Isoniazid

"inah" redirects here. For "INAH", see Instituto Nacional de Antropología e Historia.
Isoniazid
Systematic (IUPAC) name
Isonicotinohydrazide
Clinical data
Trade names Hydra, Isovit, Laniazid, Nydrazid
AHFS/Drugs.com monograph
MedlinePlus a682401
Pregnancy
category
  • C
Legal status
  • prescription only (US)
Routes of
administration		 oral, intramuscular, intravenous
Pharmacokinetic data
Protein binding Very low (0-10%)
Metabolism liver; CYP450: 2C19, 3A4 inhibitor
Biological half-life 0.5-1.6h (fast acetylators), 2-5h (slow acetylators)
Excretion urine (primarily), feces
Identifiers
CAS Number 54-85-3 YesY
ATC code J04AC01
PubChem CID 3767
DrugBank DB00951 YesY
ChemSpider 3635 YesY
UNII V83O1VOZ8L YesY
KEGG D00346 YesY
ChEBI CHEBI:6030 YesY
ChEMBL CHEMBL64 YesY
NIAID ChemDB 007657
Synonyms Isonicotinic Acid Hydrazide, Isonicotinyl hydrazine, INHA, INH
Chemical data
Formula C6H7N3O
Molar mass 137.139 g/mol
  (verify)

Isoniazid, marketed under other names including isonicotinylhydrazide (INH) and Hydra, is an antibiotic used as a first-line agent in the prevention and treatment of both latent and active tuberculosis.[1] It is effective against mycobacteria, particularly Mycobacterium tuberculosis. It is also active against some atypical strains like M. kansasii and M. xenopi.[2] Isoniazid is an organic compound that is available in tablet, syrup, and injectable forms.[3][4][5]

The most common side effect seen with isoniazid use is an increase in liver enzymes; however it is usually harmless. Uncommon side effects include numbness in the arms or legs and liver inflammation. Isoniazid has a boxed warning on the risk of liver toxicity and thus liver function should be monitored carefully on all patients receiving isoniazid.[6] The proposed mechanism of action is the blocking of the formation of mycolic acid, which is an essential part of the mycobacterial cell wall. Disruption of the cell wall results in cell death and isoniazid can fight colonization at both the intracellular and extracellular level.[7]

It was first made in the early 20th century,[8] but its activity against tuberculosis was first reported in the early 1950s. Three pharmaceutical companies unsuccessfully attempted to patent the drug at the same time,[9] the most prominent one being Roche, which launched its version, Rimifon, in 1952.[10] With the introduction of isoniazid, a cure for tuberculosis was first considered possible. It is available worldwide, is inexpensive, and is generally well tolerated. It is on the World Health Organization's List of Essential Medicines, a list of medicines that constitute the bare minimum for a basic health system.[11]

Medical uses

Isoniazid is approved for latent and active tuberculosis infections; for the latter, it is used in combination with other anti-tuberculosis medications to also limit drug resistance.

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

Special populations

Pregnant or breastfeeding women — It is recommended that pregnant women with active TB take isoniazid. Preventative therapy is advised for after giving birth.[13] Nursing mothers excrete a minimal, nontoxic concentration of INH in breast milk; the baby is at low risk for adverse events. Both pregnant women and infants being breastfed by mothers on INH are advised to take vitamin B6 in its pyridoxine form.[14] Vitamin B6 is used to prevent isoniazid-induced B6 deficiency and neuropathy in people with a risk factor; such as pregnancy, lactation, HIV, alcoholism, diabetes, kidney failure, or malnutrition.[15]

Persons with liver dysfunction — Persons with liver dysfunction are at a higher risk for drug-induced liver toxicity and may need a lower dose.[13]

Baseline transaminase should be measured and frequently checked in daily alcohol drinkers, pregnant women, IV drug users, people over 35, or who have active chronic liver disease, severe kidney dysfunction, peripheral neuropathy, or HIV since they are more prone to hepatitis.[13]

Side effects

Common adverse reactions involve multiple systems. Up to 20% of patients taking isoniazid experience peripheral neuropathy at higher doses of 6 mg/kg/day or higher.[16] Gastrointestinal reactions include nausea and vomiting.[12] Aplastic anemia, thrombocytopenia, and agranulocytosis can also occur with use.[12] Hypersensitivity reactions are also common and can present with a maculopapular rash and fever.[12]

Isoniazid has a boxed warning concerning the incidence of severe and sometimes fatal hepatitis, which is age-dependent at a rate of 0.3% in people 21–35 years and over 2% in those over 50.[12][17] Common symptoms indicative of severe hepatotoxicity include nausea, vomiting, abdominal pain, dark urine, right upper quadrant pain, and loss of appetite.[12] Black and Hispanic women are at higher risk for isoniazid-induced hepatotoxicity.[12] Isoniazid-induced hepatotoxicity has been shown to occur is 50% of patients within the first 2 months of therapy.[18]

Headache, poor concentration, weight gain, poor memory, insomnia, and depression have all been associated with isoniazid use.[19] All patients and healthcare workers should be aware of these serious adverse effects, especially if suicidal ideation or behavior are suspected.[19][20][21]

As previously mentioned, isoniazid is associated with pyridoxine deficiency. Pyridoxal phosphate (derivative of pyridoxine) 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.[15]

Drug interactions

Acetaminophen: persons 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.[22][23]

Carbamazepine: Isoniazid decreases the metabolism of carbamazepine, thus slowing down its clearance from the body. Persons on carbamazepine should have their carbamazepine levels monitored and, if necessary, have their dose adjusted accordingly.[24]

Ketoconazole: It is possible that isoniazid may decrease the serum levels of ketoconazole after long term treatment. This is seen with concomitant use of rifampin, isoniazid, and ketoconazole.[25]

Phenytoin: Isoniazid may increase the amount of phenytoin in the body. Phenytoin may need to be dose adjusted when given with isoniazid.[26][27]

Theophylline: Isoniazid may increase the plasma levels of theophylline. There are some cases of theophylline slowing down isoniazid elimination. Monitor both theophylline and isoniazid levels.[28]

Valproate: Valproate levels may increase when taken with isoniazid. Monitor valproate levels. Valproate dose adjustment may be necessary.[26]

Mechanism of action

Isoniazid is a prodrug and must be activated by a bacterial catalase-peroxidase enzyme that in mycobacterium tuberculosis is called KatG.[29] 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,[30] which has also been shown to be important in the action of another antimycobacterial prodrug pretomanid.[31]

Isoniazid is bactericidal to rapidly dividing mycobacteria, but is bacteriostatic if the mycobacteria are slow-growing.[32] It inhibits the P450 system and hence acts as a source of free radicals.[33]

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.

History

The drug was first tested at Many Farms, a Navajo community, 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.[34]

Preparation

Isoniazid is manufactured using 4-Cyanopyridine and hydrazine hydrate.[35] The former reagent is produced via the ammoxidation of 4-methylpyridine.[36]

Other uses

Chromatography

Isonicotinic acid hydrazide is also used in chromatography to differentiate between various degrees of conjugation in organic compounds barring the ketone functional group.[37] The test works by forming a hydrazone which can be detected by its bathochromic shift.

See also

References

  1. ↑ "CDC | TB | Treatment". www.cdc.gov. Retrieved 2015-11-03.
  2. ↑ Berning SE, Peloquin CA. Antimycobacterial agents: Isoniazid. In: Antimicrobial Therapy and Vaccines, Yu V, Merigan T, Barriere S (Eds), Williams and Wilkins, Baltimore 1998.
  3. ↑ Isoniazid [package insert]. Eatontown, NJ: West-Ward Pharmaceutical Corp; 2014.
  4. ↑ Isoniazid [package insert]. Atlanta, GA: Mikart, Inc; 2015
  5. ↑ Isoniazid [package insert]. Princeton, NJ: Sandoz, Inc; 2009.
  6. ↑ "DailyMed - ISONIAZID- isoniazid tablet". dailymed.nlm.nih.gov. Retrieved 2015-11-05.
  7. ↑ Lei, Benfang; Wei, Chih-Jen; Tu, Shiao-Chun (2000-01-28). "Action Mechanism of Antitubercular Isoniazid ACTIVATION BY MYCOBACTERIUM TUBERCULOSIS KatG, ISOLATION, AND CHARACTERIZATION OF InhA INHIBITOR". Journal of Biological Chemistry 275 (4): 2520–2526. doi:10.1074/jbc.275.4.2520. ISSN 0021-9258.
  8. ↑ Meyer H, Mally J (1912). "On hydrazine derivatives of pyridine carbonic acids" (PDF). Monatshefte Chemie verwandte Teile anderer Wissenschaften (in German) 33 (4): 393–414. doi:10.1007/BF01517946.
  9. ↑ Hans L Riede (2009). "Fourth-generation fluoroquinolones in tuberculosis". Lancet 373 (9670): 1148–1149. doi:10.1016/S0140-6736(09)60559-6. PMID 19345815.
  10. ↑ Roche USA
  11. ↑ "WHO Model List of Essential Medicines" (PDF). World Health Organization. October 2013. Retrieved 2 February 2015.
  12. 1 2 3 4 5 6 7 "Isoniazid (package insert)".
  13. 1 2 3 https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5ab01773-d1e4-4b87-884a-9e5b3f13bdcb
  14. ↑ Bothamley, G (2001). "Drug treatment for tuberculosis during pregnancy: safety considerations.". Drug safety 24 (7): 553–65. doi:10.2165/00002018-200124070-00006. PMID 11444726.
  15. 1 2 Steichen, O; Martinez-Almoyna, L; De Broucker, T (April 2006). "[Isoniazid induced neuropathy: consider prevention].". Revue des maladies respiratoires 23 (2 Pt 1): 157–60. PMID 16788441.
  16. ↑ Alldredge, Brian (February 12, 2013). Applied Therapeutics. ISBN 9781609137137.
  17. ↑ Trevor, A., & Katzung, B. (2013). Katzung et Trevor's Pharmacology: Examination et board review (10.th ed., p. 417). New York [u.a.: McGraw-Hill Medical, Lange.
  18. ↑ "Isoniazid UpToDate".
  19. 1 2 Alao AO, Yolles JC (September 1998). "Isoniazid-induced psychosis". The Annals of Pharmacotherapy 32 (9): 889–91. doi:10.1345/aph.17377. PMID 9762376.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ Murphy, R., et al: Annuals of Internal Medicine; 1990: November 15; volume 113: 799-800.
  23. ↑ Burke, R.F.,et al: Res Commun Chem Pathol Pharmacol; 1990: July; vol. 69: 115-118.
  24. ↑ Fleenor, M.F.,et al: Chest (United States) Letter; 1991: June; 99(6): 1554.
  25. ↑ Baciewicz, A.M. and Baciewicz, Jr. F.A.: Arch Int Med 1993: September; volume 153: 1970-1971.
  26. 1 2 Jonviller, A.P.,et al: European Journal of Clinical Pharmacol (Germany), 1991: 40 (2) p198.
  27. ↑ American Thoracic Society/Centers for Disease Control: Treatment of Tuberculosis and Tuberculosis Infection in Adults and Children. Amer. J. Respir Crit Care Med. 1994; 149: p1359-1374.
  28. ↑ Hoglund P.,et al: European Journal of Respir Dis (Denmark) 1987: February; 70 (2) p110-116.
  29. ↑ 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.
  30. ↑ 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.
  31. ↑ 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.
  32. ↑ 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.
  33. ↑ Harvey (November 2009). Pharmacology (4th ed.).
  34. ↑ 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.
  35. ↑ William Andrew Publishing (2008). Pharmaceutical Manufacturing Encyclopedia (3rd ed.). Norwich, NY: Elsevier Science. p. 1968-1970. ISBN 9780815515265.
  36. ↑ Shimizu, Shinkichi; Watanabe, Nanao; Kataoka, Toshiaki; Shoji, Takayuki; Abe, Nobuyuki; Morishita, Sinji; Ichimura, Hisao (2000). "Pyridine and Pyridine Derivatives". Ullmann's Encyclopedia of Industrial Chemistry: 17. doi:10.1002/14356007.a22_399.
  37. ↑ Smith, L.L.; Foell, Theodore (1959). "Differentiation of Δ4-3-Ketosteroids and Δ1,4-3-Ketosteroids with Isonicotinic Acid Hydrazide". Analytical Chemistry 31 (1): 102–105. doi:10.1021/ac60145a020.

External links

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
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