Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Ethosuximide: Difference between pages

{{Short description|Medication used to treat absence seizures}}

| Watchedfields = changed

| verifiedrevid = 461096657

| image = Ethosuximide.svg

| width = 140

| image2 = 3D Model of Ethosuximide.png

| chirality = [[Racemic mixture]]

<!--Clinical data-->| tradename = Zarontin, others

| Drugs.com = {{drugs.com|monograph|ethosuximide}}

| MedlinePlus = a682327

| DailyMedID = Ethosuximide

| pregnancy_AU = D

| routes_of_administration = By mouth ([[Capsule (pharmacy)|capsules]], [[Solution (chemistry)|solution]])

| ATC_prefix = N03

| ATC_suffix = AD01

| legal_BR = C1

| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-04-04}}</ref>

| legal_US = Rx-only

| legal_EU = Rx-only

| legal_EU_comment = <ref>{{cite web|url=https://www.ema.europa.eu/documents/psusa/cyproterone/ethinylestradiol-list-nationally-authorised-medicinal-products-psusa/00000906/202005_en.pdf|title=List of nationally authorised medicinal products|publisher=European Medicines Agency}}</ref>

| legal_status = Rx-only

<!--Pharmacokinetic data-->| bioavailability = 93%<ref name = "bioavailability" />

| metabolism = [[liver]] ([[CYP3A4]], [[CYP2E1]])

| excretion = [[kidney]] (20%)

<!--Identifiers-->| IUPHAR_ligand = 7182

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 77-67-8

| PubChem = 3291

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB00593

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 3175

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 5SEH9X1D1D

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D00539

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEBI = 4887

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 696

<!--Chemical data-->| drug_name = Ethosuximide

| IUPAC_name = (''RS'')-3-Ethyl-3-methyl-pyrrolidine-2,5-dione

| C = 7

| H = 11

| N = 1

| O = 2

| SMILES = O=C1NC(=O)CC1(C)CC

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C7H11NO2/c1-3-7(2)4-5(9)8-6(7)10/h3-4H2,1-2H3,(H,8,9,10)

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = HAPOVYFOVVWLRS-UHFFFAOYSA-N

| melting_point = 64

| melting_high = 65

<!-- Definition and medical uses -->

'''Ethosuximide''', sold under the brand name '''Zarontin''' among others, is a medication used to treat [[absence seizures]].<ref name=AHFS2016/> It may be used by itself or with other [[anticonvulsants|antiseizure medications]] such as [[valproic acid]].<ref name=AHFS2016/> Ethosuximide is taken by mouth.<ref name=AHFS2016>{{cite web|title=Ethosuximide|url=https://www.drugs.com/monograph/ethosuximide.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161221003723/https://www.drugs.com/monograph/ethosuximide.html|archive-date=21 December 2016}}</ref>

<!-- Side effects and mechanism -->

Ethosuximide is usually well tolerated.<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 | hdl-access=free | pages=69, 74–75 }}</ref> Common side effects include loss of appetite, abdominal pain, diarrhea, and feeling tired.<ref name=AHFS2016/> Serious side effects include [[suicidal thoughts]], [[cytopenia|low blood cell levels]], and [[lupus erythematosus]].<ref name=AHFS2016/><ref name=WHO2008/> It is unclear if it has adverse effects on the fetus during [[pregnancy]].<ref name=AHFS2016/> Ethosuximide is in the [[succinimide]] family of medications. Its mechanism of action is thought to be due to antagonism of the postsynaptic T-type voltage-gated calcium channel.<ref>{{cite journal |last1=Huguenard |first1=John R. |title=Block of T -Type Ca2+ Channels Is an Important Action of Succinimide Antiabsence Drugs |journal=Epilepsy Currents |date=March 2002 |volume=2 |issue=2 |pages=49–52 |doi=10.1046/j.1535-7597.2002.00019.x |pmid=15309165 |pmc=320968 }}</ref>

<!-- History and culture -->

Ethosuximide was approved for medical use in the United States in 1960.<ref name="fdaApproved">{{cite web |title=Drugs@FDA: FDA-Approved Drugs |url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=012380 |website=U.S. Food and Drug Administration |access-date=29 December 2020}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<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> Ethosuximide is available as a [[generic medication]].<ref name=AHFS2016/> {{As of|2019}}, its availability was limited in many countries, with concerns about [[price fixing]] in the United States.<ref name=Hem2019/><ref>{{cite press release |title= Attorney General Tong leads 44-state coalition in antitrust lawsuit against Teva Pharmaceuticals, 19 other generic drug manufacturers, 15 individuals in conspiracy to fix prices and allocate markets for more than 100 different generic drugs |url=https://portal.ct.gov/AG/Press-Releases/2019-Press-Releases/TONG-LEADS-LAWSUIT-AGAINST-GENERIC-DRUG-MANUFACTURERS-IN-CONSPIRACY-TO-FIX-PRICES-FOR-OVER-100-DRUGS |access-date=5 April 2020 |date= 12 May 2019 |publisher= Office of the Attorney General of the State of Connecticut}}</ref><ref name=CA2019/>

{{TOC limit}}

== Medical uses ==

Ethosuximide is approved for [[absence seizures]],<ref name = "approved_use" /> and is considered the first choice medication for treating them, in part because it lacks the idiosyncratic [[hepatotoxicity]] of the alternative anti-absence drug, [[valproic acid]].<ref name = "approved_use_2" />

==Adverse effects==

As with other anticonvulsants, ethosuximide carries a warning about use during pregnancy. Although a causal relationship with birth defects has not be established, the potential for harm to the baby is weighed against the known harm caused by a mother having even minor seizures.<ref name=AHFS2016/>

===Central nervous system===

====Common====

* [[Somnolence|drowsiness]]

* [[Confusion|mental confusion]]

* [[insomnia]]

* [[headache]]

* [[ataxia]]

====Rare====

* [[paranoia|paranoid]] [[psychosis]]

* increased [[libido]]

* exacerbation of [[Major depressive disorder|depression]]

===Gastrointestinal===

* [[Indigestion|dyspepsia]]

* [[vomiting]]

* [[nausea]]

* cramps

* [[constipation]]

* [[diarrhea]]

* stomach pain

* loss of appetite

* weight loss

* [[Gingival enlargement|gum enlargement]]

* swelling of tongue

* abnormal [[liver|liver function]]

===Genitourinary===

* microscopic [[hematuria]]

* vaginal bleeding

===Blood===

''The following can occur with or without bone marrow loss:''

* [[pancytopenia]]

* [[agranulocytosis]]

* [[leukopenia]]

* [[eosinophilia]]

===Skin===

* [[urticaria]]

* [[systemic lupus erythematosus]]

* [[Stevens–Johnson syndrome]]

* [[hirsutism]]

* [[Itch|pruritic]] [[erythema]]tous [[rash]]es

===Eyes===

* [[myopia]]

==Drug interactions==

[[Valproate]]s can either decrease or increase the levels of ethosuximide; however, combinations of [[valproate]]s and ethosuximide had a greater [[protective index]] than either drug alone.<ref name = "combo" />

It may elevate serum [[phenytoin]] levels.

==Mechanism of action==

The mechanism by which ethosuximide affects neuronal excitability includes block of [[T-type calcium channel]]s, and may include effects of the drug on other classes of ion channel. The primary finding that ethosuximide is a T-type calcium channel blocker gained widespread support, but initial attempts to replicate the finding were inconsistent. Subsequent experiments on recombinant T-type channels in cell lines demonstrated conclusively that ethosuximide blocks all T-type calcium channel isoforms.{{citation needed|date=May 2014}} Significant T-type calcium channel density occurs in dendrites of neurons, and recordings from reduced preparations that strip away this dendritic source of T-type calcium channels may have contributed to reports of ethosuximide ineffectiveness.

In March 1989, Coulter, Huguenard and Prince showed that ethosuximide and [[dimethadione]], both effective anti-absence agents, reduced low-threshold [[calcium|Ca²⁺]] [[electric current|current]]s in [[T-type calcium channel]]s in freshly removed [[Thalamus|thalamic]] [[neuron]]s.<ref name = "Coulter1989-1" /> In June of that same year, they also found the mechanism of this reduction to be [[voltage]]-dependent, using acutely dissociated neurons of rats and guinea pigs; it was also noted that [[Valproate|valproic acid]], which is also used in absence seizures, did not do that.<ref name="Coulter1989-2" /> The next year, they showed that anticonvulsant succinimides did this and that the [[Convulsant|pro-convulsant]] ones did not.<ref name = "Coulter1990" /> The first part was supported by [[Platon Kostyuk|Kostyuk]] et al. in 1992, who reported a substantial reduction in current in [[Dorsal root of spinal nerve|dorsal root]] [[ganglion|ganglia]] at concentrations ranging from 7 μmol/L to 1&nbsp;mmol/L.<ref name = "Kostyuk" />

That same year, however, Herrington and Lingle found no such effect at concentrations of up to 2.5&nbsp;mmol/L.<ref name = "Herrington-Lingle" /> The year after, a study conducted on human [[neocortex|neocortical]] cells removed during surgery for intractable epilepsy, the first to use human tissue, found that ethosuximide had no effect on Ca²⁺ currents at the concentrations typically needed for a therapeutic effect.<ref name = "sayer1993" />

In 1998, Slobodan M. Todorovic and Christopher J. Lingle of Washington University reported a 100% block of T-type current in dorsal root ganglia at 23.7 ± 0.5&nbsp;mmol/L, far higher than Kostyuk reported.<ref name = "Todorovic_Lingle" /> That same year, Leresche et al. reported that ethosuximide had no effect on T-type currents, but did decrease noninactivating [[sodium|Na⁺]] current by 60% and the Ca²⁺-activated K⁺ currents by 39.1 ± 6.4% in rat and cat thalamocortical cells. It was concluded that the decrease in Na⁺ current is responsible for the anti-absence properties.<ref name = "Leresche_et_al_1998" />

In the introduction of a paper published in 2001, Dr. Juan Carlos Gomora and colleagues at the [[University of Virginia]] in [[Charlottesville, Virginia|Charlottesville]] pointed out that past studies were often done in isolated neurons that had lost most of their T-type channels.<ref name = "Gomora_et_al_2001" /> Using cloned [[CACNA1G|α₁G]], [[CACNA1H|α₁H]], and [[CACNA1I|α₁I]] T-type calcium channels, Gomora's team found that ethosuximide blocked the channels with an [[IC50|IC₅₀]] of 12 ± 2&nbsp;mmol/L and that of ''N''-desmethylmethsuximide (the active metabolite of [[mesuximide]]) is 1.95 ± 0.19&nbsp;mmol/L for α₁G, 1.82 ± 0.16&nbsp;mmol/L for α₁I, and 3.0 ± 0.3&nbsp;mmol/L for α₁H. It was suggested that the blockade of open channels is facilitated by ethosuximide's physically plugging the channels when current flows inward.

== Stereochemistry ==

Ethosuximide is a chiral drug with a [[stereocenter]]. Therapeutically, the [[racemate]], the 1: 1 mixture of ('' S '') and ('' R '') - isomers used.<ref name="Rote Liste">Rote Liste Service GmbH (Hrsg.): ''Rote Liste 2017 – Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte)''. Rote Liste Service GmbH, Frankfurt/Main, 2017, Aufl. 57, {{ISBN|978-3-946057-10-9}}, S. 182.</ref>

{| class="wikitable" style="text-align:center"

|- class="hintergrundfarbe6"

! colspan="2"| Enantiomers of ethosuximide

|-

| [[File:(R)-Ethosuximid Structural Formula V1.svg|140 px]]<br /><small> CAS-Nummer: 39122-20-8</small>

| [[File:(S)-Ethosuximid Structural Formula V1.svg|140 px]]<br /><small> CAS-Nummer: 39122-19-5</small>

|}

==Society and culture==

===Cost===

As of 2019 there were concerns in the United States that the price of ethosuximide was inflated by manufacturers.<ref name=CA2019>{{cite web |title=States sue generic drug makers, claiming a conspiracy to fix prices |url=https://www.consumeraffairs.com/news/states-sue-generic-drug-makers-claiming-a-conspiracy-to-fix-prices-051419.html |website=consumeraffairs.com |access-date=5 April 2020 |language=en |date=14 May 2019}}</ref><ref>{{cite news |last1=Staff |first1=WMBF News |title=South Carolina joins lawsuit against manufacturers in alleged conspiracy to fix prescription drug prices |url=https://www.wmbfnews.com/2019/05/13/south-carolina-joins-lawsuit-against-manufacturers-alleged-conspiracy-fix-prescription-drug-prices/ |access-date=5 April 2020 |work=wmbfnews.com}}</ref>

===Availability===

Availability of ethosuximide is limited in many countries.<ref name=Hem2019>{{cite book |last1=Hempel |first1=Georg |title=Methods of Therapeutic Drug Monitoring Including Pharmacogenetics |date=2019 |publisher=Elsevier |isbn=978-0-444-64067-3 |page=241 |url=https://books.google.com/books?id=I5G3DwAAQBAJ&dq=Ethosuximide+%22inexpensive%22+OR+%22low+cost%22&pg=PA241 |language=en}}</ref> It was marketed under the trade names Emeside and Zarontin. However, both capsule preparations were discontinued from production, leaving only generic preparations available. Emeside capsules were discontinued by their manufacturer, [[Laboratories for Applied Biology]], in 2005.<ref name=pharmjethosux>{{cite journal |url=http://www.pharmj.com/Editorial/20051029/news/p539ethosuximide.html |title=Concern over ethosuximide capsule discontinuation |journal=Pharm J |date=Oct 29, 2005 |volume=275 |page=539 |access-date=2008-08-31 |url-status=live |archive-url=https://web.archive.org/web/20081013220747/http://www.pharmj.com/Editorial/20051029/news/p539ethosuximide.html |archive-date=2008-10-13 }} (paywalled archive)</ref> Similarly, Zarontin capsules were discontinued by [[Pfizer]] in 2007.<ref name=epiwatchethosux>{{cite web|url=http://www.epilepsy.org.uk/news/drugwatch/ethosuximide|title=Zarontin capsules discontinued|access-date=2012-10-24|url-status=live|archive-url=https://web.archive.org/web/20120626002021/http://www.epilepsy.org.uk/news/drugwatch/ethosuximide|archive-date=2012-06-26}}</ref> Syrup preparations of both brands remained available.

== See also ==

*[[Phensuximide]]

*[[Methsuximide]]

== References ==

{{reflist|refs =

<ref name = "bioavailability">{{cite journal | vauthors = Patsalos PN | title = Properties of antiepileptic drugs in the treatment of idiopathic generalized epilepsies | journal = Epilepsia | volume = 46 Suppl 9 | issue = s9 | pages = 140–8 | date = November 2005 | pmid = 16302888 | doi = 10.1111/j.1528-1167.2005.00326.x | s2cid = 19462889 | doi-access = free }}</ref>

<ref name = "approved_use">{{cite web | author = Pharmaceutical Associates, Incorporated | year = 2000 | url = http://www.accessdata.fda.gov/drugsatfda_docs/anda/2000/40253_Ethosuximide_Prntlbl.pdf | title = Ethosuximide Approval Label | work = Label and Approval History | publisher = [[Food and Drug Administration]] Center for Drug Evaluation and Research | access-date = 2006-02-05}}</ref>

<ref name = "approved_use_2">{{cite book|contribution=Drugs used in generalized seizures |editor=Katzung, B. |title=Basic and Clinical Pharmacology |edition=9th |year=2003 |publisher=Lange Medical Books/McGraw-Hill |isbn=0071410929}}</ref>

<!-- <ref name = "Andrulonis_et_al_1980">{{cite journal | vauthors = Andrulonis PA, Donnelly J, Glueck BC, Stroebel CF, Szarek BL | title = Preliminary data on ethosuximide and the episodic dyscontrol syndrome | journal = The American Journal of Psychiatry | volume = 137 | issue = 11 | pages = 1455–6 | date = November 1980 | pmid = 7435689 | doi = 10.1176/ajp.137.11.1455 }}</ref> -->

<ref name = "Coulter1989-1">{{cite journal | vauthors = Coulter DA, Huguenard JR, Prince DA | title = Specific petit mal anticonvulsants reduce calcium currents in thalamic neurons | journal = Neuroscience Letters | volume = 98 | issue = 1 | pages = 74–8 | date = March 1989 | pmid = 2710401 | doi = 10.1016/0304-3940(89)90376-5 | s2cid = 13413993 }}</ref>

<ref name = "Coulter1989-2">{{cite journal | vauthors = Coulter DA, Huguenard JR, Prince DA | title = Characterization of ethosuximide reduction of low-threshold calcium current in thalamic neurons | journal = Annals of Neurology | volume = 25 | issue = 6 | pages = 582–93 | date = June 1989 | pmid = 2545161 | doi = 10.1002/ana.410250610 | s2cid = 20670160 }}</ref>

<ref name = "Coulter1990">{{cite journal | vauthors = Coulter DA, Huguenard JR, Prince DA | title = Differential effects of petit mal anticonvulsants and convulsants on thalamic neurones: calcium current reduction | journal = British Journal of Pharmacology | volume = 100 | issue = 4 | pages = 800–6 | date = August 1990 | pmid = 2169941 | pmc = 1917607 | doi = 10.1111/j.1476-5381.1990.tb14095.x }}</ref>

<ref name = "Kostyuk">{{cite journal | vauthors = Kostyuk PG, Molokanova EA, Pronchuk NF, Savchenko AN, Verkhratsky AN | title = Different action of ethosuximide on low- and high-threshold calcium currents in rat sensory neurons | journal = Neuroscience | volume = 51 | issue = 4 | pages = 755–8 | date = December 1992 | pmid = 1336826 | doi = 10.1016/0306-4522(92)90515-4 | s2cid = 41451332 }}</ref>

<ref name = "Herrington-Lingle">{{cite journal | vauthors = Herrington J, Lingle CJ | title = Kinetic and pharmacological properties of low voltage-activated Ca2+ current in rat clonal (GH3) pituitary cells | journal = Journal of Neurophysiology | volume = 68 | issue = 1 | pages = 213–32 | date = July 1992 | pmid = 1325546 | doi = 10.1152/jn.1992.68.1.213 }}</ref>

<ref name = "sayer1993">{{cite journal | vauthors = Sayer RJ, Brown AM, Schwindt PC, Crill WE | title = Calcium currents in acutely isolated human neocortical neurons | journal = Journal of Neurophysiology | volume = 69 | issue = 5 | pages = 1596–606 | date = May 1993 | pmid = 8389832 | doi = 10.1152/jn.1993.69.5.1596 }}</ref>

<ref name = "Todorovic_Lingle">{{cite journal | vauthors = Todorovic SM, Lingle CJ | title = Pharmacological properties of T-type Ca2+ current in adult rat sensory neurons: effects of anticonvulsant and anesthetic agents | journal = Journal of Neurophysiology | volume = 79 | issue = 1 | pages = 240–52 | date = January 1998 | pmid = 9425195 | doi = 10.1152/jn.1998.79.1.240 }}</ref>

<ref name = "Leresche_et_al_1998">{{cite journal | vauthors = Leresche N, Parri HR, Erdemli G, Guyon A, Turner JP, Williams SR, Asprodini E, Crunelli V | display-authors = 6 | title = On the action of the anti-absence drug ethosuximide in the rat and cat thalamus | journal = The Journal of Neuroscience | volume = 18 | issue = 13 | pages = 4842–53 | date = July 1998 | pmid = 9634550 | pmc = 6792570 | url = | doi = 10.1523/JNEUROSCI.18-13-04842.1998 }}</ref>

<ref name = "Gomora_et_al_2001">{{cite journal | vauthors = Gomora JC, Daud AN, Weiergräber M, Perez-Reyes E | title = Block of cloned human T-type calcium channels by succinimide antiepileptic drugs | journal = Molecular Pharmacology | volume = 60 | issue = 5 | pages = 1121–32 | date = November 2001 | pmid = 11641441 | doi = 10.1124/mol.60.5.1121 | s2cid = 7098669 }}</ref>

<ref name = "combo">{{cite journal | vauthors = Bourgeois BF | title = Combination of valproate and ethosuximide: antiepileptic and neurotoxic interaction | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 247 | issue = 3 | pages = 1128–32 | date = December 1988 | pmid = 3144596 }}</ref>

}}

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