Isoniazid

Isoniazid is a synthetic hydrazide of isonicotinic acid and the most potent bactericidal drug against actively dividing Mycobacterium tuberculosis. It forms part of the four-drug intensive phase and the two-drug continuation phase for drug-susceptible tuberculosis, and it is the usual single agent for latent tuberculosis infection. Hepatitis and peripheral neuropathy are its main toxicities, and both are commoner in slow acetylators, alcohol use, malnutrition, HIV infection and older age.

Class. First-line antimycobacterial; isonicotinic acid hydrazide.

Mechanism. A prodrug activated by the bacterial catalase-peroxidase KatG. The active form inhibits InhA and blocks mycolic acid synthesis. KatG mutations give high-level resistance; inhA promoter mutations give low-level resistance with cross-resistance to ethionamide.

Pharmacodynamics. Strong early bactericidal activity against rapidly dividing bacilli, weaker sterilising activity, and rapid emergence of resistance if used alone.

Pharmacokinetics. Near-complete oral absorption, reduced by food and aluminium antacids. Peak level at 1 to 2 hours. Hepatic acetylation by NAT2 gives fast and slow acetylators, with half life about 1 hour in fast and 3 hours or more in slow. Penetrates cerebrospinal fluid, crosses the placenta and enters breast milk.

Drug-susceptible tuberculosis (first line). - Adults: 5 mg/kg (range 4 to 6) orally once daily, usual 300 mg; maximum 300 mg daily. - Children: 10 mg/kg (range 7 to 15) orally once daily; maximum 300 mg. - Duration: 2 months with rifampicin, pyrazinamide and ethambutol, then 4 months with rifampicin. - Loading dose: none. Titration: none. Daily dosing is preferred, especially with HIV infection.

Latent tuberculosis infection. - Isoniazid 5 mg/kg daily (maximum 300 mg; children 10 mg/kg, maximum 300 mg) for 6 to 9 months. - Alternatives: isoniazid 5 mg/kg plus rifampicin 10 mg/kg daily for 3 months; isoniazid 15 mg/kg (maximum 900 mg) with rifapentine once weekly for 12 weeks; isoniazid 300 mg with rifapentine 600 mg daily for 1 month in people aged 13 and over.

Specialist use. - Rifampicin-resistant disease with isoniazid susceptibility or low-level inhA resistance: 10 to 15 mg/kg daily within an individualised regimen, with closer liver and neuropathy monitoring. - Intermittent dosing (10 mg/kg three times weekly, maximum 900 mg) is a fallback under direct observation only.

Pyridoxine cover. Pyridoxine 10 mg daily prevents neuropathy in most patients; use 25 to 50 mg daily in pregnancy, HIV infection, diabetes, alcohol use, malnutrition, kidney failure and epilepsy. Established neuropathy is treated with 50 to 100 mg daily.

Contraindications. Previous isoniazid hepatitis or severe hypersensitivity, and acute liver disease. Caution in chronic liver disease, alcohol dependence, epilepsy, severe kidney failure and porphyria.

Serious adverse effects. Hepatitis (boxed-warning-level, risk rises with age over 35 years, alcohol, pregnancy and the 3 months after delivery), peripheral neuropathy, optic neuritis, psychosis, seizures, lupus-like syndrome, haemolysis in G6PD deficiency, agranulocytosis, severe skin reactions.

Common adverse effects. Nausea, epigastric pain, rash, drug fever and mild asymptomatic rise in transaminases.

Regional points. In East Africa HIV co-infection is common, so daily dosing, routine pyridoxine and early liver testing matter; national programmes mainly supply weight-banded fixed-dose combination tablets.

Interactions. - Raises levels of phenytoin, carbamazepine, theophylline and warfarin effect. - Disulfiram adds psychosis and ataxia risk; valproate and paracetamol add hepatotoxicity. - Reduces levodopa effect; ketoconazole lowers isoniazid levels; aluminium antacids reduce absorption. - Weak monoamine oxidase inhibition: flushing, headache and palpitations after aged cheese, red wine and tuna or skipjack.

Common prescribing errors. Giving the child dose to adults, omitting pyridoxine in at-risk patients, exceeding 300 mg daily, continuing the drug through jaundice or vomiting, and using it as a single agent for active disease.

Special groups. - Pregnancy: used when needed, with pyridoxine; monitor liver tests closely, including after delivery. - Breastfeeding: compatible; watch the infant for jaundice and irritability. - Children: 10 mg/kg; pyridoxine for malnourished or HIV-exposed children. - Older adults: higher hepatitis risk; check liver tests more often. - Kidney impairment: usual dose; on haemodialysis give after the session. - Liver impairment: avoid in active hepatitis; in stable chronic disease use only under specialist supervision with frequent liver tests.

Formulations. Tablets 100 mg and 300 mg, fixed-dose combination tablets with rifampicin, pyrazinamide and ethambutol, and oral solution. Injection (100 mg/mL, intramuscular or slow intravenous) exists but is rarely supplied.

Administration. Once daily on an empty stomach, 1 hour before or 2 hours after food; a small snack is acceptable for gastric upset. Separate from aluminium antacids by at least 2 hours.

Baseline. Liver tests in patients with alcohol use, liver disease, hepatitis B or C, HIV infection, pregnancy, the postpartum period, age over 35 years or other hepatotoxic drugs. Weight, HIV status and pregnancy status.

Monitoring. Symptom review at every visit (nausea, jaundice, dark urine, numbness). In at-risk patients check liver tests at 2 and 4 weeks, then monthly.

Stopping thresholds. Stop isoniazid, rifampicin and pyrazinamide if ALT is over three times the upper limit of normal with symptoms, or over five times without symptoms. Use a non-hepatotoxic regimen under specialist care and reintroduce drugs one at a time once ALT is under two times the upper limit of normal.

Referral and escalation. Refer for hepatitis, seizures, psychosis, optic neuritis, haemolysis or suspected drug resistance.