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antibacterial drug (trade name Nydrazid) used to treat tuberculosis (同)INH, Nydrazid

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/05/10 07:46:40」(JST)

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Isoniazid (Laniazid, Nydrazid), also known as isonicotinylhydrazine (INH), is an organic compound that is the first-line medication in prevention and treatment of tuberculosis. The compound was first synthesized in the early 20th century,^[1] but its activity against tuberculosis was first reported in the early 1950s, and three pharmaceutical companies attempted unsuccessfully to simultaneously patent the drug,^[2] the most prominent one being Roche, which launched its version, Rimifon, in 1952.^[3] The drug was first tested at Many Farms, a Navajo community, due to the Navajo reservation's dire tuberculosis problem and the fact that the population was naïve with respect to streptomycin, the main tuberculosis treatment at the time.^[4] With the introduction of isoniazid, a cure for tuberculosis was first considered reasonable.

Isoniazid is available in tablet, syrup, and injectable forms (given intramuscularly or intravenously). It is available worldwide, is inexpensive and is generally well tolerated. It is manufactured from isonicotinic acid, which is produced from 4-methylpyridine.^[5]

Preparation

Isoniazid may be prepared by the base hydrolysis of 4-cyanopyridine to give the amide, followed by displacement of ammonia by hydrazine:^[6]^{[not in citation given]}

Mechanism of action

Isoniazid is a prodrug and must be activated by a bacterial catalase-peroxidase enzyme that in M. tuberculosis is called KatG.^[7] KatG couples the isonicotinic acyl with NADH to form isonicotinic acyl-NADH complex. This complex binds tightly to the enoyl-acyl carrier protein reductase known as InhA, thereby blocking the natural enoyl-AcpM substrate and the action of fatty acid synthase. This process inhibits the synthesis of mycolic acid, required for the mycobacterial cell wall. A range of radicals are produced by KatG activation of isoniazid, including nitric oxide,^[8] which has also been shown to be important in the action of another antimycobacterial prodrug PA-824.^[9]

Isoniazid is bactericidal to rapidly dividing mycobacteria, but is bacteriostatic if the mycobacteria are slow-growing.^[10]

Isoniazid inhibits the P450 system.^[11]

Metabolism

Isoniazid reaches therapeutic concentrations in serum, cerebrospinal fluid, and within caseous granulomas. It is metabolized in the liver via acetylation. 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 peaks at one and three hours in the US population. The metabolites are excreted in the urine. Doses do not usually have to be adjusted in case of renal failure.

Dosing

The standard dose of isoniazid in adults is 5 mg/kg/day (max 300 mg daily) for 6 months.^[12] The CDC and the WHO differ in their recommendation of intermittent dosing. The CDC recommends 15 mg/kg/day twice weekly (900 mg max dose), and the WHO recommends 10 mg/kg/day three times weekly (900 mg max dose) for either 6 or 9 months.^[13]^[14] When prescribed intermittently (twice or thrice weekly), the dose is 10–15 mg/kg (max 900 mg daily), depending on the regimen chosen. Patients with slow clearance of the drug (via acetylation as described above) may require reduced dosages to avoid toxicity. The American Academy of Pediatrics recommends dosing for children of either 10–15 mg/kg/day for a daily regimen or 20–30 mg/kg/day for a twice weekly regimen. The recommended duration of treatment is 9 months in children.^[15]

Side effects

Adverse reactions include rash, abnormal liver function tests, hepatitis, sideroblastic anemia, high anion gap metabolic acidosis, peripheral neuropathy, mild central nervous system (CNS) effects, drug interactions resulting in increased phenytoin (Dilantin) or disulfiram (Antabuse) levels, intractable seizures (status epilepticus) and drug-induced lupus erythematosus.

Peripheral neuropathy and CNS effects are associated with the use of isoniazid and are due to pyridoxine (vitamin B₆) depletion, but are uncommon at doses of 5 mg/kg. Persons with conditions in which neuropathy is common (e.g., diabetes, uremia, alcoholism, malnutrition, and HIV infection), as well as pregnant women and persons with a seizure disorder, may be given pyridoxine (vitamin B₆) (10–50 mg/day) with isoniazid.

Isoniazid may cause severe and sometimes fatal liver damage. 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 acetylation 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 one to two hours, while in slow acetylators, it is two to five hours. Elimination is largely independent of renal function, but 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.^[16]

Headache, poor concentration, weight gain, poor memory, insomnia 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.^[17]^[18]^[19]

INH is known to reduce cytochrome P450 and in theory promotes the efficacy of contraceptives. Therapy is often combined with rifampin. Rifampin increases the P450 enzyme and also can reduce the efficacy of contraceptives. Alternative means of birth control should be used when taking these medications.

As previously mentioned, isoniazid is associated with pyridoxine deficiency. Pyridoxyl phosphate (derivative of pyridoxine, i.e. Vitamin B6) is required for d-aminolevulinic acid synthase, the enzyme responsible for the rate-limiting step in heme synthesis. As such, isoniazid-induced pyridoxine-deficiency leads to insufficient heme formation in early red blood cells, leading to sideroblastic anemia.

Synonyms and abbreviations

Isonicotinyl hydrazine
Isonicotinic acid hydrazide
INH
H (for "hydrazide", and also the WHO standard abbreviation)

References

^ Meyer H, Mally J (1912). "On hydrazine derivatives of pyridine carbonic acids". Monatshefte Chemie verwandte Teile anderer Wissenschaften (in German) 33 (4): 393–414. doi:10.1007/BF01517946.
^ Hans L Riede (2009). "Fourth-generation fluoroquinolones in tuberculosis". Lancet 373 (9670): 1148–1149. doi:10.1016/S0140-6736(09)60559-6. PMID 19345815.
^ Roche USA
^ Jones, David (2002). "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. doi:10.1353/bhm.2002.0186. PMID 12446978.
^ Shinkichi Shimizu, Nanao Watanabe, Toshiaki Kataoka, Takayuki Shoji, Nobuyuki Abe, Sinji Morishita, Hisao Ichimura (2007). "Pyridine and Pyridine Derivatives". Ullmann's Encyclopedia of Industrial Chemistry. New York: John Wiley & Sons. doi:10.1002/14356007.a22_399. ^{[page needed]}
^ T. P. Sycheva, T. N. Pavlova and M. N. Shchukina (1972). "Synthesis of isoniazid from 4-cyanopyridine". Pharmaceutical Chemistry Journal 6 (11): 696–698. doi:10.1007/BF00771896.
^ Suarez J, Ranguelova K, Jarzecki AA, et al. (March 2009). "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): 7017–29. doi:10.1074/jbc.M808106200. PMC 2652337. PMID 19139099.
^ Timmins GS, Master S, Rusnak F, Deretic V (August 2004). "Nitric oxide generated from isoniazid activation by KatG: source of nitric oxide and activity against Mycobacterium tuberculosis". Antimicrobial Agents and Chemotherapy 48 (8): 3006–9. doi:10.1128/AAC.48.8.3006-3009.2004. PMC 478481. PMID 15273113.
^ Singh R, Manjunatha U, Boshoff HI, et al. (November 2008). "PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release". Science 322 (5906): 1392–5. doi:10.1126/science.1164571. PMC 2723733. PMID 19039139.
^ Ahmad, Z.; Klinkenberg, L. G.; Pinn, M. L.; Fraig, M. M.; Peloquin, C. A.; Bishai, W. R.; Nuermberger, E. L.; Grosset, J. H.; Karakousis, P. C. (2009). "Biphasic Kill Curve of Isoniazid Reveals the Presence of Drug‐Tolerant, Not Drug‐Resistant,Mycobacterium tuberculosisin the Guinea Pig". The Journal of Infectious Diseases 200 (7): 1136–1143. doi:10.1086/605605. PMID 19686043. edit
^ Harvey (November 2009). Pharmacology (4th ed.).
^ http://whqlibdoc.who.int/publications/2010/9789241547833_eng.pdf?ua=1
^ http://www.cdc.gov/tb/publications/ltbi/treatment.htm
^ http://whqlibdoc.who.int/publications/2010/9789241547833_eng.pdf?ua=1
^ http://pediatrics.aappublications.org/content/114/Supplement_4/1175.full.pdf
^ http://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/CPS-%20Monographs/CPS-%20(General%20Monographs-%20I)/ISONIAZID.html
^ Alao AO, Yolles JC (September 1998). "Isoniazid-induced psychosis". The Annals of Pharmacotherapy 32 (9): 889–91. doi:10.1345/aph.17377. PMID 9762376.
^ Iannaccone, R; Sue, YJ; Avner, JR (2002). "Suicidal psychosis secondary to isoniazid". Pediatric emergency care 18 (1): 25–7. doi:10.1097/00006565-200202000-00008. PMID 11862134.
^ Pallone KA, Goldman MP, Fuller MA (February 1993). "Isoniazid-associated psychosis: case report and review of the literature". The Annals of Pharmacotherapy 27 (2): 167–70. PMID 8439690.

External links

Core Curriculum on Tuberculosis (2000) Division of Tuberculosis Elimination, Centers for Disease Control and Prevention

See Chapter 6, Treatment of LTBI Regimens - Isoniazid::
See Chapter 7 - Treatment of TB Disease Monitoring - Adverse Reactions to First-Line TB Drugs - Isoniazid::
See Table 5 First-Line Anti-TB Medications

Isoniazid Overdose: Recognition and Management American Family Physician 1998 Feb 15

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. イソニアジド：概要 isoniazid an overview
2. イソニアジド（INH）中毒 isoniazid inh poisoning
3. イソニアジド肝毒性 isoniazid hepatotoxicity
4. HIV陰性成人における潜伏結核感染の治療 treatment of latent tuberculosis infection in hiv negative adults
5. HIV陰性患者における肺結核の治療 treatment of pulmonary tuberculosis in hiv negative patients

English Journal

Classical against molecular-genetic methods for susceptibility testing of antituberculotics.

Porvaznik I1, Mokry J, Solovic I.
Advances in experimental medicine and biology.Adv Exp Med Biol.2015;835:15-22. doi: 10.1007/5584_2014_28.
Tuberculosis currently belongs to rare respiratory diseases in Slovakia. However, the emergence and spread of multi-drug resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) are major challenges for global tuberculosis control, since the treatment of resistant forms c
PMID 25252893

Simple and accurate quantitative analysis of 20 anti-tuberculosis drugs in human plasma using liquid chromatography-electrospray ionization-tandem mass spectrometry.

Kim HJ1, Seo KA1, Kim HM1, Jeong ES1, Ghim JL1, Lee SH2, Lee YM3, Kim DH4, Shin JG5.
Journal of pharmaceutical and biomedical analysis.J Pharm Biomed Anal.2015 Jan;102:9-16. doi: 10.1016/j.jpba.2014.08.026. Epub 2014 Sep 1.
A simple and accurate liquid chromatography (LC)-tandem mass spectrometry (MS/MS) method for the quantitation of 20 anti-tuberculosis (anti-TB) drugs in human plasma, was developed as a tool for therapeutic drug monitoring. Two protein precipitation methods were adopted; one using methanol containin
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Acquired Rifampicin Resistance in Thrice-Weekly Antituberculosis Therapy: Impact of HIV and Antiretroviral Therapy.

Narendran G1, Menon PA1, Venkatesan P1, Vijay K1, Padmapriyadarsini C1, Ramesh Kumar S1, Bhavani KP1, Sekar L1, Gomathi SN1, Chandrasekhar C2, Kumar S2, Sridhar R3, Swaminathan S1.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.Clin Infect Dis.2014 Dec 15;59(12):1798-804. doi: 10.1093/cid/ciu674. Epub 2014 Aug 25.
BACKGROUND: Risk factors for acquired rifampicin resistance (ARR) in human immunodeficiency virus (HIV)/tuberculosis coinfection, in the highly active antiretroviral therapy (HAART) era, needs evaluation. We studied the impact of HIV and HAART on ARR among patients taking thrice-weekly antituberculo
PMID 25156114

Japanese Journal

GenoType MTBDRplusによる多剤耐性結核菌同定に関する検討

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NAID 40018950982

Molecular characterization of rifampicin- and isoniazid-resistant Mycobacterium tuberculosis strains isolated in Kazakhstan

Kozhamkulov Ulan,Akhmetova Ainur,Rakhimova Saule [他]
Japanese Journal of Infectious Diseases 64(3), 253-255, 2011-05
NAID 40018820944

Related Pictures

★リンクテーブル★

国試過去問	「080B082」
リンク元	「イソニアジド」「INH」
拡張検索	「isoniazid sodium methanesulfonate」

「080B082」

Isoniazid
Systematic (IUPAC) name
	isonicotinohydrazide
Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a682401
Pregnancy cat.	C
Legal status	prescription only (US)
Routes	oral, intramuscular, intravenous
Pharmacokinetic data
Protein binding	Very low (0-10%)
Metabolism	liver; CYP450: 2C19, 3A4 inhibitor
Half-life	0.5-1.6h (fast acetylators), 2-5h (slow acetylators)
Excretion	urine (primarily), feces
Identifiers
CAS number	54-85-3
ATC code	J04AC01
PubChem	CID 3767
DrugBank	DB00951
ChemSpider	3635
UNII	V83O1VOZ8L
KEGG	D00346
ChEBI	CHEBI:6030
ChEMBL	CHEMBL64
NIAID ChemDB	007657
Chemical data
Formula	C6H7N3O
Mol. mass	137.139 g/mol
	SMILES O=C(NN)c1ccncc1;
	InChI InChI=1S/C6H7N3O/c7-9-6(10)5-1-3-8-4-2-5/h1-4H,7H2,(H,9,10) ; Key:QRXWMOHMRWLFEY-UHFFFAOYSA-N ;
(what is this?) (verify)

　　[★]

ペラグラの原因となるのはどれか？

「イソニアジド」

　　[★]

英: isoniazid INH
同: イソニコチン酸ヒドラジド isonicotinic acid hydrazide INAH
商: イスコチン、ヒドラ、ネオイスコチン
関: 抗結核薬、結核、イソニアジドメタンスルホン酸ナトリウム、ビタミンB6、ビタミンB6欠乏症; 抗結核剤

概念

抗結核薬

作用機序

結核菌の細胞壁を構成するミコール酸の生合成を阻害。

副作用

肝障害(AST,ALT上昇。可逆的)(肝細胞障害型薬物性肝障害)、末梢神経炎(INHがビタミンB6の排泄を促進するため。VB6の服用により予防可能)

添付文書

イスコチン原末／イスコチン錠１００ｍｇ

http://www.info.pmda.go.jp/go/pack/6222001F3037_2_03/6222001F3037_2_03?view=body

参考

1. Isoniazid hepatotoxicity - uptodate [1]

「INH」

　　[★] イソニアジド isoniazid

「isoniazid sodium methanesulfonate」

　　[★] イソニアジドメタンスルホン酸ナトリウム

[1] Meyer H, Mally J (1912). "On hydrazine derivatives of pyridine carbonic acids". Monatshefte Chemie verwandte Teile anderer Wissenschaften (in German) 33 (4): 393–414. doi:10.1007/BF01517946.

[2] Hans L Riede (2009). "Fourth-generation fluoroquinolones in tuberculosis". Lancet 373 (9670): 1148–1149. doi:10.1016/S0140-6736(09)60559-6. PMID 19345815.

[3] Roche USA

[4] Jones, David (2002). "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. doi:10.1353/bhm.2002.0186. PMID 12446978.

[5] Shinkichi Shimizu, Nanao Watanabe, Toshiaki Kataoka, Takayuki Shoji, Nobuyuki Abe, Sinji Morishita, Hisao Ichimura (2007). "Pyridine and Pyridine Derivatives". Ullmann's Encyclopedia of Industrial Chemistry. New York: John Wiley & Sons. doi:10.1002/14356007.a22_399. ^{[page needed]}

[6] T. P. Sycheva, T. N. Pavlova and M. N. Shchukina (1972). "Synthesis of isoniazid from 4-cyanopyridine". Pharmaceutical Chemistry Journal 6 (11): 696–698. doi:10.1007/BF00771896.

[7] Suarez J, Ranguelova K, Jarzecki AA, et al. (March 2009). "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): 7017–29. doi:10.1074/jbc.M808106200. PMC 2652337. PMID 19139099.

[8] Timmins GS, Master S, Rusnak F, Deretic V (August 2004). "Nitric oxide generated from isoniazid activation by KatG: source of nitric oxide and activity against Mycobacterium tuberculosis". Antimicrobial Agents and Chemotherapy 48 (8): 3006–9. doi:10.1128/AAC.48.8.3006-3009.2004. PMC 478481. PMID 15273113.

[9] Singh R, Manjunatha U, Boshoff HI, et al. (November 2008). "PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release". Science 322 (5906): 1392–5. doi:10.1126/science.1164571. PMC 2723733. PMID 19039139.

[10] Ahmad, Z.; Klinkenberg, L. G.; Pinn, M. L.; Fraig, M. M.; Peloquin, C. A.; Bishai, W. R.; Nuermberger, E. L.; Grosset, J. H.; Karakousis, P. C. (2009). "Biphasic Kill Curve of Isoniazid Reveals the Presence of Drug‐Tolerant, Not Drug‐Resistant,Mycobacterium tuberculosisin the Guinea Pig". The Journal of Infectious Diseases 200 (7): 1136–1143. doi:10.1086/605605. PMID 19686043. edit

[11] Harvey (November 2009). Pharmacology (4th ed.).

[12] ttp://whqlibdoc.who.int/publications/2010/9789241547833_eng.pdf?ua=1

[13] ttp://www.cdc.gov/tb/publications/ltbi/treatment.htm

[14] ttp://whqlibdoc.who.int/publications/2010/9789241547833_eng.pdf?ua=1

[15] ttp://pediatrics.aappublications.org/content/114/Supplement_4/1175.full.pdf

[16] ttp://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/CPS-%20Monographs/CPS-%20(General%20Monographs-%20I)/ISONIAZID.html

[17] Alao AO, Yolles JC (September 1998). "Isoniazid-induced psychosis". The Annals of Pharmacotherapy 32 (9): 889–91. doi:10.1345/aph.17377. PMID 9762376.

[18] Iannaccone, R; Sue, YJ; Avner, JR (2002). "Suicidal psychosis secondary to isoniazid". Pediatric emergency care 18 (1): 25–7. doi:10.1097/00006565-200202000-00008. PMID 11862134.

[19] Pallone KA, Goldman MP, Fuller MA (February 1993). "Isoniazid-associated psychosis: case report and review of the literature". The Annals of Pharmacotherapy 27 (2): 167–70. PMID 8439690.

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isoniazid