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

{{Short description|Chemical compound}}

| verifiedrevid = 461096398

| image = Ethionamide.svg

| image2 = Ethionamide 3D spacefill.png

| width2 = 150

| tradename = Trecator, others

| pregnancy_US = C

| legal_US = Rx-only

| legal_US_comment = <ref name="Trecator FDA label">{{cite web | title=Trecator- ethionamide tablet, film coated | website=DailyMed | date=20 May 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=04a413fe-95f4-47a7-42ac-283a9e78297d | access-date=28 July 2020}}</ref>

| routes_of_administration = [[Oral administration|by mouth]]

| bioavailability =

| protein_bound = ~30%

| metabolism =

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

| ATC_supplemental =

| C=8 | H=10 | N=2 | S=1

| melting_point = 164

| melting_high = 166

| melting_notes = (dec.)

<!-- Definition and medical uses -->

'''Ethionamide''' is an [[antibiotic]] used to treat [[tuberculosis]].<ref name=AHFS2016/> Specifically it is used, along with other [[antituberculosis medications]], to treat active [[multidrug-resistant tuberculosis]].<ref name=AHFS2016/> It is no longer recommended for [[leprosy]].<ref>{{Cite web|url=https://www.hrsa.gov/hansensdisease/diagnosis/chemotherapy.html|title=Standard Chemotherapy|website=www.hrsa.gov|access-date=2016-12-15|url-status=live|archive-url=https://web.archive.org/web/20161220151945/https://www.hrsa.gov/hansensdisease/diagnosis/chemotherapy.html|archive-date=2016-12-20}}</ref><ref name=AHFS2016/> It is taken by mouth.<ref name=AHFS2016>{{cite web|title=Ethionamide|url=https://www.drugs.com/monograph/ethionamide.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161220231359/https://www.drugs.com/monograph/ethionamide.html|archive-date=20 December 2016}}</ref>

<!-- Side effects and mechanism -->

Ethionamide has a high rate of side effects.<ref Name=Wol2012>{{cite journal | vauthors = Wolff KA, Nguyen L | title = Strategies for potentiation of ethionamide and folate antagonists against Mycobacterium tuberculosis | journal = Expert Review of Anti-Infective Therapy | volume = 10 | issue = 9 | pages = 971–981 | date = September 2012 | pmid = 23106273 | pmc = 3971469 | doi = 10.1586/eri.12.87 }}</ref> Common side effects include nausea, [[diarrhea]], [[abdominal pain]], and loss of appetite. Serious side effects may include [[hepatitis|liver inflammation]] and [[Depression (mood)|depression]].<ref name=AHFS2016/> It should not be used in people with significant [[liver problems]]. Use in [[pregnancy]] is not recommended as safety is unclear.<ref name=AHFS2016/> Ethionamide is in the [[thioamides]] family of medications. It is believed to work by interfering with the use of [[mycolic acid]].<ref name=GTC2012/>

<!-- History and culture -->

Ethionamide was [[1956 in science#Medicine|discovered in 1956]] and approved for medical use in the United States in 1965.<ref name=GTC2012>{{cite web | publisher= Global Tuberculosis Community Advisory Board | url= http://www.tbonline.info/posts/2011/8/24/ethionamide/ | title= Ethionamide | work= TB Online | access-date= 2012-08-18 | url-status= live | archive-url= https://web.archive.org/web/20130914063743/http://www.tbonline.info/posts/2011/8/24/ethionamide/ | archive-date= 2013-09-14 }}</ref><ref name=AHFS2016/> 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>

==Medical uses==

Ethionamide is used in combination with other antituberculosis agents as part of a second-line regimen for active tuberculosis.<ref name=":3">{{Cite web|url=http://apps.who.int/prequal/whopar/whoparproducts/TB133part4v1.pdf|title=Summary of Product Characteristics|publisher=World Health Organization|access-date=2016-12-14|url-status=dead|archive-url=https://web.archive.org/web/20160305003213/http://apps.who.int/prequal/whopar/whoparproducts/TB133part4v1.pdf|archive-date=2016-03-05}}</ref>

Ethionamide is well absorbed orally with or without food, but is often administered with food to improve tolerance.<ref>{{cite journal | vauthors = Auclair B, Nix DE, Adam RD, James GT, Peloquin CA | title = Pharmacokinetics of ethionamide administered under fasting conditions or with orange juice, food, or antacids | journal = Antimicrobial Agents and Chemotherapy | volume = 45 | issue = 3 | pages = 810–814 | date = March 2001 | pmid = 11181366 | pmc = 90379 | doi = 10.1128/AAC.45.3.810-814.2001 }}</ref><ref name=":1">{{Cite book|title=Mandell, Douglas, and Bennett's principles and practice of infectious diseases| vauthors = Bennett JE, Dolin R, Blaser M, Mandell GL |year=2015|isbn=978-0-323-40161-6|chapter=38 - Antimycobacterial Agents|publisher=Elsevier/Saunders |oclc=889211235}}</ref> It crosses the [[Blood–brain barrier|blood brain barrier]] to achieve concentrations in the [[Cerebrospinal fluid|cerebral-spinal fluid]] equivalent to [[Blood plasma|plasma]].<ref name=":1" />

The antimicrobial spectrum of ethionamide includes [[Mycobacterium tuberculosis|''M. tuberculosis'']], ''M. bovis'' and ''M. smegmatis''.<ref name="pmid8672093">{{cite journal | vauthors = Rastogi N, Labrousse V, Goh KS | title = In vitro activities of fourteen antimicrobial agents against drug susceptible and resistant clinical isolates of Mycobacterium tuberculosis and comparative intracellular activities against the virulent H37Rv strain in human macrophages | journal = Current Microbiology | volume = 33 | issue = 3 | pages = 167–175 | date = September 1996 | pmid = 8672093 | doi = 10.1007/s002849900095 | s2cid = 35058684 }}</ref> It also is used rarely against infections with ''[[Mycobacterium leprae|M. leprae]]''<ref name=":2">{{Cite web|url=http://apps.who.int/medicinedocs/en/d/Js5511e/3.4.html|title=WHO Model Prescribing Information: Drugs Used in Mycobacterial Diseases: Leprosy: Ethionamide and protionamide|website=apps.who.int|access-date=2016-12-14|url-status=dead|archive-url=https://web.archive.org/web/20161220183804/http://apps.who.int/medicinedocs/en/d/Js5511e/3.4.html|archive-date=2016-12-20}}</ref> and other [[nontuberculous mycobacteria]] such as ''[[Mycobacterium avium-intracellulare infection|M. avium]]''<ref name=":4">{{Cite book|title=Mandell, Douglas, and Bennett's principles and practice of infectious diseases | vauthors = Bennett JE, Dolin R, Blaser M, Mandell GL|year=2015|isbn=978-0-323-40161-6|pages=2832–2843.e3|chapter=253 - Mycobacterium avium Complex|publisher=Elsevier/Saunders |oclc=889211235}}</ref> and ''[[M. kansasii]].''<ref name=":3" /> While working in a similar manner to isoniazid, cross resistance is only seen in 13% of strains, since they are both prodrugs but activated by different pathways.<ref>{{cite journal | vauthors = Belardinelli JM, Morbidoni HR | title = Recycling and refurbishing old antitubercular drugs: the encouraging case of inhibitors of mycolic acid biosynthesis | journal = Expert Review of Anti-Infective Therapy | volume = 11 | issue = 4 | pages = 429–440 | date = April 2013 | pmid = 23566152 | doi = 10.1586/eri.13.24 | s2cid = 31560270 }}</ref> Resistance can emerge from mutations in ethA, which is needed to activate the drug, or ethR, which can be overexpressed to repress ethA. Mutations in inhA or the promoter of inhA can also lead to resistance through changing the binding site or overexpression.<ref Name=Wol2012/>

The [[Food and Drug Administration|FDA]] has placed it in [[Pregnancy category|pregnancy category C]], because it has caused birth defects in animal studies.<ref name="Trecator FDA label" /><ref>{{Cite web|url=https://www.drugs.com/pregnancy/ethionamide.html|title=Ethionamide Use During Pregnancy |website=Drugs.com|access-date=2016-12-14|url-status=live|archive-url=https://web.archive.org/web/20161221010313/https://www.drugs.com/pregnancy/ethionamide.html|archive-date=2016-12-21}}</ref> It is not known whether ethionamide is excreted into breast milk.<ref name=":3" />

==Adverse effects==

Ethionamide frequently causes gastrointestinal distress with nausea and vomiting which can lead patients to stop taking it.<ref name=":1" /> This can sometimes be improved by taking it with food.<ref name=":3" />

Ethionamide can cause [[Hepatocyte|hepatocellular]] toxicity and is contraindicated in patients with severe [[Liver disease|liver impairment]]. Patients on ethionamide should have regular monitoring of their [[liver function tests]].<ref name=":3" /> Liver toxicity occurs in up to 5% of patients and follows a pattern similar to [[isoniazid]], usually arising in the first 1 to 3 months of therapy, but can occur even after more than 6 months of therapy.<ref name=":5">{{Cite web|url=https://livertox.nlm.nih.gov/Ethionamide.htm|title=Ethionamide|website=livertox.nlm.nih.gov|access-date=2016-12-14|url-status=live|archive-url=https://web.archive.org/web/20161224030624/https://livertox.nlm.nih.gov/Ethionamide.htm|archive-date=2016-12-24}}</ref> The pattern of liver function test derangement is often a rise in the [[Alanine aminotransferase|ALT]] and [[Aspartate transaminase|AST]].<ref name=":5" />

Both central neurological side effects such as psychiatric disturbances and [[encephalopathy]], along with [[peripheral neuropathy]] have been reported.<ref name=":3" /><ref name=":4" /> Administering [[pyridoxine]] along with ethionamide may reduce these effects and is recommended.<ref name=":3" />

Ethionamide is structurally similar to [[methimazole]], which is used to inhibit thyroid hormone synthesis, and has been linked to [[hypothyroidism]] in several TB patients.<ref>{{cite journal | vauthors = McDonnell ME, Braverman LE, Bernardo J | title = Hypothyroidism due to ethionamide | journal = The New England Journal of Medicine | volume = 352 | issue = 26 | pages = 2757–2759 | date = June 2005 | pmid = 15987931 | doi = 10.1056/NEJM200506303522621 | doi-access = free }}</ref> Periodic monitoring of [[Thyroid function tests|thyroid function]] while on ethionamide is recommended.<ref name=":3" />

=== Interactions ===

Ethionamide may worsen the adverse effects of other antituberculous drugs being taken at the same time. It boosts levels of isoniazid when taken together and can lead to increased rates of peripheral neuropathy and hepatotoxicity.<ref name=":3" /> When taken with [[cycloserine]], [[Epileptic seizure|seizures]] have been reported. High rates of hepatotoxicty have been reported when taken with [[rifampicin]].<ref name=":3" /> The drug's labeling cautions against excessive alcohol ingestion as it may provoke a psychotic reaction.<ref name="Trecator FDA label" />

==Mechanism of action==

Ethionamide is a [[prodrug]]<ref name="pmid11823459">{{cite journal | vauthors = Vannelli TA, Dykman A, Ortiz de Montellano PR | title = The antituberculosis drug ethionamide is activated by a flavoprotein monooxygenase | journal = The Journal of Biological Chemistry | volume = 277 | issue = 15 | pages = 12824–12829 | date = April 2002 | pmid = 11823459 | doi = 10.1074/jbc.M110751200 | doi-access = free }}</ref> which is activated by the enzyme ethA, a mono-oxygenase in ''[[Mycobacterium tuberculosis]]'', and then binds NAD+ to form an [[adduct]] which inhibits InhA in the same way as [[isoniazid]]. The mechanism of action is thought to be through disruption of [[mycolic acid]].<ref name=GTC2012/><ref name="pmid1416831">{{cite journal | vauthors = Quémard A, Lanéelle G, Lacave C | title = Mycolic acid synthesis: a target for ethionamide in mycobacteria? | journal = Antimicrobial Agents and Chemotherapy | volume = 36 | issue = 6 | pages = 1316–1321 | date = June 1992 | pmid = 1416831 | pmc = 190338 | doi = 10.1128/aac.36.6.1316 }}</ref>

Expression of the ethA gene is controlled by ethR, a transcriptional [[repressor]]. It is thought that improving ethA expression will increase the efficacy of ethionamide and prompting interest by drug developers in EthR inhibitors as a co-drug.<ref Name=Wol2012/>

==Other names==

* 1314<ref>{{cite journal | vauthors = Somner AR | title = 2-Ethylisothionicotinamide ('1314') in pulmonary tuberculosis: a controlled trial of drug tolerance | journal = Tubercle | volume = 40 | issue = 6 | pages = 457–461 | date = December 1959 | pmid = 13832783 | doi = 10.1016/S0041-3879(59)80101-X }}</ref>

* 2-ethylisothionicotinamide{{medcn|date=July 2020}}

* amidazine{{medcn|date=July 2020}}

* thioamide{{medcn|date=July 2020}}

* iridocin{{medcn|date=July 2020}}

It is sold under the brand name Trecator<ref name="Trecator FDA label" /> by [[Wyeth Pharmaceuticals]] which was purchased by [[Pfizer]] in 2009.{{citation needed|date=July 2020}}

== References ==

{{Reflist}}

== External links ==

* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/ethionamide | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Ethionamide }}

* [http://www.inchem.org/documents/pims/pharm/ethionam.htm Ethionamide (PIM 224)]

{{Antimycobacterials}}

{{portal bar|Medicine}}

[[Category:Pyridines]]

[[Category:World Health Organization essential medicines]]

[[Category:Thioamides]]

[[Category:Wikipedia medicine articles ready to translate]]

[[Category:Anti-tuberculosis drugs]]

[[Category:Antileprotic drugs]]