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{{Short description|Antibiotic for treatment of tuberculosis}}
'''{{Drugbox
{{redirect|Inah|"INAH"|Instituto Nacional de Antropología e Historia}}
| verifiedrevid = 443884719
{{redirect|FSR 3|FidelityFX Super Resolution v3|GPUOpen#FidelityFX Super Resolution}}
| IUPAC_name = isonicotinohydrazide
{{cs1 config |name-list-style=vanc |display-authors=6}}
| image = Isoniazid skeletal.svg
{{Drugbox
| width = 160
|Watchedfields = changed
| image2 = Isoniazid 3d.png
|verifiedrevid = 459455986
| width2 = 220
|image = Isoniazid skeletal.svg
|width = 160
|alt =
|image2 = Isoniazid 3d.png
|width2 = 220
|alt2 =
|tradename = Hydra, Hyzyd, Isovit, others
|Drugs.com = {{drugs.com|monograph|isoniazid}}
|MedlinePlus = a682401
|DailyMedID = Isoniazid
|pregnancy_AU = A
|pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Isoniazid (Nydrazid) Use During Pregnancy | website=Drugs.com | date=7 October 2019 | url=https://www.drugs.com/pregnancy/isoniazid.html | access-date=24 January 2020}}</ref>
|routes_of_administration = ], ], ]
|ATC_prefix = J04
|ATC_suffix = AC01
|ATC_supplemental = {{ATC|J04|AC51}}, {{ATC|J04|AM01}}, {{ATC|J04|AM02}}, {{ATC|J04|AM03}}, {{ATC|J04|AM04}}, {{ATC|J04|AM05}}, {{ATC|J04|AM06}}, {{ATC|J04|AM07}}, {{ATC|J04|AM08}}, {{ATC|J04|AM09}}, {{ATC|J04|AM12}}


|legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
<!--Clinical data-->
|legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F-->
| tradename =
|legal_CA = Rx-only
| Drugs.com = {{drugs.com|monograph|isoniazid}}
|legal_CA_comment = <ref>{{cite web | title=Drug and medical device highlights 2018: Helping you maintain and improve your health | website=] | date=14 October 2020 | url=https://www.canada.ca/en/health-canada/services/publications/drugs-health-products/drug-medical-device-highlights-2018.html | access-date=17 April 2024}}</ref>
| MedlinePlus = a682401
|legal_DE = <!-- Anlage I, II, III or Unscheduled-->
| pregnancy_category = C
|legal_NZ = <!-- Class A, B, C -->
| legal_status = prescription only (US)
|legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
| routes_of_administration = oral, intramuscular, intravenous
|legal_US = Rx-only
|legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->
|legal_status = <!--For countries not listed above-->
|protein_bound = Very low (0–10%)
|metabolism = liver; CYP450: 2C19, 3A4 inhibitor
|elimination_half-life = 0.5–1.6h (fast acetylators), 2-5h (slow acetylators)
|excretion = urine (primarily), feces
|synonyms = isonicotinic acid hydrazide, isonicotinyl hydrazine, INH, INAH, INHA
|CAS_number_Ref = {{cascite|correct|??}}
|CAS_number = 54-85-3
|PubChem = 3767
|DrugBank_Ref = {{drugbankcite|correct|drugbank}}
|DrugBank = DB00951
|ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
|ChemSpiderID = 3635
|UNII_Ref = {{fdacite|correct|FDA}}
|UNII = V83O1VOZ8L
|KEGG_Ref = {{keggcite|correct|kegg}}
|KEGG = D00346
|KEGG2_Ref = {{keggcite|correct|kegg}}
|KEGG2 = C07054
|ChEBI_Ref = {{ebicite|correct|EBI}}
|ChEBI = 6030
|ChEMBL_Ref = {{ebicite|correct|EBI}}
|ChEMBL = 64
|NIAID_ChemDB = 007657
|IUPAC_name = Pyridine-4-carbohydrazide
|C=6 | H=7 | N=3 | O=1
|SMILES = C1=CN=CC=C1C(=O)NN
|StdInChI_Ref = {{stdinchicite|correct|chemspider}}
|StdInChI = 1S/C6H7N3O/c7-9-6(10)5-1-3-8-4-2-5/h1-4H,7H2,(H,9,10)
|StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
|StdInChIKey = QRXWMOHMRWLFEY-UHFFFAOYSA-N
}}


'''Isoniazid''', also known as '''isonicotinic acid hydrazide''' ('''INH'''), is an ] used for the ].<ref name=AHFS2016>{{cite web|title=Isoniazid|url=https://www.drugs.com/monograph/isoniazid.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161220231039/https://www.drugs.com/monograph/isoniazid.html|archive-date=20 December 2016}}</ref> For active tuberculosis, it is often used together with ], ], and either ] or ].<ref name=WHO2008>{{cite book | title = WHO Model Formulary 2008 | year = 2009 | isbn = 9789241547659 | vauthors = ((World Health Organization)) | veditors = Stuart MC, Kouimtzi M, Hill SR | hdl = 10665/44053 | author-link = World Health Organization | publisher = World Health Organization | hdl-access=free |page=136 }}</ref> For latent tuberculosis, it is often used alone.<ref name=AHFS2016/> It may also be used for ], such as '']'', '']'', and '']''.<ref name=AHFS2016/> It is usually taken by mouth, but may be used by ].<ref name=AHFS2016/>
<!--Pharmacokinetic data-->
| protein_bound = Very low (0-10%)
| metabolism = liver; CYP450: 2C19, 3A4 inhibitor
| elimination_half-life = 0.5-1.6h (fast acetylators), 2-5h (slow acetylators)
| excretion = urine (primarily), feces


==History==
<!--Identifiers-->
First synthesis was described in 1912.<ref>{{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 | language = de | journal = Pulmonary Circulation | volume = 10 | issue = 1 | pages = 393–414 | date = 1912-04-01 | pmid = 32166015 | doi = 10.1177/2045894020908782 | pmc = 7052475 }}</ref> 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,<ref>{{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}}</ref> the most prominent one being Roche, which launched its version, Rimifon, in 1952.<ref>{{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}}</ref>
| CASNo_Ref = {{cascite|correbct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 54-85-3
| ATC_prefix = J04
| ATC_suffix = AC01
| PubChem = 3767
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00951
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 3635
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = V83O1VOZ8L
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00346
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 6030
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 64


The drug was first tested at ], a ] community in ], due to the Navajo reservation's tuberculosis problem and because the population had not previously been treated with ], the main tuberculosis treatment at the time.<ref>{{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 }}</ref> The research was led by ], an infectious disease researcher with an interest in public health, who had previously taken isoniazid to treat his own tuberculosis.<ref>{{cite book|chapter-url=https://www.nap.edu/read/1652/chapter/15#283|chapter=Walsh McDermott|pages=282–307|publisher=]|title=Biographical Memoirs | volume = 59 |year=1990| vauthors = Beeson PB |doi=10.17226/1652|isbn=978-0-309-04198-0}}</ref>
<!--Chemical data-->
| C=6 | H=7 | N=3 | O=1
| molecular_weight = 137.139 g/mol
| smiles = O=C(NN)c1ccncc1
| InChI = 1/C6H7N3O/c7-9-6(10)5-1-3-8-4-2-5/h1-4H,7H2,(H,9,10)
| InChIKey = QRXWMOHMRWLFEY-UHFFFAOYAD
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C6H7N3O/c7-9-6(10)5-1-3-8-4-2-5/h1-4H,7H2,(H,9,10)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = QRXWMOHMRWLFEY-UHFFFAOYSA-N
}}


Isoniazid and a related drug, ], were among the first drugs to be referred to as ]s.<ref>{{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/10193706/1/Moncrieff_1-s2.0-S0277953608000129-main.pdf }}</ref> Psychiatric use stopped in 1961 following reports of hepatotoxicity. Use against tuberculosis continued, as isoniazid's effectiveness against the disease outweighs its risks.<ref name=mania>{{cite journal | url=https://onlinelibrary.wiley.com/doi/full/10.1111/bdi.13272 | doi=10.1111/bdi.13272 | title=Isoniazid-induced mania and the history of antidepressant drugs: Case report and literature review | date=2023 | journal=Bipolar Disorders | volume=25 | issue=1 | pages=84–87 | pmid=36380697 | vauthors = Samouco AI, Alves SP | doi-access=free }}</ref>
'''Isoniazid''' ('''Laniazid''', '''Nydrazid'''), also known as '''isonicotinylhydrazine''' ('''INH'''), is an ] that is the first-line anti] medication in prevention and treatment. It was first discovered in 1912, and later in 1951 it was found to be effective against tuberculosis by inhibiting its ] (wax coat). Isoniazid is never used on its own to treat active tuberculosis because resistance quickly develops. Isoniazid also has an ] effect, and it was one of the first antidepressants discovered. Isoniazid can also be used in the treatment of a ].


It is on the ].<ref name="WHO21st">{{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 = ] | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free | last1 = Organization | first1 = World Health }}</ref> The World Health Organization classifies isoniazid as critically important for human medicine.<ref>{{cite book | year=2019 | title=Critically important antimicrobials for human medicine | edition=6th revision | publisher = ] | location = Geneva | hdl=10665/312266 | isbn=9789241515528 | hdl-access=free}}</ref> Isoniazid is available as a ].<ref name=AHFS2016/>
The compound was first synthesised in the early 20th century,<ref>{{Cite journal|author=Meyer H, Mally J|title=On hydrazine derivatives of pyridine carbonic acids|journal=Monatshefte Chemie verwandte Teile anderer Wissenschaften|volume=33|pages=393&ndash;414|language=German|year=1912}}</ref> but its activity against tuberculosis was first reported in the early 1950s and three pharmaceutical companies attempted unsuccessfully to simultaneously patent the drug<ref>{{Cite journal|journal=Lancet|volume=373|issue=9670|pages=1148&ndash;1149|year=2009
|doi=10.1016/S0140-6736(09)60559-6|title=Fourth-generation fluoroquinolones in tuberculosis|author=Hans L Riede|pmid=19345815}}</ref> (the most prominent one being Roche, who launched their version, , in 1952). With the introduction of isoniazid, a cure for tuberculosis was first considered reasonable.


==Medical uses==
Isoniazid is available in tablet, syrup, and injectable forms (given intramuscularly or intravenously). Isoniazid is available worldwide, is inexpensive and is generally well tolerated. It is manufactured from ], which is produced from ].<ref>{{Cite book|author=Shinkichi Shimizu, Nanao Watanabe, Toshiaki Kataoka, Takayuki Shoji, Nobuyuki Abe, Sinji Morishita, Hisao Ichimura|chapter=Pyridine and Pyridine Derivatives|title=Ullmann's Encyclopedia of Industrial Chemistry|year=2007|publisher=John Wiley &amp; Sons|location=New York}}{{Page needed|date=September 2010}}</ref>
===Tuberculosis===
Isoniazid is often used to treat latent and active tuberculosis infections. In persons with isoniazid-sensitive '']'' 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.<ref>{{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 }}</ref>


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&nbsp;mm induration
* Contacts of people with tuberculosis and who have a PPD reaction at least 5&nbsp;mm induration
* People whose PPD reactions convert from negative to positive in a two-year period – at least 10&nbsp;mm induration for those up to 35 years of age, and at least 15&nbsp;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&nbsp;mm induration
* Injection drug users whose HIV status is negative who have a PPD reaction at least 10&nbsp;mm induration
* People with a PPD of greater than or equal to 10&nbsp;mm induration who are foreign-born from high prevalence geographical regions, low-income populations, and patients residing in long-term facilities<ref name=":0" /><ref>{{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}}</ref>


Isoniazid can be used alone or in combination with ] for treatment of latent tuberculosis, or as part of a four-drug regimen for treatment of active tuberculosis.<ref name=":3">{{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|oclc=228373703}}</ref> The drug regimen typically requires daily or weekly oral administration for a period of three to nine months, often under ] (DOT) supervision.<ref name=":3" />
==Preparation==
Isoniazid may be prepared by the base hydrolysis of 4-cyanopyridine to give the ], followed by displacement of ammonia by ]:<ref>{{Cite journal| journal = ] | volume= 6 | issue = 11 | year = 1972 | doi = 10.1007/BF00771896 | pages = 696–698 | title = Synthesis of isoniazid from 4-cyanopyridine | author = T. P. Sycheva, T. N. Pavlova and M. N. Shchukina}}</ref>


===Non-tuberculous mycobacteria===
:]
Isoniazid was widely used in the treatment of ] as part of a regimen including rifampicin and ethambutol.<ref>{{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 | last1 = Research Committee Of The British Thoracic Society }}</ref> Evidence suggests that isoniazid prevents mycolic acid synthesis in ''M. avium'' complex as in ''M. tuberculosis''<ref>{{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 }}</ref> 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.<ref>{{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 }}</ref>


===Special populations===
==Mechanism of action==
It is recommended that women with active tuberculosis who are pregnant or breastfeeding take isoniazid. Preventive therapy should be delayed until after giving birth.<ref name="Isoniazid label">{{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 }}</ref> 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 ] in its ] form to minimize the risk of peripheral nerve damage.<ref>{{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}}</ref>
Isoniazid is a ] and must be activated by a bacterial catalase-peroxidase enzyme that in ''M. tuberculosis'' is called KatG.<ref>{{Cite journal|author=Suarez J, Ranguelova K, Jarzecki AA, ''et al.'' |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=7017–29 |year=2009 |month=March |pmid=19139099 |doi=10.1074/jbc.M808106200 |pmc=2652337}}</ref> KatG couples the isonicotinic acyl with ] to form isonicotinic acyl-NADH complex. This complex binds tightly to the ] known as InhA, thereby blocking the natural enoyl-AcpM substrate and the action of ]. This process inhibits the synthesis of ], required for the ] cell wall. A range of radicals are produced by KatG activation of Isoniazid, including ],<ref>{{Cite journal|author=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=3006–9 |year=2004 |month=August |pmid=15273113 |pmc=478481 |doi=10.1128/AAC.48.8.3006-3009.2004}}</ref> which has also been shown to be important in the action of another antimycobacterial prodrug ].<ref>{{Cite journal|author=Singh R, Manjunatha U, Boshoff HI, ''et al.'' |title=PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release |journal=Science |volume=322 |issue=5906 |pages=1392–5 |year=2008 |month=November |pmid=19039139 |doi=10.1126/science.1164571 |pmc=2723733}}</ref>
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.<ref name=":2">{{cite journal | vauthors = Steichen O, Martinez-Almoyna L, De Broucker T | title = | 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}}</ref>


People with liver dysfunction are at a higher risk for hepatitis caused by INH, and may need a lower dose.<ref name="Isoniazid label"/>
Isoniazid is ] to rapidly-dividing ] but is ] if the mycobacterium is slow-growing.{{Citation needed|date=November 2009}}


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.<ref name="Isoniazid label"/><ref>{{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}}</ref>
Isoniazid inhibits the ].<ref>{{Cite book|title=Pharmacology, Harvey 4th edition|date=November 2009}}</ref>


==Metabolism== ==Side effects==
Up to 20% of people taking isoniazid experience ] when taking daily doses of 6&nbsp;mg/kg of body weight or higher.<ref>{{cite book|title=Applied Therapeutics| vauthors = Alldredge B |date=February 12, 2013| publisher = Lippincott Williams & Wilkins |isbn=9781609137137}}</ref> Gastrointestinal reactions include nausea and vomiting.<ref name=":0">{{cite web|url=http://medlibrary.org/lib/rx/meds/isoniazid-10/|title=Isoniazid (package insert)|date=30 March 2023 }}</ref> ], ], and ] due to lack of production of red blood cells, platelets, and white blood cells by the bone marrow respectively, can also occur.<ref name=":0"/> Hypersensitivity reactions are also common and can present with a ] rash and fever.<ref name=":0" /> ] may occur.<ref name=":3" />
Isoniazid reaches therapeutic concentrations in serum, ] (CSF), and within caseous granulomas. Isoniazid is metabolized in the liver via ]. There are two forms of the enzyme responsible for acetylation, so that some patients metabolize the drug more quickly than others. Hence, the ] is ] with peaks at 1 hour and 3 hours in the US population. The metabolites are excreted in the urine. Doses do not usually have to be adjusted in case of ].


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.<ref name=cdc-ltbi>{{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}}</ref> 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.<ref name=":0" /><ref>Trevor, A. & Katzung, B. (2013). Katzung & Trevor's Pharmacology: examination & board review (10th ed., p. 417). New York. McGraw-Hill Medical, Lange.</ref> Symptoms suggestive of liver toxicity include nausea, vomiting, abdominal pain, dark urine, right upper quadrant pain, and loss of appetite.<ref name=":0" /> Black and Hispanic women are at higher risk for isoniazid-induced hepatotoxicity.<ref name=":0" /> When it happens, isoniazid-induced liver toxicity has been shown to occur in 50% of patients within the first 2 months of therapy.<ref>{{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}}</ref>
==Dosing==
The standard dose of isoniazid in adults is 5&nbsp;mg/kg/day (max 300&nbsp;mg daily). When prescribed intermittently (twice or thrice weekly) the dose is 15&nbsp;mg/kg (max 900&nbsp;mg daily). Patients with slow clearance of the drug (via acetylation as described above) may require reduced dosages to avoid ]. The recommended dose for children is 8 to 12&nbsp;mg/kg/day.<ref>{{Cite journal|author=McIlleron H, Willemse M, Werely CJ, ''et al.'' |title=Isoniazid plasma concentrations in a cohort of South African children with tuberculosis: implications for international pediatric dosing guidelines |journal=Clinical Infectious Diseases |volume=48 |issue=11 |pages=1547–53 |year=2009 |month=June |pmid=19392636 |doi=10.1086/598192}}</ref>


Some recommend that liver function should be monitored carefully in all people receiving it,<ref name="Isoniazid label"/> but others recommend monitoring only in certain populations.<ref name=cdc-ltbi/><ref>{{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}}</ref><ref>{{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 }}</ref>
==Side effects==
Adverse reactions include ], abnormal ], ], ], ], ], mild ] (CNS) effects, ]s resulting in increased ] (Dilantin) or ] (Antabuse) levels and intractable seizures (]).


Headache, poor concentration, weight gain, poor memory, insomnia, and depression have all been associated with isoniazid use.<ref name=":1" /> All patients and healthcare workers should be aware of these serious side effects, especially if suicidal ideation or behavior are suspected.<ref name=":1">{{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}}</ref><ref>{{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 }}</ref><ref>{{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}}</ref>
] and ] effects are associated with the use of isoniazid and are due to ] (vitamin B<sub>6</sub>) depletion, but are uncommon at doses of 5&nbsp;mg/kg. Persons with conditions in which neuropathy is common (e.g., ], ], ], ], ]-infection), as well as ] women and persons with a ] disorder, may be given ] (vitamin B<sub>6</sub>) (10–50&nbsp;mg/day) with isoniazid.


Isoniazid is associated with ] (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-], 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 ].<ref name=":2" />
Hepatotoxicity of INH is by nitrogen group in its chemical structure, as it is metabolized in the liver and gets converted in to an ammonium molecule, which causes hepatitis.


Isoniazid was found to significantly elevate the in vivo concentration of ] and ] in a single subject via ].<ref>{{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 | pages = 113738 | date = June 2020 | pmid = 32302606 | doi = 10.1016/j.ab.2020.113738 | s2cid = 215809029 }}</ref>
Hepatotoxicity can be avoided with close clinical monitoring of the patient, to be specific, nausea, vomiting, abdominal pain, and appetite. Isoniazid is metabolized by the liver mainly by ] and dehydrazination. The N-acetylhydrazine metabolite is believed to be responsible for the hepatotoxic effects seen in patients treated with isoniazid. The rate of acetylation is genetically determined. Approximately 50% of blacks and Caucasians are slow inactivators; the majority of Inuit and Asians are rapid inactivators. The half-life in fast acetylators is 1 to 2 hours, while in slow acetylators it is 2 to 5 hours. Elimination is largely independent of renal function, however the half-life may be prolonged in liver disease. The rate of acetylation has not been shown to significantly alter the effectiveness of isoniazid. However, slow acetylation may lead to higher blood concentrations with chronic administration of the drug, with an increased risk of toxicity. Fast acetylation leads to higher blood levels of the toxic metabolite acetylisoniazid and thus to an increase in toxic reactions - hepatitis which is 250 times more common than in slow acetylators. Isoniazid and its metabolites are excreted in the urine with 75 to 95% of the dose excreted in 24 hours. Small amounts are also excreted in saliva, sputum, and feces. Isoniazid is removed by hemodialysis and peritoneal dialysis.<ref>http://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/CPS-%20Monographs/CPS-%20(General%20Monographs-%20I)/ISONIAZID.html</ref>


==Drug interactions==
Headache, poor concentration, weight-gain, poor memory, and depression have all been associated with isoniazid use. All patients and healthcare workers should be aware of these serious adverse effects, especially if suicidal thinking or behavior are suspected.<ref>{{Cite journal|author=Alao AO, Yolles JC |title=Isoniazid-induced psychosis |journal=The Annals of Pharmacotherapy |volume=32 |issue=9 |pages=889–91 |year=1998 |month=September |pmid=9762376 |doi=10.1345/aph.17377}}</ref><ref><nowiki>http://journals.lww.com/pec-online/Fulltext/2002/02000/Suicidal_psychosis_secondary_to_isoniazid.8.aspx</nowiki>{{Dead link|date=November 2009}}</ref><ref>{{Cite journal|author=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=167–70 |year=1993 |month=February |pmid=8439690}}</ref>
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.<ref>{{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 }}</ref><ref>{{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 }}</ref>


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.<ref>{{cite journal | vauthors = Fleenor ME, Harden JW, Curtis G | title = Interaction between carbamazepine and antituberculosis agents | journal = Chest | volume = 99 | issue = 6 | pages = 1554 | date = June 1991 | pmid = 2036861 | doi = 10.1378/chest.99.6.1554a | doi-access = free }}</ref>
INH is known to reduce cytochrome P450 and in theory promote the efficacy of Contraceptives. Therapy is often combined with ]. Rifampin increases the P450 enzyme and can reduce the efficacy of contraceptives. Alternative means of birth control should be used when taking these medications.


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.<ref>{{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 }}</ref>
As p450 is required for porphyrin synthesis its deficiency leads to poor heme formation in early RBCs leads to ].


Isoniazid may increase the amount of phenytoin in the body. The doses of phenytoin may need to be adjusted when given with isoniazid.<ref name=Jonville>{{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 }}</ref><ref>{{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}}</ref>
==Synonyms and abbreviations==
* Isonicotinyl hydrazine
* Isonicotinic acid hydrazide
* INH
* H (for "hydrazide", and also the ] standard abbreviation)


Isoniazid may increase the plasma levels of ]. There are some cases of theophylline slowing down isoniazid elimination. Both theophylline and isoniazid levels should be monitored.<ref>{{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}}</ref>
==See also==
*]
*]
*'']''


] levels may increase when taken with isoniazid. Valproate levels should be monitored and its dose adjusted if necessary.<ref name="Jonville"/>
==References==
{{Reflist|2}}


==External links== ==Mechanism of action==
Isoniazid is a ] that inhibits the formation of the ] cell wall. Isoniazid must be activated by KatG, a bacterial catalase-peroxidase enzyme in '']''.<ref>{{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 }}</ref> KatG catalyzes the formation of the isonicotinic acyl radical, which spontaneously couples with ] to form the nicotinoyl-NAD adduct. This complex binds tightly to the ] InhA, thereby blocking the natural enoyl-AcpM substrate and the action of ]. This process inhibits the synthesis of ], which are required components of the ] cell wall. A range of radicals are produced by KatG activation of isoniazid, including ],<ref>{{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 }}</ref> which has also been shown to be important in the action of another antimycobacterial prodrug ].<ref>{{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}}</ref>
:* Division of Tuberculosis Elimination, Centers for Disease Control and Prevention
::See Chapter 6, Treatment of LTBI Regimens - ::<br>See Chapter 7 - Treatment of TB Disease Monitoring - ::<br>See Table 5


]
:* American Family Physician 1998 Feb 15

Isoniazid is ] to rapidly dividing ], but is ] if the mycobacteria are slow-growing.<ref>{{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 }}</ref> It inhibits the ] and hence acts as a source of free radicals.<ref>{{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= 9780781741187| edition= 4th}}</ref>

Isoniazid is a mild non-selective ] (MAO-I).<ref name=maoi>{{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}}</ref> It inhibits ] more strongly. These two actions are possible explanations for its antidepressant action<ref name="isbn1-86036-010-6">{{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}}</ref> as well as its ability to cause mania.<ref name=mania/>

==Metabolism==
Isoniazid reaches therapeutic concentrations in serum, ], and within ]. It is metabolized in the liver via ] into acetylhydrazine. Two forms of the enzyme are responsible for acetylation, so some patients metabolize the drug more quickly than others. Hence, the ] is ], 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 ].{{cn|date=August 2022}}


==Preparation==
Isoniazid is an ] ]. It is manufactured using ] and ].<ref name=William>{{cite book|last1=William Andrew Publishing|title=Pharmaceutical Manufacturing Encyclopedia|date=2008|publisher=Elsevier Science|location=Norwich, NY|isbn=9780815515265|pages=1968–1970|edition=3rd|url=https://books.google.com/books?id=bRX8MwEACAAJ&q=9780815515265}}</ref> In another method, isoniazid was claimed to have been made from ] starting material.<ref name="BaizerDub1956">{{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 | volume = 45 | issue = 7 | pages = 478–480 | date = July 1956 | pmid = 13345683 | doi = 10.1002/jps.3030450714}}</ref>

It can in theory be made from ], which is labelled a ].

==Brand names==
Hydra, Hyzyd, Isovit, Laniazid, Nydrazid, Rimifon, and Stanozide.<ref>{{cite web|title=Drugs@FDA|url=http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm|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}}</ref>

==Other uses==
===Chromatography===
Isonicotinic acid hydrazide is also used in ] to differentiate between various degrees of ] in ]s barring the ] ].<ref>{{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 | doi = 10.1021/ac60145a020 | pmc = 7052475 }}</ref> The test works by forming a ] which can be detected by its ].{{cn|date=December 2022}}

===Dogs===
Isoniazid may be used for dogs, but there have been concerns it can cause seizures.<ref>{{cite book | vauthors = Sykes JE |title= Canine and Feline Infectious Diseases |format= E-Book |date=2013 |publisher= Elsevier Health Sciences |isbn=978-0323241946 |page=425 |url= https://books.google.com/books?id=cb0kTIlb8HgC&pg=PA425 | via = Google Books}}</ref>

== References ==
{{Reflist}}

== Further reading ==
* {{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-date = 2011-11-01 | archive-url = https://web.archive.org/web/20111101092427/http://www.aafp.org/afp/980215ap/romero.html | url-status = dead}}

== External links ==
* {{Commonscatinline}}


{{Antimycobacterials}} {{Antimycobacterials}}
{{Cell wall disruptive antibiotics}} {{Cell wall disruptive antibiotics}}
{{Monoamine metabolism modulators}}
{{GABA metabolism and transport modulators}}
{{Hydrazines}} {{Hydrazines}}
{{Portal bar | Medicine}}
{{Authority control}}


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