Isoniazid
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Isoniazid
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| Systematic (IUPAC) name | |
| isonicotinohydrazide | |
| Identifiers | |
| CAS number | |
| ATC code | J04 |
| PubChem | |
| DrugBank | |
| ChemSpider | |
| Chemical data | |
| Formula | C6H7N3O |
| Mol. mass | 137.139 g/mol |
| SMILES | & |
| Pharmacokinetic data | |
| Bioavailability | ? |
| 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 |
| Therapeutic considerations | |
| Pregnancy cat. |
C |
| Legal status |
prescription only (US) |
| Routes | oral, intramuscular, intravenous |
Isoniazid (also called isonicotinyl hydrazine or INH; sold as Laniazid, Nydrazid) is an organic compound that is the first-line antituberculosis medication in prevention and treatment. First discovered in 1912 as an inhibitor of the MAO enzyme, it was first used as an antidepressant, but discontinued due to side effects. In 1951, it was later discovered that isoniazid was effective against TB. Isoniazid is never used on its own to treat active tuberculosis because resistance quickly develops.
The compound was first synthesised in the early 20th century,[1] but its activity against tuberculosis was first reported in the early 1950's and three pharmaceutical companies attempted unsuccessfully to simultaneously patent the drug[2] (most prominently, Roche, who launched their version, Rimifon, in 1952). 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). Isoniazid is available worldwide, is inexpensive and is generally well tolerated. It is manufactured from isonicotinic acid, which is produced from 4-methylpyridine.[3]
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[edit] Mechanism of action
Isoniazid is a prodrug and must be activated by bacterial catalase.[4] It is activated by catalase-peroxidase enzyme KatG which couples the isonicotinic acyl with NADH to form isonicotinic acyl-NADH complex. This complex binds tightly to ketoenoylreductase 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.
Isoniazid is bactericidal to rapidly-dividing mycobacteria but is bacteriostatic if the mycobacterium is slow-growing. Isoniazid inhibits the P450 system.
[edit] Metabolism
Isoniazid reaches therapeutic concentrations in serum, cerebrospinal fluid (CSF), and within caseous granulomas. Isoniazid is metabolized in the liver via acetylation. There are two forms of the enzyme responsible for acetylation, so that some patients metabolize the drug more quickly than others. Hence, the half-life is bimodal 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 renal failure.
[edit] Dosing
The standard dose of isoniazid in adults is 5 mg/kg/day (max 300mg daily). When prescribed intermittently (twice or thrice weekly) the dose is 15mg/kg (max 900mg daily). Patients with slow clearance of the drug (via acetylation as described above) may require reduced dosages to avoid toxicity. The recommended dose for children is 8 to 12 mg/kg/day.[5]
[edit] Side effects
Adverse reactions include rash, abnormal liver function tests, hepatitis, sideroblastic anemia, peripheral neuropathy, mild central nervous system (CNS) effects, drug interactions resulting in increased phenytoin (Dilantin) or disulfiram (Antabuse) levels and intractable seizures (status epilepticus).
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, 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.
Hepatotoxicity can be avoided with close clinical monitoring of the patient, specifically 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 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. 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.[1]
Headache, poor concentration, poor memory and depression have all been associated with isoniazid use. The frequency of these side effects is not known, and the association with isoniazid is not well validated. The presence of these symptoms is rarely disabling and is certainly not a reason to stop treatment with isoniazid; the patient should be strongly encouraged to continue treatment despite these symptoms. It must be explained to the patient that the harm done from not taking isoniazid far outweighs the problems arising from these symptoms.
INH therapy will decrease the efficacy of hormonal birth control when combined with Rifampin.
[edit] Synonyms and abbreviations
- Isonicotinyl hydrazine
- Isonicotinic acid hydrazide
- INH
- H (for "hydrazide", and also the WHO standard abbreviation)
[edit] See also
[edit] References
- ^ Meyer H, Mally J. "On hydrazine derivatives and pyridine carbonic acids" (in German). Monatshefte Chemie verwandte Teile anderer Wissenschaften 23: 393–414.
- ^ Hans L Riede (2009). "Fourth-generation fluoroquinolones in tuberculosis". Lancet 373 (9670): 1148–1149. doi:.
- ^ 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.
- ^ Timmins GS, Deretic V (2006). "Mechanisms of action of isoniazid". Mol. Microbiol. 62 (5): 1220–7. doi:. PMID 17074073. http://www.blackwell-synergy.com/doi/full/10.1111/j.1365-2958.2006.05467.x.
- ^ McIlleron H, Willemse M, Werely CJ, et al. (2009). "Isoniazid plasma concentrations in a cohort of South African children with tuberculosis: Implications for international pediatric dosing guidelines". Clin Infect Dis 48 (11): 1547–1553. doi:.
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- 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
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- Isoniazid Overdose: Recognition and Management American Family Physician 1998 Feb 15
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