isoniazid
antitubercular· Brands: NydrazidIMIVPO
Mechanism of action
Isoniazid is a prodrug that is activated by the bacterial catalase-peroxidase enzyme KatG to form reactive species that inhibit the synthesis of mycolic acids, essential components of the mycobacterial cell wall. This disrupts cell wall integrity and is bactericidal against actively growing tubercle bacilli.
Pharmacokinetics
Isoniazid is well absorbed after oral administration, with peak plasma concentrations reaching within 1 to 2 hours. It is metabolised in the liver by acetylation, and the rate of acetylation is genetically determined (fast vs slow acetylators). The half-life is about 1 to 3 hours in fast acetylators and 2 to 5 hours in slow acetylators. It is excreted primarily in urine, mostly as metabolites. It distributes widely into body fluids and tissues, including cerebrospinal fluid.
Indications & dosing
Active tuberculosis (in combination with other antitubercular agents)
Weight-based: 5 mg/kg (max 300 mg).
- adult · PO: 300 mg once daily · Weight-based: 5 mg/kg (max 300 mg).
Active tuberculosis (in combination with other antitubercular agents)
Max 300 mg/day.
- pediatric · PO: 10 mg/kg once daily · Max 300 mg/day.
Latent tuberculosis infection (prophylaxis)
Usually given for 9 months.
- adult · PO: 300 mg once daily · Usually given for 9 months.
Contraindications & precautions
- Hypersensitivity to isoniazid or any component of the formulation
- Acute liver disease or severe hepatic impairment · Isoniazid is hepatotoxic; avoid in patients with active liver disease.
- Previous isoniazid-induced hepatic injury or hepatitis · Recurrence of severe hepatic injury is likely on re-exposure.
- Monitor liver function tests before and during treatment, especially in patients with pre-existing liver disease or alcohol use.
- Give pyridoxine (vitamin B6) to prevent or treat peripheral neuropathy, particularly in patients with diabetes, malnutrition, or alcohol dependence.
- Use with caution in patients with epilepsy or other seizure disorders, as isoniazid can lower the seizure threshold.
- Be aware of drug interactions, as isoniazid inhibits CYP450 enzymes, raising levels of phenytoin, carbamazepine, and other drugs.
- Avoid alcohol during treatment to minimise hepatotoxicity.
Adverse effects
- Hepatotoxicityserious
- Peripheral neuropathyserious
- Drug-induced lupus-like syndromeserious
- Optic neuritisserious
- Psychosis or confusionserious
- Nausea and vomiting
- Rash
Interactions
- phenytoinmajorMonitor plasma phenytoin concentrations closely, especially within the first two weeks of concurrent therapy. Reduce the phenytoin dose as needed to maintain therapeutic levels. Advise patients to report symptoms of toxicity. If isoniazid is stopped, monitor for decreased phenytoin levels and increase the dose if required.
Renal & hepatic adjustment
- eGFR 0+: No dose adjustment is generally required. Use with caution in severe renal impairment.
- Hepatic impairment (mild): Use with caution. Consider dose reduction and monitor liver function.
- Hepatic impairment (moderate): Use with caution. Consider dose reduction and monitor liver function closely.
- Hepatic impairment (severe): Avoid use. Alternative agent should be considered. (avoid)
Monitoring, pregnancy & toxicity
- Liver function tests (ALT, AST, bilirubin) · At baseline, then monthly for the first 3 months, and as clinically indicated
- Clinical signs of hepatotoxicity (jaundice, dark urine, nausea, vomiting) · At each review
- Neurological symptoms (peripheral neuropathy, paraesthesia) · At each review
- Visual acuity and colour vision (if symptoms of optic neuritis) · As clinically indicated
- Pregnancy: Isoniazid is generally considered safe in pregnancy when used for tuberculosis treatment. It should be used when clearly indicated. Monitor liver function closely and consider pyridoxine supplementation.
- Toxicity: Hepatotoxicity (elevated liver enzymes, hepatitis, which may be severe and sometimes fatal) · Stop isoniazid, monitor liver function, provide supportive care. Avoid re-challenge.
- Toxicity: Peripheral neuropathy (tingling, burning, paraesthesia, particularly in the hands and feet) · Give pyridoxine 10-50 mg/day to prevent and treat. In severe neuropathy, consider dose reduction or discontinuation.
- Toxicity: CNS effects (dizziness, headache, seizures, psychosis) · Discontinue isoniazid, give pyridoxine, and manage symptoms.
- Toxicity: Hypersensitivity reactions (rash, fever, drug-induced lupus) · Stop isoniazid, treat symptoms, and consider alternatives.
Antidotes & reversal
- Pyridoxine (vitamin B6) · Gram-for-gram dose equal to INH ingested (min 5 g IV) to control seizures; plus benzodiazepines.
Clinical notes
Isoniazid is a first-line agent for the treatment and prophylaxis of tuberculosis. It is commonly used in combination with other antitubercular drugs to prevent resistance. Hepatotoxicity is a significant adverse effect, and regular monitoring of liver function tests is recommended, especially in patients with pre-existing liver disease or those who are slow acetylators. Peripheral neuropathy can be prevented with pyridoxine supplementation. Drug interactions include increased levels of phenytoin and carbamazepine, and reduced efficacy of oral contraceptives. Doses are typically given once daily or twice weekly, and the regimen must be tailored according to local guidelines and susceptibility testing.
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BNF; local formulary