Chemistry:Isoniazid

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Short description: Antibiotic for treatment of tuberculosis
Isoniazid
Isoniazid skeletal.svg
Isoniazid 3d.png
Clinical data
Trade namesHydra, Hyzyd, Isovit, others
Other namesisonicotinic acid hydrazide, isonicotinyl hydrazine, INH, INAH, INHA
AHFS/Drugs.comMonograph
MedlinePlusa682401
License data
Pregnancy
category
Routes of
administration		By mouth, intramuscular, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein bindingVery low (0–10%)
Metabolismliver; CYP450: 2C19, 3A4 inhibitor
Elimination half-life0.5–1.6h (fast acetylators), 2-5h (slow acetylators)
Excretionurine (primarily), feces
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
Chemical and physical data
FormulaC6H7N3O
Molar mass137.142 g·mol−1
3D model (JSmol)
  (verify)

Isoniazid, also known as isonicotinic acid hydrazide (INH), is an antibiotic used for the treatment of tuberculosis.[2] For active tuberculosis, it is often used together with rifampicin, pyrazinamide, and either streptomycin or ethambutol.[3] For latent tuberculosis, it is often used alone.[2] It may also be used for atypical types of mycobacteria, such as M. avium, M. kansasii, and M. xenopi.[2] It is usually taken by mouth, but may be used by injection into muscle.[2]

Side effects and mechanism of action

Common side effects include increased blood levels of liver enzymes and numbness in the hands and feet.[2] Serious side effects may include liver inflammation and acute liver failure.[2] It is unclear if use during pregnancy is safe for the baby.[4] Use during breastfeeding is likely safe.[4] Pyridoxine may be given to reduce the risk of side effects.[5] Isoniazid works in part by disrupting the formation of the bacteria's cell wall which results in cell death.[2]

History, society, and culture

Isoniazid was first made in 1952.[6] It is on the World Health Organization's List of Essential Medicines.[7] The World Health Organization classifies isoniazid as critically important for human medicine.[8] Isoniazid is available as a generic medication.[2]

Medical uses

Tuberculosis

Isoniazid is often used to treat latent and active tuberculosis infections. In persons with isoniazid-sensitive Mycobacterium tuberculosis infection, drug regimens based on isoniazid are usually effective when persons adhere to the prescribed treatment. However, in persons with isoniazid-resistant Mycobacterium tuberculosis infection, drug regimens based on isoniazid have a high rate of failure.[9]

Isoniazid has been approved as prophylactic therapy for the following populations:

  • People with HIV infection and a PPD (purified protein derivative) reaction of at least 5 mm induration
  • Contacts of people with tuberculosis and who have a PPD reaction at least 5 mm induration
  • People whose PPD reactions convert from negative to positive in a two-year period – at least 10 mm induration for those up to 35 years of age, and at least 15 mm induration for those at least 35 years old
  • People with pulmonary damage on their chest X-ray that is likely to be due to healed tuberculosis and also have a PPD reaction at least 5 mm induration
  • Injection drug users whose HIV status is negative who have a PPD reaction at least 10 mm induration
  • People with a PPD of greater than or equal to 10 mm induration who are foreign-born from high prevalence geographical regions, low-income populations, and patients residing in long-term facilities[10][11]

Isoniazid can be used alone or in combination with Rifampin for treatment of latent tuberculosis, or as part of a four-drug regimen for treatment of active tuberculosis.[12] The drug regimen typically requires daily or weekly oral administration for a period of three to nine months, often under Directly Observed Therapy (DOT) supervision.[12]

Non-tuberculous mycobacteria

Isoniazid was widely used in the treatment of Mycobacterium avium complex as part of a regimen including rifampicin and ethambutol.[13] Evidence suggests that isoniazid prevents mycolic acid synthesis in M. avium complex as in M. tuberculosis[14] and although this is not bactericidal to M. avium complex, it greatly potentiates the effect of rifampicin. The introduction of macrolides led to this use greatly decreasing. However, since rifampicin is broadly underdosed in M. avium complex treatment, this effect may be worth re-investigating.[15]

Special populations

It is recommended that women with active tuberculosis who are pregnant or breastfeeding take isoniazid. Preventive therapy should be delayed until after giving birth.[16] Nursing mothers excrete a relatively low and non-toxic concentration of INH in breast milk, and their babies are at low risk for side effects. Both pregnant women and infants being breastfed by mothers taking INH should take vitamin B6 in its pyridoxine form to minimize the risk of peripheral nerve damage.[17] Vitamin B6 is used to prevent isoniazid-induced B6 deficiency and neuropathy in people with a risk factor, such as pregnancy, lactation, HIV infection, alcoholism, diabetes, kidney failure, or malnutrition.[18]

People with liver dysfunction are at a higher risk for hepatitis caused by INH, and may need a lower dose.[16]

Levels of liver enzymes in the bloodstream should be frequently checked in daily alcohol drinkers, pregnant women, IV drug users, people over 35, and those who have chronic liver disease, severe kidney dysfunction, peripheral neuropathy, or HIV infection since they are more likely to develop hepatitis from INH.[16][19]

Side effects

Up to 20% of people taking isoniazid experience peripheral neuropathy when taking daily doses of 6 mg/kg of body weight or higher.[20] Gastrointestinal reactions include nausea and vomiting.[10] Aplastic anemia, thrombocytopenia, and agranulocytosis due to lack of production of red blood cells, platelets, and white blood cells by the bone marrow respectively, can also occur.[10] Hypersensitivity reactions are also common and can present with a maculopapular rash and fever.[10] Gynecomastia may occur.[12]

Asymptomatic elevation of serum liver enzyme concentrations occurs in 10% to 20% of people taking INH, and liver enzyme concentrations usually return to normal even when treatment is continued.[21] Isoniazid has a boxed warning for severe and sometimes fatal hepatitis, which is age-dependent at a rate of 0.3% in people 21 to 35 years old and over 2% in those over age 50.[10][22] Symptoms suggestive of liver toxicity include nausea, vomiting, abdominal pain, dark urine, right upper quadrant pain, and loss of appetite.[10] Black and Hispanic women are at higher risk for isoniazid-induced hepatotoxicity.[10] When it happens, isoniazid-induced liver toxicity has been shown to occur in 50% of patients within the first 2 months of therapy.[23]

Some recommend that liver function should be monitored carefully in all people receiving it,[16] but others recommend monitoring only in certain populations.[21][24][25]

Headache, poor concentration, weight gain, poor memory, insomnia, and depression have all been associated with isoniazid use.[26] All patients and healthcare workers should be aware of these serious side effects, especially if suicidal ideation or behavior are suspected.[26][27][28]

Isoniazid is associated with pyridoxine (vitamin B6) deficiency because of its similar structure. Isoniazid is also associated with increased excretion of pyridoxine. Pyridoxal phosphate (a derivative of pyridoxine) is required for δ-aminolevulinic acid synthase, the enzyme responsible for the rate-limiting step in heme synthesis. Therefore, isoniazid-induced pyridoxine deficiency causes insufficient heme formation in early red blood cells, leading to sideroblastic anemia.[18]

Isoniazid was found to significantly elevate the in vivo concentration of GABA and homocarnosine in a single subject via magnetic resonance spectroscopy.[29]

Drug interactions

People taking isoniazid and acetaminophen are at risk of acetaminophen toxicity. Isoniazid is thought to induce a liver enzyme which causes a larger amount of acetaminophen to be metabolized to a toxic form.[30][31]

Isoniazid decreases the metabolism of carbamazepine, thus slowing down its clearance from the body. People taking carbamazepine should have their carbamazepine levels monitored and, if necessary, have their dose adjusted accordingly.[32]

It is possible that isoniazid may decrease the serum levels of ketoconazole after long-term treatment. This is seen with the simultaneous use of rifampin, isoniazid, and ketoconazole.[33]

Isoniazid may increase the amount of phenytoin in the body. The doses of phenytoin may need to be adjusted when given with isoniazid.[34][35]

Isoniazid may increase the plasma levels of theophylline. There are some cases of theophylline slowing down isoniazid elimination. Both theophylline and isoniazid levels should be monitored.[36]

Valproate levels may increase when taken with isoniazid. Valproate levels should be monitored and its dose adjusted if necessary.[34]

Mechanism of action

Isoniazid is a prodrug that inhibits the formation of the mycobacterial cell wall. Isoniazid must be activated by KatG, a bacterial catalase-peroxidase enzyme in Mycobacterium tuberculosis.[37] KatG catalyzes the formation of the isonicotinic acyl radical, which spontaneously couples with NADH to form the nicotinoyl-NAD adduct. This complex binds tightly to the enoyl-acyl carrier protein reductase InhA, thereby blocking the natural enoyl-AcpM substrate and the action of fatty acid synthase. This process inhibits the synthesis of mycolic acids, which are required components of the mycobacterial cell wall. A range of radicals are produced by KatG activation of isoniazid, including nitric oxide,[38] which has also been shown to be important in the action of another antimycobacterial prodrug pretomanid.[39]

Isoniazid (INH) is activated by KatG to the isonicotinic acyl radical, which subsequently reacts with NAD to form the isonicotinic acyl-NADH complex.

Isoniazid is bactericidal to rapidly dividing mycobacteria, but is bacteriostatic if the mycobacteria are slow-growing.[40] It inhibits the cytochrome P450 system and hence acts as a source of free radicals.[41]

Isoniazid is a mild monoamine oxidase inhibitor(MAO-I).[42]

Metabolism

Isoniazid reaches therapeutic concentrations in serum, cerebrospinal fluid, and within caseous granulomas. It is metabolized in the liver via acetylation into acetylhydrazine. Two forms of the enzyme are responsible for acetylation, so some patients metabolize the drug more quickly than others. Hence, the half-life is bimodal, with "slow acetylators" and "fast acetylators". A graph of number of people versus time shows peaks at one and three hours. The height of the peaks depends on the ethnicities of the people being tested. The metabolites are excreted in the urine. Doses do not usually have to be adjusted in case of renal failure.[citation needed]

History

First synthesis was described in 1912.[43] A. Kachugin invented the drug against tuberculosis under name Tubazid in 1949. Three pharmaceutical companies unsuccessfully attempted to patent the drug at the same time,[44] the most prominent one being Roche, which launched its version, Rimifon, in 1952.[45] With the introduction of isoniazid, a cure for tuberculosis was first considered possible.[citation needed]

The drug was first tested at Many Farms, a Navajo community in Arizona, due to the Navajo reservation's tuberculosis problem and because the population had not previously been treated with streptomycin, the main tuberculosis treatment at the time.[46] The research was led by Walsh McDermott, an infectious disease researcher with an interest in public health, who had previously taken isoniazid to treat his own tuberculosis.[47]

Isoniazid and a related drug, iproniazid, were among the first drugs to be referred to as antidepressants.[48]

Preparation

Isoniazid is an isonicotinic acid derivative. It is manufactured using 4-cyanopyridine and hydrazine hydrate.[49] In another method, isoniazid was claimed to have been made from citric acid starting material.[50]

It can in theory be made from methyl isonicotinate, which is labelled a semiochemical.

Brand names

Hydra, Hyzyd, Isovit, Laniazid, Nydrazid, Rimifon, and Stanozide.[51]

Other uses

Chromatography

Isonicotinic acid hydrazide is also used in chromatography to differentiate between various degrees of conjugation in organic compounds barring the ketone functional group.[52] The test works by forming a hydrazone which can be detected by its bathochromic shift.[citation needed]

Dogs

Isoniazid may be used for dogs, but there have been concerns it can cause seizures.[53]

References

  1. ↑ "Isoniazid (Nydrazid) Use During Pregnancy". 7 October 2019. https://www.drugs.com/pregnancy/isoniazid.html. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 "Isoniazid". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/isoniazid.html. 
  3. ↑ WHO Model Formulary 2008. World Health Organization. 2009. p. 136. ISBN 9789241547659. 
  4. ↑ 4.0 4.1 "Isoniazid (Nydrazid) Use During Pregnancy". https://www.drugs.com/pregnancy/isoniazid.html. 
  5. ↑ Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. 2015. p. 49. ISBN 9781284057560. 
  6. ↑ Trends and Changes in Drug Research and Development. Springer Science & Business Media. 2012. p. 109. ISBN 9789400926592. https://books.google.com/books?id=FB_2CAAAQBAJ&pg=PA109. 
  7. ↑ Organization, World Health (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  8. ↑ Critically important antimicrobials for human medicine (6th revision ed.). Geneva: World Health Organization. 2019. ISBN 9789241515528. 
  9. ↑ "Treatment of isoniazid-resistant tuberculosis with first-line drugs: a systematic review and meta-analysis". The Lancet. Infectious Diseases 17 (2): 223–234. February 2017. doi:10.1016/S1473-3099(16)30407-8. PMID 27865891. 
  10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 10.6 "Isoniazid (package insert)". 30 March 2023. http://medlibrary.org/lib/rx/meds/isoniazid-10/. 
  11. ↑ "The Use of Preventive Therapy for Tuberculosis Infection in the United States – Recommendations of the Advisory Committee for Elimination of Tuberculosis". Morbidity and Mortality Weekly Report 39 (RR-8): 9–12. May 18, 1990. https://www.cdc.gov/mmwr/preview/mmwrhtml/00001643.htm. Retrieved 22 February 2016. 
  12. ↑ 12.0 12.1 12.2 Medical-surgical nursing : assessment and management of clinical problems (Ninth ed.). St. Louis, Missouri. 5 December 2013. ISBN 978-0-323-10089-2. OCLC 228373703. 
  13. ↑ Research Committee Of The British Thoracic Society (March 2001). "First randomised trial of treatments for pulmonary disease caused by M avium intracellulare, M malmoense, and M xenopi in HIV negative patients: rifampicin, ethambutol and isoniazid versus rifampicin and ethambutol". Thorax 56 (3): 167–172. doi:10.1136/thorax.56.3.167. PMID 11182006. 
  14. ↑ "Mechanisms involved in the intrinsic isoniazid resistance of Mycobacterium avium". Molecular Microbiology 27 (6): 1223–1233. March 1998. doi:10.1046/j.1365-2958.1998.00774.x. PMID 9570407. 
  15. ↑ "The pharmacokinetics and pharmacodynamics of pulmonary Mycobacterium avium complex disease treatment". American Journal of Respiratory and Critical Care Medicine 186 (6): 559–565. September 2012. doi:10.1164/rccm.201204-0682OC. PMID 22744719. 
  16. ↑ 16.0 16.1 16.2 16.3 "Isoniazid tablet". 18 October 2018. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1553312b-ed76-421c-a055-2579bdcf366c. 
  17. ↑ "Drug treatment for tuberculosis during pregnancy: safety considerations". Drug Safety 24 (7): 553–565. 2001. doi:10.2165/00002018-200124070-00006. PMID 11444726. 
  18. ↑ 18.0 18.1 "[Isoniazid induced neuropathy: consider prevention]". Revue des Maladies Respiratoires 23 (2 Pt 1): 157–160. April 2006. doi:10.1016/S0761-8425(06)71480-2. PMID 16788441. 
  19. ↑ "An official ATS statement: hepatotoxicity of antituberculosis therapy". American Journal of Respiratory and Critical Care Medicine 174 (8): 935–952. October 2006. doi:10.1164/rccm.200510-1666ST. PMID 17021358. 
  20. ↑ Applied Therapeutics. Lippincott Williams & Wilkins. February 12, 2013. ISBN 9781609137137. 
  21. ↑ 21.0 21.1 "Latent Tuberculosis Infection: A Guide for Primary Health Care Providers". Center for Disease Control. https://www.cdc.gov/tb/publications/ltbi/treatment.htm. 
  22. ↑ Trevor, A. & Katzung, B. (2013). Katzung & Trevor's Pharmacology: examination & board review (10th ed., p. 417). New York. McGraw-Hill Medical, Lange.
  23. ↑ "Isoniazid UpToDate". http://www.uptodate.com/contents/isoniazid-an-overview. 
  24. ↑ "Treatment of Tuberculosis – Guidelines (4th ed.)". World Health Organization. http://apps.who.int/iris/bitstream/10665/44165/1/9789241547833_eng.pdf?ua=1&ua=1. 
  25. ↑ "Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998. Joint Tuberculosis Committee of the British Thoracic Society". Thorax 53 (7): 536–548. July 1998. doi:10.1136/thx.53.7.536. PMID 9797751. 
  26. ↑ 26.0 26.1 "Isoniazid-induced psychosis". The Annals of Pharmacotherapy 32 (9): 889–891. September 1998. doi:10.1345/aph.17377. PMID 9762376. 
  27. ↑ "Suicidal psychosis secondary to isoniazid". Pediatric Emergency Care 18 (1): 25–27. February 2002. doi:10.1097/00006565-200202000-00008. PMID 11862134. 
  28. ↑ "Isoniazid-associated psychosis: case report and review of the literature". The Annals of Pharmacotherapy 27 (2): 167–170. February 1993. doi:10.1177/106002809302700205. PMID 8439690. 
  29. ↑ "Elevated homocarnosine and GABA in subject on isoniazid as assessed through 1H MRS at 7T". Analytical Biochemistry 599: 113738. June 2020. doi:10.1016/j.ab.2020.113738. PMID 32302606. 
  30. ↑ "Severe acetaminophen toxicity in a patient receiving isoniazid". Annals of Internal Medicine 113 (10): 799–800. November 1990. doi:10.7326/0003-4819-113-10-799. PMID 2240884. 
  31. ↑ "Isoniazid potentiation of acetaminophen hepatotoxicity in the rat and 4-methylpyrazole inhibition of it". Research Communications in Chemical Pathology and Pharmacology 69 (1): 115–118. July 1990. PMID 2218067. 
  32. ↑ "Interaction between carbamazepine and antituberculosis agents". Chest 99 (6): 1554. June 1991. doi:10.1378/chest.99.6.1554a. PMID 2036861. 
  33. ↑ "Ketoconazole and fluconazole drug interactions". Archives of Internal Medicine 153 (17): 1970–1976. September 1993. doi:10.1001/archinte.153.17.1970. PMID 8357281. 
  34. ↑ 34.0 34.1 "Interaction between isoniazid and valproate: a case of valproate overdosage". European Journal of Clinical Pharmacology 40 (2): 197–198. 1991. doi:10.1007/BF00280078. PMID 2065702. 
  35. ↑ "Treatment of tuberculosis and tuberculosis infection in adults and children. American Thoracic Society and The Centers for Disease Control and Prevention". American Journal of Respiratory and Critical Care Medicine 149 (5): 1359–1374. May 1994. doi:10.1164/ajrccm.149.5.8173779. PMID 8173779. 
  36. ↑ "Interaction between isoniazid and theophylline". European Journal of Respiratory Diseases 70 (2): 110–116. February 1987. PMID 3817069. 
  37. ↑ "An oxyferrous heme/protein-based radical intermediate is catalytically competent in the catalase reaction of Mycobacterium tuberculosis catalase-peroxidase (KatG)". The Journal of Biological Chemistry 284 (11): 7017–7029. March 2009. doi:10.1074/jbc.M808106200. PMID 19139099. 
  38. ↑ "Nitric oxide generated from isoniazid activation by KatG: source of nitric oxide and activity against Mycobacterium tuberculosis". Antimicrobial Agents and Chemotherapy 48 (8): 3006–3009. August 2004. doi:10.1128/AAC.48.8.3006-3009.2004. PMID 15273113. 
  39. ↑ "PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release". Science 322 (5906): 1392–1395. November 2008. doi:10.1126/science.1164571. PMID 19039139. Bibcode: 2008Sci...322.1392S. 
  40. ↑ "Biphasic kill curve of isoniazid reveals the presence of drug-tolerant, not drug-resistant, Mycobacterium tuberculosis in the guinea pig". The Journal of Infectious Diseases 200 (7): 1136–1143. October 2009. doi:10.1086/605605. PMID 19686043. 
  41. ↑ Pharmacology. 864 (4th ed.). Lippincott Williams & Wilkins. 2006. ISBN 9780781741187. 
  42. ↑ "Isoniazid and antidepressants: is there cause for concern?". International Clinical Psychopharmacology 9 (2): 123–125. 1994. doi:10.1097/00004850-199400920-00009. PMID 8056994. 
  43. ↑ "Transcriptional profiling of lung cell populations in idiopathic pulmonary arterial hypertension" (in de). Pulmonary Circulation 10 (1): 393–414. 1912-04-01. doi:10.1177/2045894020908782. PMID 32166015. 
  44. ↑ "Fourth-generation fluoroquinolones in tuberculosis". Lancet 373 (9670): 1148–1149. April 2009. doi:10.1016/S0140-6736(09)60559-6. PMID 19345815. 
  45. ↑ "History". Roche USA. http://www.rocheusa.com/about/history.html. 
  46. ↑ "The health care experiments at Many Farms: the Navajo, tuberculosis, and the limits of modern medicine, 1952-1962". Bulletin of the History of Medicine 76 (4): 749–790. 2002. doi:10.1353/bhm.2002.0186. PMID 12446978. 
  47. ↑ "Walsh McDermott". Biographical Memoirs. 59. National Academies Press. 1990. pp. 282–307. doi:10.17226/1652. ISBN 978-0-309-04198-0. https://www.nap.edu/read/1652/chapter/15#283. 
  48. ↑ "The creation of the concept of an antidepressant: an historical analysis". Social Science & Medicine 66 (11): 2346–2355. June 2008. doi:10.1016/j.socscimed.2008.01.047. PMID 18321627. 
  49. ↑ William Andrew Publishing (2008). Pharmaceutical Manufacturing Encyclopedia (3rd ed.). Norwich, NY: Elsevier Science. pp. 1968–1970. ISBN 9780815515265. https://books.google.com/books?id=bRX8MwEACAAJ&q=9780815515265. 
  50. ↑ "Synthesis of isoniazid from citric acid". Journal of the American Pharmaceutical Association 45 (7): 478–480. July 1956. doi:10.1002/jps.3030450714. PMID 13345683. 
  51. ↑ "Drugs@FDA". United States Food and Drug Administration. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. 
  52. ↑ "Transcriptional profiling of lung cell populations in idiopathic pulmonary arterial hypertension". Pulmonary Circulation 10 (1): 102–105. 1959. doi:10.1021/ac60145a020. PMID 32166015. 
  53. ↑ (E-Book) Canine and Feline Infectious Diseases. Elsevier Health Sciences. 2013. p. 425. ISBN 978-0323241946. https://books.google.com/books?id=cb0kTIlb8HgC&pg=PA425. 

Further reading

External links



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