Ethionamide

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Ethionamide
Ethionamide.svg
Ethionamide 3D spacefill.png
Clinical data
Trade names Trecator, others
AHFS/Drugs.com Monograph
MedlinePlus a682402
Routes of
administration 		by mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding ~30%
Elimination half-life 2 to 3 hours
Identifiers
  • 2-ethylpyridine-4-carbothioamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.007.846 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C8H10N2S
Molar mass 166.24 g·mol−1
3D model (JSmol)
Melting point 164 to 166 °C (327 to 331 °F) (dec.)
  • S=C(c1ccnc(c1)CC)N
  • InChI=1S/C8H10N2S/c1-2-7-5-6(8(9)11)3-4-10-7/h3-5H,2H2,1H3,(H2,9,11) Yes check.svgY
  • Key:AEOCXXJPGCBFJA-UHFFFAOYSA-N Yes check.svgY
   (verify)

Ethionamide is an antibiotic used to treat tuberculosis. [2] Specifically it is used, along with other antituberculosis medications, to treat active multidrug-resistant tuberculosis. [2] It is no longer recommended for leprosy. [3] [2] It is taken by mouth. [2]

Contents

Ethionamide has a high rate of side effects. [4] Common side effects include nausea, diarrhea, abdominal pain, and loss of appetite. Serious side effects may include liver inflammation and depression. [2] It should not be used in people with significant liver problems. Use in pregnancy is not recommended as safety is unclear. [2] Ethionamide is in the thioamides family of medications. It is believed to work by interfering with the use of mycolic acid. [5]

Ethionamide was discovered in 1956 and approved for medical use in the United States in 1965. [5] [2] It is on the World Health Organization's List of Essential Medicines. [6]

Medical uses

Ethionamide is used in combination with other antituberculosis agents as part of a second-line regimen for active tuberculosis. [7]

Ethionamide is well absorbed orally with or without food, but is often administered with food to improve tolerance. [8] [9] It crosses the blood brain barrier to achieve concentrations in the cerebral-spinal fluid equivalent to plasma. [9]

The antimicrobial spectrum of ethionamide includes M. tuberculosis, M. bovis and M. smegmatis. [10] It also is used rarely against infections with M. leprae [11] and other nontuberculous mycobacteria such as M. avium [12] and M. kansasii. [7] 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. [13] 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. [4]

The FDA has placed it in pregnancy category C, because it has caused birth defects in animal studies. [1] [14] It is not known whether ethionamide is excreted into breast milk. [7]

Adverse effects

Ethionamide frequently causes gastrointestinal distress with nausea and vomiting which can lead patients to stop taking it. [9] This can sometimes be improved by taking it with food. [7]

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. [7] 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. [15] The pattern of liver function test derangement is often a rise in the ALT and AST. [15]

Both central neurological side effects such as psychiatric disturbances and encephalopathy, along with peripheral neuropathy have been reported. [7] [12] Administering pyridoxine along with ethionamide may reduce these effects and is recommended. [7]

Ethionamide is structurally similar to methimazole, which is used to inhibit thyroid hormone synthesis, and has been linked to hypothyroidism in several TB patients. [16] Periodic monitoring of thyroid function while on ethionamide is recommended. [7]

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. [7] When taken with cycloserine, seizures have been reported. High rates of hepatotoxicty have been reported when taken with rifampicin. [7] The drug's labeling cautions against excessive alcohol ingestion as it may provoke a psychotic reaction. [1]

Mechanism of action

Ethionamide is a prodrug [17] 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. [5] [18]

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. [4]

Other names

It is sold under the brand name Trecator [1] by Wyeth Pharmaceuticals which was purchased by Pfizer in 2009.[ citation needed ]

Related Research Articles

<i>Mycobacterium tuberculosis</i> Species of pathogenic bacteria that causes tuberculosis

Mycobacterium tuberculosis, also known as Koch's bacillus, is a species of pathogenic bacteria in the family Mycobacteriaceae and the causative agent of tuberculosis. First discovered in 1882 by Robert Koch, M. tuberculosis has an unusual, waxy coating on its cell surface primarily due to the presence of mycolic acid. This coating makes the cells impervious to Gram staining, and as a result, M. tuberculosis can appear weakly Gram-positive. Acid-fast stains such as Ziehl–Neelsen, or fluorescent stains such as auramine are used instead to identify M. tuberculosis with a microscope. The physiology of M. tuberculosis is highly aerobic and requires high levels of oxygen. Primarily a pathogen of the mammalian respiratory system, it infects the lungs. The most frequently used diagnostic methods for tuberculosis are the tuberculin skin test, acid-fast stain, culture, and polymerase chain reaction.

<i>Mycobacterium</i> Genus of bacteria

Mycobacterium is a genus of over 190 species in the phylum Actinomycetota, assigned its own family, Mycobacteriaceae. This genus includes pathogens known to cause serious diseases in mammals, including tuberculosis and leprosy in humans. The Greek prefix myco- means 'fungus', alluding to this genus' mold-like colony surfaces. Since this genus has cell walls with a waxy lipid-rich outer layer that contains high concentrations of mycolic acid, acid-fast staining is used to emphasize their resistance to acids, compared to other cell types.

<span class="mw-page-title-main">Isoniazid</span> Antibiotic for treatment of tuberculosis

Isoniazid, also known as isonicotinic acid hydrazide (INH), is an antibiotic used for the treatment of tuberculosis. For active tuberculosis, it is often used together with rifampicin, pyrazinamide, and either streptomycin or ethambutol. For latent tuberculosis, it is often used alone. It may also be used for atypical types of mycobacteria, such as M. avium, M. kansasii, and M. xenopi. It is usually taken by mouth, but may be used by injection into muscle.

<span class="mw-page-title-main">Rifampicin</span> Antibiotic medication

Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), Mycobacterium avium complex, leprosy, and Legionnaires' disease. It is almost always used together with other antibiotics with two notable exceptions: when given as a "preferred treatment that is strongly recommended" for latent TB infection; and when used as post-exposure prophylaxis to prevent Haemophilus influenzae type b and meningococcal disease in people who have been exposed to those bacteria. Before treating a person for a long period of time, measurements of liver enzymes and blood counts are recommended. Rifampicin may be given either by mouth or intravenously.

<span class="mw-page-title-main">Trimethoprim/sulfamethoxazole</span> Combination of two antibiotic drugs

Trimethoprim/sulfamethoxazole, sold under the brand name Bactrim among others, is a fixed-dose combination antibiotic medication used to treat a variety of bacterial infections. It consists of one part trimethoprim to five parts sulfamethoxazole. It is used to treat urinary tract infections, methicillin-resistant Staphylococcus aureus (MRSA) skin infections, travelers' diarrhea, respiratory tract infections, and cholera, among others. It is used both to treat and prevent pneumocystis pneumonia and toxoplasmosis in people with HIV/AIDS and other causes of immunosuppression. It can be given orally or intravenous infusion.

<span class="mw-page-title-main">Tuberculosis management</span>

Tuberculosis management describes the techniques and procedures utilized for treating tuberculosis (TB) or simply a treatment plan for TB.

<span class="mw-page-title-main">Pyrazinamide</span> Medication

Pyrazinamide is a medication used to treat tuberculosis. For active tuberculosis, it is often used with rifampicin, isoniazid, and either streptomycin or ethambutol. It is not generally recommended for the treatment of latent tuberculosis. It is taken by mouth.

<span class="mw-page-title-main">Ethambutol</span> Chemical compound

Ethambutol is a medication primarily used to treat tuberculosis. It is usually given in combination with other tuberculosis medications, such as isoniazid, rifampicin and pyrazinamide. It may also be used to treat Mycobacterium avium complex, and Mycobacterium kansasii. It is taken by mouth.

<span class="mw-page-title-main">4-Aminosalicylic acid</span> Anti-tuberculosis and anti-inflammatory drug

4-Aminosalicylic acid, also known as para-aminosalicylic acid (PAS) and sold under the brand name Paser among others, is an antibiotic primarily used to treat tuberculosis. Specifically it is used to treat active drug resistant tuberculosis together with other antituberculosis medications. It has also been used as a second line agent to sulfasalazine in people with inflammatory bowel disease such as ulcerative colitis and Crohn's disease. It is typically taken by mouth.

<span class="mw-page-title-main">Iproniazid</span> Antidepressant

Iproniazid is a non-selective, irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine class. It is a xenobiotic that was originally designed to treat tuberculosis, but was later most prominently used as an antidepressant drug. However, it was withdrawn from the market because of its hepatotoxicity. The medical use of iproniazid was discontinued in most of the world in the 1960s, but remained in use in France until its discontinuation in 2015.

<span class="mw-page-title-main">Clofazimine</span> Medication

Clofazimine, sold under the brand name Lamprene, is a medication used together with rifampicin and dapsone to treat leprosy. It is specifically used for multibacillary (MB) leprosy and erythema nodosum leprosum. Evidence is insufficient to support its use in other conditions though a retrospective study found it 95% effective in the treatment of Mycobacterium avium complex (MAC) when administered with a macrolide and ethambutol, as well as the drugs amikacin and clarithromycin. However, in the United States, clofazimine is considered an orphan drug, is unavailable in pharmacies, and its use in the treatment of MAC is overseen by the Food and Drug Administration. It is taken orally.

<span class="mw-page-title-main">Rifapentine</span> Chemical compound

Rifapentine, sold under the brand name Priftin, is an antibiotic used in the treatment of tuberculosis. In active tuberculosis it is used together with other antituberculosis medications. In latent tuberculosis it is typically used with isoniazid. It is taken by mouth.

<span class="mw-page-title-main">Rifampicin/isoniazid/pyrazinamide</span> Combination drug

Rifampicin/isoniazid/pyrazinamide, also known as rifampin/isoniazid/pyrazinamide, and sold under the trade name Rifater, is a medication used to treat tuberculosis. It is a fixed dose combination of rifampicin, isoniazid, and pyrazinamide. It is used either by itself or along with other antituberculosis medication. It is taken by mouth.

<span class="mw-page-title-main">Thioacetazone</span> Chemical compound

Thioacetazone, also known as amithiozone (USAN), is an oral antibiotic which is used in the treatment of tuberculosis. It has fallen into almost complete disuse due to toxicity and the introduction of improved anti-tuberculosis drugs like isoniazid. The drug has only weak activity against Mycobacterium tuberculosis and is only useful in preventing resistance to more powerful drugs such as isoniazid and rifampicin. It is never used on its own to treat tuberculosis; it is used in a similar way to ethambutol.

<span class="mw-page-title-main">Multidrug-resistant tuberculosis</span> Medical condition

Multidrug-resistant tuberculosis (MDR-TB) is a form of tuberculosis (TB) infection caused by bacteria that are resistant to treatment with at least two of the most powerful first-line anti-TB medications (drugs): isoniazid and rifampin. Some forms of TB are also resistant to second-line medications, and are called extensively drug-resistant TB (XDR-TB).

<span class="mw-page-title-main">Bedaquiline</span> Medication used to treat tuberculosis

Bedaquiline, sold under the brand name Sirturo, is a medication used to treat active tuberculosis. Specifically, it is used to treat multi-drug-resistant tuberculosis (MDR-TB) along with other medications for tuberculosis. It is used by mouth.

<span class="mw-page-title-main">Pretomanid</span> Chemical compound

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<span class="mw-page-title-main">Beta-ketoacyl-ACP synthase III</span> Enzyme

In enzymology, a β-ketoacyl-[acyl-carrier-protein] synthase III (EC 2.3.1.180) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Simeprevir</span> Chemical compound

Simeprevir, sold under the brand name Olysio among others, is a medication used in combination with other medications for the treatment of hepatitis C. It is specifically used for hepatitis C genotype 1 and 4. Medications it is used with include sofosbuvir or ribavirin and peginterferon-alfa. Cure rates are in 80s to 90s percent. It may be used in those who also have HIV/AIDS. It is taken by mouth once daily for typically 12 weeks.

Delamanid, sold under the brand name Deltyba, is a medication used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, for active multidrug-resistant tuberculosis. It is taken by mouth.

References

  1. 1 2 3 4 "Trecator- ethionamide tablet, film coated". DailyMed. 20 May 2020. Retrieved 28 July 2020.
  2. 1 2 3 4 5 6 7 "Ethionamide". The American Society of Health-System Pharmacists. Archived from the original on 20 December 2016. Retrieved 8 December 2016.
  3. ↑ "Standard Chemotherapy". www.hrsa.gov. Archived from the original on 2016-12-20. Retrieved 2016-12-15.
  4. 1 2 3 Wolff KA, Nguyen L (September 2012). "Strategies for potentiation of ethionamide and folate antagonists against Mycobacterium tuberculosis". Expert Review of Anti-Infective Therapy. 10 (9): 971–981. doi:10.1586/eri.12.87. PMC   3971469 . PMID   23106273.
  5. 1 2 3 "Ethionamide". TB Online. Global Tuberculosis Community Advisory Board. Archived from the original on 2013-09-14. Retrieved 2012-08-18.
  6. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  7. 1 2 3 4 5 6 7 8 9 10 "Summary of Product Characteristics" (PDF). World Health Organization. Archived from the original (PDF) on 2016-03-05. Retrieved 2016-12-14.
  8. ↑ Auclair B, Nix DE, Adam RD, James GT, Peloquin CA (March 2001). "Pharmacokinetics of ethionamide administered under fasting conditions or with orange juice, food, or antacids". Antimicrobial Agents and Chemotherapy. 45 (3): 810–814. doi:10.1128/AAC.45.3.810-814.2001. PMC   90379 . PMID   11181366.
  9. 1 2 3 Bennett JE, Dolin R, Blaser M, Mandell GL (2015). "38 - Antimycobacterial Agents". Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Elsevier/Saunders. ISBN   978-0-323-40161-6. OCLC   889211235.
  10. ↑ Rastogi N, Labrousse V, Goh KS (September 1996). "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". Current Microbiology. 33 (3): 167–175. doi:10.1007/s002849900095. PMID   8672093. S2CID   35058684.
  11. ↑ "WHO Model Prescribing Information: Drugs Used in Mycobacterial Diseases: Leprosy: Ethionamide and protionamide". apps.who.int. Archived from the original on 2016-12-20. Retrieved 2016-12-14.
  12. 1 2 Bennett JE, Dolin R, Blaser M, Mandell GL (2015). "253 - Mycobacterium avium Complex". Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Elsevier/Saunders. pp. 2832–2843.e3. ISBN   978-0-323-40161-6. OCLC   889211235.
  13. ↑ Belardinelli JM, Morbidoni HR (April 2013). "Recycling and refurbishing old antitubercular drugs: the encouraging case of inhibitors of mycolic acid biosynthesis". Expert Review of Anti-Infective Therapy. 11 (4): 429–440. doi:10.1586/eri.13.24. PMID   23566152. S2CID   31560270.
  14. ↑ "Ethionamide Use During Pregnancy". Drugs.com. Archived from the original on 2016-12-21. Retrieved 2016-12-14.
  15. 1 2 "Ethionamide". livertox.nlm.nih.gov. Archived from the original on 2016-12-24. Retrieved 2016-12-14.
  16. ↑ McDonnell ME, Braverman LE, Bernardo J (June 2005). "Hypothyroidism due to ethionamide". The New England Journal of Medicine. 352 (26): 2757–2759. doi: 10.1056/NEJM200506303522621 . PMID   15987931.
  17. ↑ Vannelli TA, Dykman A, Ortiz de Montellano PR (April 2002). "The antituberculosis drug ethionamide is activated by a flavoprotein monooxygenase". The Journal of Biological Chemistry. 277 (15): 12824–12829. doi: 10.1074/jbc.M110751200 . PMID   11823459.
  18. ↑ Quémard A, Lanéelle G, Lacave C (June 1992). "Mycolic acid synthesis: a target for ethionamide in mycobacteria?". Antimicrobial Agents and Chemotherapy. 36 (6): 1316–1321. doi:10.1128/aac.36.6.1316. PMC   190338 . PMID   1416831.
  19. ↑ Somner AR (December 1959). "2-Ethylisothionicotinamide ('1314') in pulmonary tuberculosis: a controlled trial of drug tolerance". Tubercle. 40 (6): 457–461. doi:10.1016/S0041-3879(59)80101-X. PMID   13832783.
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