ethionamide
{{Short description|Chemical compound}}
{{Drugbox
| verifiedrevid = 461096398
| IUPAC_name = 2-ethylpyridine-4-carbothioamide
| image = Ethionamide.svg
| image_class = skin-invert-image
| image2 = Ethionamide 3D spacefill.png
| image_class2 = bg-transparent
| width2 = 150
| tradename = Trecator, others
| Drugs.com = {{drugs.com|monograph|ethionamide}}
| MedlinePlus = a682402
| pregnancy_US = C
| legal_US = Rx-only
| routes_of_administration = by mouth
| bioavailability =
| protein_bound = ~30%
| metabolism =
| elimination_half-life = 2 to 3 hours
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 536-33-4
| ATC_prefix = J04
| ATC_suffix = AD03
| ATC_supplemental =
| PubChem = 2761171
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00609
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 2041901
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = OAY8ORS3CQ
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00591
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 4885
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1441
| C=8 | H=10 | N=2 | S=1
| smiles = S=C(c1ccnc(c1)CC)N
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C8H10N2S/c1-2-7-5-6(8(9)11)3-4-10-7/h3-5H,2H2,1H3,(H2,9,11)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = AEOCXXJPGCBFJA-UHFFFAOYSA-N
| melting_point = 164
| melting_high = 166
| melting_notes = (dec.)
}}
Ethionamide (aka ETA or ETH){{Cite book |title=Logan's Medical and Scientific Abbreviations |vauthors=Logan CM, Rice MK |publisher=J. B. Lippincott |year=1987 |isbn=0-397-54589-4 |page=182 |type=Hardbound book}} is an antibiotic used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, to treat active multidrug-resistant tuberculosis. It is no longer recommended for leprosy.{{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}} It is taken by mouth.{{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}}
Ethionamide has a high rate of side effects.{{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 }} Common side effects include nausea, diarrhea, abdominal pain, and loss of appetite. Serious side effects may include liver inflammation and depression. It should not be used in people with significant liver problems. Use in pregnancy is not recommended as safety is unclear. Ethionamide is in the thioamides family of medications. It is believed to work by interfering with the use of mycolic acid.
Ethionamide was discovered in 1956 and approved for medical use in the United States in 1965.{{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 }} It is on the World Health Organization's List of Essential Medicines.{{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 }}
Medical uses
Ethionamide is used in combination with other antituberculosis agents as part of a second-line regimen for active tuberculosis.{{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}}
Ethionamide is well absorbed orally with or without food, but is often administered with food to improve tolerance.{{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 }}{{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}} It crosses the blood brain barrier to achieve concentrations in the cerebral-spinal fluid equivalent to plasma.
The antimicrobial spectrum of ethionamide includes M. tuberculosis, M. bovis and M. smegmatis.{{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 }} It also is used rarely against infections with M. leprae{{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}} and other nontuberculous mycobacteria such as M. avium{{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}} and M. kansasii. 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.{{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 }} 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.
The FDA has placed it in pregnancy category C, because it has caused birth defects in animal studies.{{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}} It is not known whether ethionamide is excreted into breast milk.
Adverse effects
Ethionamide frequently causes gastrointestinal distress with nausea and vomiting which can lead patients to stop taking it. This can sometimes be improved by taking it with food.
Ethionamide can cause hepatocellular toxicity and is contraindicated in patients with severe liver impairment. Patients on ethionamide should have regular monitoring of their liver function tests. 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. The pattern of liver function test derangement is often a rise in the ALT and AST.{{Cite web |title=Ethionamide |url=https://livertox.nlm.nih.gov/Ethionamide.htm |url-status=live |archive-url=https://web.archive.org/web/20161224030624/https://livertox.nlm.nih.gov/Ethionamide.htm |archive-date=2016-12-24 |access-date=2016-12-14 |website=livertox.nlm.nih.gov}}
Both central neurological side effects such as psychiatric disturbances and encephalopathy, along with peripheral neuropathy have been reported. Administering pyridoxine along with ethionamide may reduce these effects and is recommended.
Ethionamide is structurally similar to methimazole, which is used to inhibit thyroid hormone synthesis, and has been linked to hypothyroidism in several TB patients.{{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 }} Periodic monitoring of thyroid function while on ethionamide is recommended.
= 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. When taken with cycloserine, seizures have been reported. High rates of hepatotoxicty have been reported when taken with rifampicin. The drug's labeling cautions against excessive alcohol ingestion as it may provoke a psychotic reaction.
Mechanism of action
Ethionamide is a prodrug{{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 }} 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.{{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 }}
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.
Other names
- 1314{{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 }}
- 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 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}}
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Category:Disubstituted pyridines
Category:World Health Organization essential medicines
Category:Wikipedia medicine articles ready to translate