isoniazid

After F. Raschig developed a method to synthesize hydrazine, Hans Meyer and his doctoral student at the German University in Prague Josef Mally studied hydrazides of pyridinecarboxylic acids. By reacting ethyl isonicotinate with hydrazine hydrate they obtained a compound which, after a recrystallization, had a melting point of 163°C.{{Cite journal | vauthors = Meyer H, Mally J |date=1912 |title=Über Hydrazinderivate der Pyridincarbonsäuren |url=https://link.springer.com/article/10.1007/BF01517946 |journal=Monatshefte für Chemie und verwandte Teile anderer Wissenschaften |language=de |volume=33 |issue=4 |pages=393–414 |doi=10.1007/BF01517946 |issn=1434-4475}} Despite their results published in 1912, its pharmaceutical properties weren't investigated for decades.

In the 1940s French physicians discovered that nicotinamide had some activity against tubercle bacilli in vitro and in infected guinea pigs.{{Cite news |date=1952-05-12 |title=Qui a Découvert L'efficacité Des Nouveaux Médicaments Contre La Tuberculose? |url=https://www.lemonde.fr/archives/article/1952/05/12/qui-a-decouvert-l-efficacite-des-nouveaux-medicaments-contre-la-tuberculose_1991993_1819218.html |access-date=2025-01-29 |language=fr}}{{cite journal | vauthors = Chakraborty S, Rhee KY | title = Tuberculosis Drug Development: History and Evolution of the Mechanism-Based Paradigm | journal = Cold Spring Harbor Perspectives in Medicine | volume = 5 | issue = 8 | pages = a021147 | date = April 2015 | pmid = 25877396 | pmc = 4526730 | doi = 10.1101/cshperspect.a021147 }} At the same time, German chemists led by G. Domagk investigating sulfo drugs at Bayer developed thioacetazone.{{Cite journal | vauthors = McDermott W |date=1969 |title=The Story of INH |journal=The Journal of Infectious Diseases |volume=119 |issue=6 |pages=678–683 |doi=10.1093/infdis/119.6.678 |jstor=30102354 |pmid=4893894 |issn=0022-1899}}{{Cite book | vauthors = Grundmann E |url=https://books.google.com/books?id=sg1QAwAAQBAJ |title=Gerhard Domagk: The First Man to Triumph Over Infectious Diseases |date=2004 |publisher=LIT Verlag Münster |isbn=978-3-8258-6164-3 |language=en}} After their findings were made public, in 1950 {{Ill|André Girard (chemist)|lt=A. Girard|fr|André Girard (chimiste)}} modified it to the less toxic thiosemicarbazone of nicotinaldehyde{{Cite patent|country=FR|number=1055796|title=Thiosemicarbazone de l'aldéhyde nicotinique et son procédé de préparation|pubdate=1954-02-22|gdate=1950-08-17|invent1=Girard|inventor1-first=André|assign1=Laboratoires français de chimiothérapie}} while H. H. Fox developed similar isonicotinaldehyde thiosemicarbazone.{{US patent|2676178}} Soon, multiple laboratories discovered anti-TB activity of isoniazid.

It's believed that Soviet physicians {{Ill|Anatoliy Kachugin|lt=A. Kachugin|ru|Качугин, Анатолий Трофимович}} and Bella Keyfman also discovered this activity in 1949 but neither published their findings in a peer-reviewed article nor applied for an inventor's certificate.{{Cite web |title=Забвение — Журнальный зал |url=https://magazines.gorky.media/neva/2003/3/zabvenie.html |access-date=2025-01-30 |website=magazines.gorky.media}}{{Cite news | vauthors = Olshanskaya E |date=2011-05-24 |title=Метод Качугина | trans-title = Kachugin's method |url=https://www.svoboda.org/a/24196133.html |access-date=2025-01-30 |work=Радио Свобода (Radio Liberty) |language=ru}}

Three pharmaceutical companies unsuccessfully attempted to patent the drug at the same time,{{cite journal | vauthors = Rieder HL | title = Fourth-generation fluoroquinolones in tuberculosis | journal = Lancet | volume = 373 | issue = 9670 | pages = 1148–1149 | date = April 2009 | pmid = 19345815 | doi = 10.1016/S0140-6736(09)60559-6 | s2cid = 43789954 }} the most prominent one being Roche in January 1951,{{US patent|2685580}} which launched its version, Rimifon, in 1952.{{cite web| url= http://www.rocheusa.com/about/history.html |title= History| website= rocheusa.com| publisher= Roche USA| archive-url= https://web.archive.org/web/20071212082842/http://www.rocheusa.com/about/history.html | archive-date=2007-12-12}}

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.{{cite journal | vauthors = Jones DS | title = The health care experiments at Many Farms: the Navajo, tuberculosis, and the limits of modern medicine, 1952-1962 | journal = Bulletin of the History of Medicine | volume = 76 | issue = 4 | pages = 749–790 | year = 2002 | pmid = 12446978 | doi = 10.1353/bhm.2002.0186 | s2cid = 30166423 }} 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.{{cite book|chapter-url=https://www.nap.edu/read/1652/chapter/15#283|chapter=Walsh McDermott|pages=282–307|publisher=National Academies Press|title=Biographical Memoirs | volume = 59 |year=1990| vauthors = Beeson PB |doi=10.17226/1652|isbn=978-0-309-04198-0}}

Isoniazid and a related drug, iproniazid, were among the first drugs to be referred to as antidepressants.{{cite journal | vauthors = Moncrieff J | title = The creation of the concept of an antidepressant: an historical analysis | journal = Social Science & Medicine | volume = 66 | issue = 11 | pages = 2346–2355 | date = June 2008 | pmid = 18321627 | doi = 10.1016/j.socscimed.2008.01.047 | url = https://discovery.ucl.ac.uk/id/eprint/10193706/ }} Psychiatric use stopped in 1961 following reports of hepatotoxicity. Use against tuberculosis continued, as isoniazid's effectiveness against the disease outweighs its risks.{{cite journal | vauthors = Samouco AI, Alves SP | title = Isoniazid-induced mania and the history of antidepressant drugs: Case report and literature review | journal = Bipolar Disorders | volume = 25 | issue = 1 | pages = 84–87 | date = February 2023 | pmid = 36380697 | doi = 10.1111/bdi.13272 | doi-access = free }}

It is on the World Health Organization's List of Essential Medicines.{{cite book | 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 | vauthors = Organization WH }} The World Health Organization classifies isoniazid as critically important for human medicine.{{cite book | year=2019 | title=Critically important antimicrobials for human medicine | edition=6th revision | publisher = World Health Organization | location = Geneva | hdl=10665/312266 | isbn=978-92-4-151552-8 | hdl-access=free}} Isoniazid is available as a generic medication.

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.{{cite journal | vauthors = Gegia M, Winters N, Benedetti A, van Soolingen D, Menzies D | title = Treatment of isoniazid-resistant tuberculosis with first-line drugs: a systematic review and meta-analysis | journal = The Lancet. Infectious Diseases | volume = 17 | issue = 2 | pages = 223–234 | date = February 2017 | pmid = 27865891 | doi = 10.1016/S1473-3099(16)30407-8 }}

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{{cite journal|title=The Use of Preventive Therapy for Tuberculosis Infection in the United States – Recommendations of the Advisory Committee for Elimination of Tuberculosis|journal=Morbidity and Mortality Weekly Report|date=May 18, 1990|volume=39 (RR-8)|pages=9–12|url=https://www.cdc.gov/mmwr/preview/mmwrhtml/00001643.htm|access-date=22 February 2016|url-status=live|archive-url=https://web.archive.org/web/20160302075630/http://www.cdc.gov/mmwr/preview/mmwrhtml/00001643.htm|archive-date=2 March 2016}}

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.{{cite book|title=Medical-surgical nursing: assessment and management of clinical problems| vauthors = Lewis SM, Dirksen SR, Heitkemper MM, Bucher L, Harding M |date=5 December 2013|isbn=978-0-323-10089-2|edition=Ninth|location=St. Louis, Missouri | publisher = Elsevier/Mosby |oclc=228373703}} 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.

Isoniazid was widely used in the treatment of Mycobacterium avium complex as part of a regimen including rifampicin and ethambutol.{{cite journal | title = 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 | journal = Thorax | volume = 56 | issue = 3 | pages = 167–172 | date = March 2001 | pmid = 11182006 | pmc = 1758783 | doi = 10.1136/thorax.56.3.167 |author=Research Committee of the British Thoracic Society}} Evidence suggests that isoniazid prevents mycolic acid synthesis in M. avium complex as in M. tuberculosis{{cite journal | vauthors = Mdluli K, Swanson J, Fischer E, Lee RE, Barry CE | title = Mechanisms involved in the intrinsic isoniazid resistance of Mycobacterium avium | journal = Molecular Microbiology | volume = 27 | issue = 6 | pages = 1223–1233 | date = March 1998 | pmid = 9570407 | doi = 10.1046/j.1365-2958.1998.00774.x | s2cid = 13764717 | doi-access = free }} 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.{{cite journal | vauthors = van Ingen J, Egelund EF, Levin A, Totten SE, Boeree MJ, Mouton JW, Aarnoutse RE, Heifets LB, Peloquin CA, Daley CL | title = The pharmacokinetics and pharmacodynamics of pulmonary Mycobacterium avium complex disease treatment | journal = American Journal of Respiratory and Critical Care Medicine | volume = 186 | issue = 6 | pages = 559–565 | date = September 2012 | pmid = 22744719 | doi = 10.1164/rccm.201204-0682OC | author3-link = Adeera Levin }}

It is recommended that women with active tuberculosis who are pregnant or breastfeeding take isoniazid. Preventive therapy should be delayed until after giving birth.{{cite web | title=Isoniazid tablet | website=DailyMed | date=18 October 2018 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1553312b-ed76-421c-a055-2579bdcf366c | archive-url=https://web.archive.org/web/20190313234259/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1553312b-ed76-421c-a055-2579bdcf366c | archive-date=13 March 2019 | url-status=live | access-date=24 January 2020 }} 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.{{cite journal | vauthors = Bothamley G | title = Drug treatment for tuberculosis during pregnancy: safety considerations | journal = Drug Safety | volume = 24 | issue = 7 | pages = 553–565 | date = 2001 | pmid = 11444726 | doi = 10.2165/00002018-200124070-00006 | s2cid = 10479433 }}

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.{{cite journal | vauthors = Steichen O, Martinez-Almoyna L, De Broucker T | title = [Isoniazid induced neuropathy: consider prevention] | journal = Revue des Maladies Respiratoires | volume = 23 | issue = 2 Pt 1 | pages = 157–160 | date = April 2006 | pmid = 16788441 | doi = 10.1016/S0761-8425(06)71480-2 }}

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

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.{{cite journal | vauthors = Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan CM, Peloquin CA, Gordin FM, Nunes D, Strader DB, Bernardo J, Venkataramanan R, Sterling TR | title = An official ATS statement: hepatotoxicity of antituberculosis therapy | journal = American Journal of Respiratory and Critical Care Medicine | volume = 174 | issue = 8 | pages = 935–952 | date = October 2006 | pmid = 17021358 | doi = 10.1164/rccm.200510-1666ST | s2cid = 36384722 }}

Up to 20% of people taking isoniazid experience peripheral neuropathy when taking daily doses of 6 mg/kg of body weight or higher.{{cite book|title=Applied Therapeutics| vauthors = Alldredge B |date=February 12, 2013| publisher = Lippincott Williams & Wilkins |isbn=978-1-60913-713-7}} Gastrointestinal reactions include nausea and vomiting.{{cite web|url=http://medlibrary.org/lib/rx/meds/isoniazid-10/|title=Isoniazid (package insert)|date=30 March 2023 }} 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. Hypersensitivity reactions are also common and can present with a maculopapular rash and fever. Gynecomastia may occur.

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.{{cite web|title=Latent Tuberculosis Infection: A Guide for Primary Health Care Providers|url=https://www.cdc.gov/tb/publications/ltbi/treatment.htm|website=cdc.gov|publisher=Center for Disease Control|access-date=25 March 2016|url-status=live|archive-url=https://web.archive.org/web/20160325150054/http://www.cdc.gov/tb/publications/ltbi/treatment.htm|archive-date=25 March 2016}} 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.{{cite book | vauthors = Trevor A, Katzung B | date = 2013 | title = Katzung & Trevor's Pharmacology: examination & board review | edition = 10th | page = 417 | location = New York | publisher = McGraw-Hill Medical, Lange }} Symptoms suggestive of liver toxicity include nausea, vomiting, abdominal pain, dark urine, right upper quadrant pain, and loss of appetite. Black and Hispanic women are at higher risk for isoniazid-induced hepatotoxicity. When it happens, isoniazid-induced liver toxicity has been shown to occur in 50% of patients within the first 2 months of therapy.{{cite web|url=http://www.uptodate.com/contents/isoniazid-an-overview|title=Isoniazid UpToDate|url-status=live|archive-url=https://web.archive.org/web/20151025175722/http://www.uptodate.com/contents/isoniazid-an-overview|archive-date=2015-10-25}}

Some recommend that liver function should be monitored carefully in all people receiving it, but others recommend monitoring only in certain populations.{{cite web|title=Treatment of Tuberculosis – Guidelines (4th ed.)|url=http://apps.who.int/iris/bitstream/10665/44165/1/9789241547833_eng.pdf?ua=1&ua=1|website=who.int|publisher=World Health Organization|access-date=25 March 2016|url-status=live|archive-url=https://web.archive.org/web/20160404193153/http://apps.who.int/iris/bitstream/10665/44165/1/9789241547833_eng.pdf?ua=1&ua=1|archive-date=4 April 2016}}{{cite journal | vauthors = Joint T | title = Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998. Joint Tuberculosis Committee of the British Thoracic Society | journal = Thorax | volume = 53 | issue = 7 | pages = 536–548 | date = July 1998 | pmid = 9797751 | pmc = 1745276 | doi = 10.1136/thx.53.7.536 }}

Headache, poor concentration, weight gain, poor memory, insomnia, and depression have all been associated with isoniazid use.{{cite journal | vauthors = Mukherjee S, Roy S |title=Acute Psychosis Secondary to Isoniazid in a Patient with Pulmonary Tuberculosis |journal=Bengal Physician Journal |date=4 August 2023 |volume=10 |issue=2 |pages=73–74 |doi=10.5005/jp-journals-10070-8010|doi-access=free }} All patients and healthcare workers should be aware of these serious side effects, especially if suicidal ideation or behavior are suspected.{{cite journal | vauthors = Alao AO, Yolles JC | title = Isoniazid-induced psychosis | journal = The Annals of Pharmacotherapy | volume = 32 | issue = 9 | pages = 889–891 | date = September 1998 | pmid = 9762376 | doi = 10.1345/aph.17377 | s2cid = 73122253 }}{{cite journal | vauthors = Iannaccone R, Sue YJ, Avner JR | title = Suicidal psychosis secondary to isoniazid | journal = Pediatric Emergency Care | volume = 18 | issue = 1 | pages = 25–27 | date = February 2002 | pmid = 11862134 | doi = 10.1097/00006565-200202000-00008 | s2cid = 31383347 | doi-access = free }}{{cite journal | vauthors = Pallone KA, Goldman MP, Fuller MA | title = Isoniazid-associated psychosis: case report and review of the literature | journal = The Annals of Pharmacotherapy | volume = 27 | issue = 2 | pages = 167–170 | date = February 1993 | pmid = 8439690 | doi = 10.1177/106002809302700205 | s2cid = 28637999 }}

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.

Isoniazid was found to significantly elevate the in vivo concentration of GABA and homocarnosine in a single subject via magnetic resonance spectroscopy.{{cite journal | vauthors = Landheer K, Prinsen H, Petroff OA, Rothman DL, Juchem C | title = Elevated homocarnosine and GABA in subject on isoniazid as assessed through 1H MRS at 7T | journal = Analytical Biochemistry | volume = 599 | page = 113738 | date = June 2020 | pmid = 32302606 | doi = 10.1016/j.ab.2020.113738 | s2cid = 215809029 }}

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.{{cite journal | vauthors = Murphy R, Swartz R, Watkins PB | title = Severe acetaminophen toxicity in a patient receiving isoniazid | journal = Annals of Internal Medicine | volume = 113 | issue = 10 | pages = 799–800 | date = November 1990 | pmid = 2240884 | doi = 10.7326/0003-4819-113-10-799 }}{{cite journal | vauthors = Burk RF, Hill KE, Hunt RW, Martin AE | title = Isoniazid potentiation of acetaminophen hepatotoxicity in the rat and 4-methylpyrazole inhibition of it | journal = Research Communications in Chemical Pathology and Pharmacology | volume = 69 | issue = 1 | pages = 115–118 | date = July 1990 | pmid = 2218067 }}

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.{{cite journal | vauthors = Fleenor ME, Harden JW, Curtis G | title = Interaction between carbamazepine and antituberculosis agents | journal = Chest | volume = 99 | issue = 6 | page = 1554 | date = June 1991 | pmid = 2036861 | doi = 10.1378/chest.99.6.1554a | doi-access = free }}

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.{{cite journal | vauthors = Baciewicz AM, Baciewicz FA | title = Ketoconazole and fluconazole drug interactions | journal = Archives of Internal Medicine | volume = 153 | issue = 17 | pages = 1970–1976 | date = September 1993 | pmid = 8357281 | doi = 10.1001/archinte.153.17.1970 }}

Isoniazid may increase the amount of phenytoin in the body. The doses of phenytoin may need to be adjusted when given with isoniazid.{{cite journal | vauthors = Jonville AP, Gauchez AS, Autret E, Billard C, Barbier P, Nsabiyumva F, Breteau M | title = Interaction between isoniazid and valproate: a case of valproate overdosage | journal = European Journal of Clinical Pharmacology | volume = 40 | issue = 2 | pages = 197–198 | date = 1991 | pmid = 2065702 | doi = 10.1007/BF00280078 | s2cid = 22218366 }}{{cite journal | vauthors = Bass JB, Farer LS, Hopewell PC, O'Brien R, Jacobs RF, Ruben F, Snider DE, Thornton G | title = Treatment of tuberculosis and tuberculosis infection in adults and children. American Thoracic Society and The Centers for Disease Control and Prevention | journal = American Journal of Respiratory and Critical Care Medicine | volume = 149 | issue = 5 | pages = 1359–1374 | date = May 1994 | pmid = 8173779 | doi = 10.1164/ajrccm.149.5.8173779 }}

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.{{cite journal | vauthors = Höglund P, Nilsson LG, Paulsen O | title = Interaction between isoniazid and theophylline | journal = European Journal of Respiratory Diseases | volume = 70 | issue = 2 | pages = 110–116 | date = February 1987 | pmid = 3817069 }}

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

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.{{cite journal | vauthors = Suarez J, Ranguelova K, Jarzecki AA, Manzerova J, Krymov V, Zhao X, Yu S, Metlitsky L, Gerfen GJ, Magliozzo RS | title = An oxyferrous heme/protein-based radical intermediate is catalytically competent in the catalase reaction of Mycobacterium tuberculosis catalase-peroxidase (KatG) | journal = The Journal of Biological Chemistry | volume = 284 | issue = 11 | pages = 7017–7029 | date = March 2009 | pmid = 19139099 | pmc = 2652337 | doi = 10.1074/jbc.M808106200 | doi-access = free }} 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,{{cite journal | vauthors = Timmins GS, Master S, Rusnak F, Deretic V | title = Nitric oxide generated from isoniazid activation by KatG: source of nitric oxide and activity against Mycobacterium tuberculosis | journal = Antimicrobial Agents and Chemotherapy | volume = 48 | issue = 8 | pages = 3006–3009 | date = August 2004 | pmid = 15273113 | pmc = 478481 | doi = 10.1128/AAC.48.8.3006-3009.2004 }} which has also been shown to be important in the action of another antimycobacterial prodrug pretomanid.{{cite journal | vauthors = Singh R, Manjunatha U, Boshoff HI, Ha YH, Niyomrattanakit P, Ledwidge R, Dowd CS, Lee IY, Kim P, Zhang L, Kang S, Keller TH, Jiricek J, Barry CE | title = PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release | journal = Science | volume = 322 | issue = 5906 | pages = 1392–1395 | date = November 2008 | pmid = 19039139 | pmc = 2723733 | doi = 10.1126/science.1164571 | bibcode = 2008Sci...322.1392S }}

Image:Activation of isoniazid with NAD.jpg

Isoniazid is bactericidal to rapidly dividing mycobacteria, but is bacteriostatic if the mycobacteria are slow-growing.{{cite journal | vauthors = Ahmad Z, Klinkenberg LG, Pinn ML, Fraig MM, Peloquin CA, Bishai WR, Nuermberger EL, Grosset JH, Karakousis PC | title = Biphasic kill curve of isoniazid reveals the presence of drug-tolerant, not drug-resistant, Mycobacterium tuberculosis in the guinea pig | journal = The Journal of Infectious Diseases | volume = 200 | issue = 7 | pages = 1136–1143 | date = October 2009 | pmid = 19686043 | doi = 10.1086/605605 | doi-access = free }} It inhibits the cytochrome P450 system and hence acts as a source of free radicals.{{cite book|title=Pharmacology| volume= 864| vauthors = Harvey RA, Howland RD, Mycek MJ, Champe PC | veditors = Harvey RA, Champe PC | publisher= Lippincott Williams & Wilkins| year= 2006| isbn= 978-0-7817-4118-7| edition= 4th}}

Isoniazid is a mild non-selective monoamine oxidase inhibitor (MAO-I).{{cite journal | vauthors = Judd FK, Mijch AM, Cockram A, Norman TR | title = Isoniazid and antidepressants: is there cause for concern? | journal = International Clinical Psychopharmacology | volume = 9 | issue = 2 | pages = 123–125 | date = 1994 | pmid = 8056994 | doi = 10.1097/00004850-199400920-00009 }} It inhibits diamine oxidase more strongly. These two actions are possible explanations for its antidepressant action{{cite book | vauthors = Healy D |title=The Psychopharmacologists | volume = 2 |publisher=A Hodder Arnold Publication |year=1998 |pages=132–4 |isbn=978-1-86036-010-7}} as well as its ability to cause mania.

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.{{cn|date=August 2022}}

Isoniazid is an isonicotinic acid derivative. It is manufactured using 4-cyanopyridine and hydrazine hydrate.{{cite book|last1=William Andrew Publishing|title=Pharmaceutical Manufacturing Encyclopedia|date=2008|publisher=Elsevier Science|location=Norwich, NY|isbn=978-0-8155-1526-5|pages=1968–1970|edition=3rd|url=https://books.google.com/books?id=bRX8MwEACAAJ&q=9780815515265}} In another method, isoniazid was claimed to have been made from citric acid starting material.{{cite journal | vauthors = Baizer MM, Dub M, Gister S, Steinberg NG | title = Synthesis of isoniazid from citric acid | journal = Journal of the American Pharmaceutical Association. American Pharmaceutical Association | volume = 45 | issue = 7 | pages = 478–480 | date = July 1956 | pmid = 13345683 | doi = 10.1002/jps.3030450714 }}

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

Hydra, Hyzyd, Isovit, Laniazid, Nydrazid, Rimifon, and Stanozide.{{cite web|title=Drugs@FDA|url=https://www.accessdata.fda.gov/scripts/cder/daf/|website=fda.gov|publisher=United States Food and Drug Administration|access-date=22 August 2016|url-status=live|archive-url=https://web.archive.org/web/20120814072104/http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/index.cfm|archive-date=14 August 2012}}

Isonicotinic acid hydrazide is also used in chromatography to differentiate between various degrees of conjugation in organic compounds barring the ketone functional group.{{cite journal | vauthors = Saygin D, Tabib T, Bittar HE, Valenzi E, Sembrat J, Chan SY, Rojas M, Lafyatis R | title = Transcriptional profiling of lung cell populations in idiopathic pulmonary arterial hypertension | journal = Pulmonary Circulation | volume = 10 | issue = 1 | pages = 102–105 | date = 1959 | pmid = 32166015 | pmc = 7052475 | doi = 10.1021/ac60145a020 }} The test works by forming a hydrazone which can be detected by its bathochromic shift.{{cn|date=December 2022}}

Isoniazid may be used for dogs, but there have been concerns it can cause seizures.{{cite book | vauthors = Sykes JE |title= Canine and Feline Infectious Diseases |format= E-Book |date=2013 |publisher= Elsevier Health Sciences |isbn=978-0-323-24194-6 |page=425 |url= https://books.google.com/books?id=cb0kTIlb8HgC&pg=PA425 | via = Google Books}}

{{Reflist}}

• {{cite journal | vauthors = Romero JA, Kuczler FJ | title = Isoniazid overdose: recognition and management | journal = American Family Physician | volume = 57 | issue = 4 | pages = 749–752 | date = February 1998 | pmid = 9490997 | url = http://www.aafp.org/afp/980215ap/romero.html | access-date = 2005-12-13 | archive-url = https://web.archive.org/web/20111101092427/http://www.aafp.org/afp/980215ap/romero.html | archive-date = 2011-11-01 }}

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