book | chapter-url= https://www.ncbi.nlm.nih.gov/books/NBK470596/ | pmid=29261883 | year=2022 | vauthors = Neely GA, Sabir S, Kohli A | chapter = Neostigmine | title = StatPearls | location = Treasure Island (FL) | publisher = StatPearls Publishing }}</ref><ref>{{cite web | url=https://www.drugs.com/cdi/neostigmine-injection.html | title=Neostigmine Injection: Indications, Side Effects, Warnings | work = Drugs.com }}</ref>

Another indication for use is the ] of acute colonic pseudo-obstruction, or ], in which patients get massive colonic dilatation in the absence of a true mechanical obstruction.<ref>{{cite journal | vauthors = Maloney N, Vargas HD | title = Acute intestinal pseudo-obstruction (Ogilvie's syndrome) | journal = Clinics in Colon and Rectal Surgery | volume = 18 | issue = 2 | pages = 96–101 | date = May 2005 | pmid = 20011348 | pmc = 2780141 | doi = 10.1055/s-2005-870890 }}</ref>

Neostigmine is often prescribed for underactive urinary bladder.<ref>{{cite journal | vauthors = Moro C, Phelps C, Veer V, Clark J, Glasziou P, Tikkinen KA, Scott AM | title = The effectiveness of parasympathomimetics for treating underactive bladder: A systematic review and meta-analysis | journal = Neurourology and Urodynamics | volume = 41 | issue = 1 | pages = 127–139 | date = January 2022 | pmid = 34816481 | doi = 10.1002/nau.24839 | s2cid = 244530010 | url = https://pure.bond.edu.au/ws/files/118955227/AM_The_effectiveness_of_parasympathomimetics_for_treating.pdf }}</ref>

Hospitals sometimes administer a solution containing neostigmine intravenously to delay the effects of ] through ].<ref>{{cite web | vauthors = Franklin D | url = https://www.npr.org/blogs/health/2013/07/30/207050435/potential-treatment-for-snakebites-leads-to-a-paralyzing-test | title = Potential Treatment For Snakebites Leads To A Paralyzing Test | work = NPR | archive-url = https://web.archive.org/web/20140809234546/http://www.npr.org/blogs/health/2013/07/30/207050435/potential-treatment-for-snakebites-leads-to-a-paralyzing-test | archive-date= 9 August 2014 | date = 31 July 2013 }}</ref> Some promising research results have also been reported for administering the drug nasally in order to buy time if anti-venom is not immediately available.<ref name="pmid30154870">{{cite journal | vauthors = Bulfone TC, Samuel SP, Bickler PE, Lewin MR | title = Developing Small Molecule Therapeutics for the Initial and Adjunctive Treatment of Snakebite | journal = Journal of Tropical Medicine | volume = 2018 | pages = 4320175 | date = 2018 | pmid = 30154870 | pmc = 6091453 | doi = 10.1155/2018/4320175 | doi-access = free }}</ref>

== Side effects ==

Neostigmine has a wide variety of side-effects due to its action that increases acetylcholine (ACh) binding muscarinic receptors on exocrine glandular cells throughout the body, cardiac muscle cells, and smooth muscle cells. These effects include: salivation, lacrimation, diarrhea, bradycardia, and bronchoconstriction.<ref>{{cite book | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK557541/ | pmid=32491473 | year=2022 | vauthors = Naji A, Gatling JW | chapter = Muscarinic Antagonists | title = StatPearls . | location = Treasure Island (FL) | publisher = StatPearls Publishing }}</ref> Gastrointestinal symptoms occur earliest.<ref name = "Gilman_1980" />{{rp|109}}

For this reason, it is usually given along with an ] drug such as ] or ] which act only on muscarinic receptors while permitting neostigmine action at nicotinic receptors.<ref>{{cite journal | vauthors = Howard J, Wigley J, Rosen G, D'mello J | title = Glycopyrrolate: It's time to review | journal = Journal of Clinical Anesthesia | volume = 36 | pages = 51–53 | date = February 2017 | pmid = 28183573 | doi = 10.1016/j.jclinane.2016.09.013 }}</ref>

Neostigmine can also induce generic ocular side effects including: headache, brow pain, blurred vision, phacodonesis, pericorneal injection, congestive iritis, various allergic reactions, and rarely, retinal detachment.<ref name = "Gilman_1980">{{cite book | vauthors = Gilman AG, Goodman LS, Gilman Sr A |author-link1=Alfred G. Gilman |author-link2=Louis S. Goodman |author-link3=Alfred Gilman, Sr. | name-list-style = vanc |title=Goodman & Gilman's The Pharmacological Basis of Therapeutics |edition=6th |publisher=Macmillan Publishing Co., Inc. |location=New York |year=1980 |title-link=Goodman & Gilman's The Pharmacological Basis of Therapeutics }}</ref>{{rp|114}}

== Pharmacology ==

Acetylcholine is metabolized by the enzyme ] that cleaves acetylcholine in the neuromuscular junction into acetate and choline. Neostigmine is an inhibitor of acetylcholinesterase. Neostigmine binds to the anionic and ester site of ], which blocks the ] from breaking down the ] molecules before they reach the ] receptors.
Its action leads to the accumulation of acetylcholine in the neuromuscular junction that compete with the non-depolarizing blocker agent bound to the acetylcholine receptors. By interfering with the breakdown of ], neostigmine indirectly ] both ] and ]s.<ref name = "Neely_2022" />

Unlike ], neostigmine has a quaternary nitrogen; hence, it is more polar. It does not cross the ] and enter the ].<ref>{{cite journal | vauthors = Abdelaal Ahmed Mahmoud A, Mansour AZ, Yassin HM, Hussein HA, Kamal AM, Elayashy M, Elemady MF, Elkady HW, Mahmoud HE, Cusack B, Hosny H, Abdelhaq M | display-authors = 6 | title = Addition of Neostigmine and Atropine to Conventional Management of Postdural Puncture Headache: A Randomized Controlled Trial | language = en-US | journal = Anesthesia and Analgesia | volume = 127 | issue = 6 | pages = 1434–1439 | date = December 2018 | pmid = 30169405 | doi = 10.1213/ANE.0000000000003734 | s2cid = 52142441 }}</ref>

Neostigmine is administered intravenously. The drug should be administered when a ] shows a second twitch is present or when the first twitch response is considerably above 10% of baseline. Peak effect is at 7 to 10 minutes.<ref name = "Neely_2022" /> Neostigmine has moderate duration of action – usually two to four hours.<ref>{{cite book | vauthors = Howland RD, Mycek MJ, Harvey RA, Champe PC, Mycek MJ | title = Pharmacology | edition = 3rd | publisher = Lippincott's Illustrated Reviews | date = 2008 | page = 51 }}</ref> It is metabolized by enzymes in the liver and excreted in the urine.<ref name = "Neely_2022" />

==Chemistry==
Neostigmine, 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 ] forming the desired compound.

=== Spectral data ===

Neostigmine shows notable UV/VIS absorption at 261&nbsp;nm, 267&nbsp;nm, and 225&nbsp;nm.<ref name="pmid4034636">{{cite journal | vauthors = Porst H, Kny L | title = | language = de | journal = Die Pharmazie | volume = 40 | issue = 5 | pages = 325–328 | date = May 1985 | pmid = 4034636 }}</ref>

Neostigmine's ] 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 3.8&nbsp;ppm and 3.1&nbsp;ppm are due to the electronic withdrawing nature of the tertiary and quaternary nitrogen, respectively.<ref name="pmid8103105">{{cite journal | vauthors = Ferdous AJ, Waigh RD | title = 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 = The Journal of Pharmacy and Pharmacology | volume = 45 | issue = 6 | pages = 559–562 | date = June 1993 | pmid = 8103105 | doi = 10.1111/j.2042-7158.1993.tb05598.x | s2cid = 38613106 }}</ref>

==History ==

Neostigmine was first synthesized by Aeschlimann and Reinert in 1931<ref>{{cite book| vauthors = Whitacre DM |title=Reviews of Environmental Contamination and Toxicology|url=https://books.google.com/books?id=PCIbhO_xlcEC&pg=PA57|year=2007|publisher=]|isbn=978-0-387-73162-9|page=57}}</ref> and was patented by Aeschlimann in 1933.<ref>{{cite patent | inventor = Aeschliman JA | country = US | number = 1905990 | gdate = 1933}}</ref>

Neostigmine is made by first reacting 3-dimethylaminophenol with ''N''-dimethylcarbamoyl chloride, which forms a dimethylcarbamate. Next, that product is alkylated using dimethyl sulfate, which forms neostigmine.<ref name = "Gilman_1980" />{{rp|103}}

== References ==
{{Reflist}}

== External links ==
* {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/rn/59-99-4 | publisher = U.S. National Library of Medicine| work = Drug Information Portal| title = Neostigmine }}
* {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/name/neostigmine%20methylsulfate | publisher = U.S. National Library of Medicine| work = Drug Information Portal| title = Neostigmine methylsulfate }}
* {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/name/neostigmine%20bromide | publisher = U.S. National Library of Medicine| work = Drug Information Portal| title = Neostigmine bromide }}

{{Opthalmologicals}}
{{Acetylcholine metabolism and transport modulators}}
{{Portal bar|Medicine}}

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