Isoniazid
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Isoniazid
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| Systematic (IUPAC) name | |
| pyridine-4-carbohydrazide | |
| Identifiers | |
| CAS number | |
| ATC code | J04 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C6H7N3O |
| Mol. mass | 137.139 g/mol |
| 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 is also called isonicotinyl hydrazine or INH. Isoniazid is a first-line antituberculous medication used in the prevention and treatment of tuberculosis. Isoniazid is never used on its own to treat active tuberculosis because resistance quickly develops.
Isoniazid is used in the treatment of mycobacterial infection. It was discovered in 1952 by Roche (trademarked as Rimifon), when for the first time, a cure for tuberculosis was considered reasonable. It is available in tablet, syrup, and injectable forms (given intramuscularly or intravenously). Isoniazid is available world-wide, is inexpensive to produce and is generally well tolerated.
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[edit] Mechanism of action
Isoniazid is a prodrug and must be activated by bacterial catalase.[1] It is activated by catalase-peroxidase enzyme KatG to form isonicotinic acyl anion or radical. These forms will then react with a NADH radical or anion to form isonicotinic acyl-NADH complex. This complex will bind tightly to ketoenoylreductase known as InhA and prevents access of the natural enoyl-AcpM substrate. This mechanism inhibits the synthesis of mycolic acid in the mycobacterial cell wall.
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 quicker 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.
Isoniazid is bactericidal to rapidly-dividing mycobacteria, but is bacteriostatic if the mycobacterium is slow-growing.
[edit] Dosing
The standard dose of isoniazid is 3-5mg/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.
[edit] Side effects
Adverse reactions include rash, abnormal liver function tests, hepatitis, sideroblastic anemia, peripheral neuropathy, mild central nervous system (CNS) effects, and drug interactions resulting in increased phenytoin (Dilantin) or disulfiram (Antabuse) levels.
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.
Hepatoxicity 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 Orientals 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 not frequently 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] Wikipedia links
[edit] References
- ^ Timmins GS, Deretic V (2006). "Mechanisms of action of isoniazid". Mol. Microbiol. 62 (5): 1220–7. doi:. PMID 17074073.
- 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
