Anti-Tubercular Drugs — Mechanisms, Resistance Genes, Adverse Effects, Interactions and Monitoring

Drug-sensitive TB is treated with four first-line drugs — isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E) — in an intensive phase followed by a continuation phase. This page covers the pharmacology; the phases, weight bands and drug-resistant regimens are on TB under NTEP — treatment regimens.

Resistance in M. tuberculosis arises from chromosomal mutations in the drug's target or activating enzyme, selected when a drug is effectively given alone. That is why TB is never treated with monotherapy — resistance develops rapidly with isoniazid or rifampicin alone.

Isoniazid is inactivated in the liver and gut by N-acetyltransferase 2 (NAT2), so its half-life depends on whether a patient is a fast or slow acetylator. Acetylhydrazine is then oxidised by CYP2E1 into hepatotoxic metabolites.

Rifampicin is a semisynthetic rifamycin. It undergoes enterohepatic circulation, is widely distributed (including into CSF) and its absorption falls by about 30% with food — it is preferably taken on an empty stomach. It colours urine, sweat, saliva, tears and sputum orange-red and can permanently stain soft contact lenses: warn every patient.

• Dose-dependent: orange secretions, nausea, anorexia, diarrhoea; hepatotoxicity.
• Immunological (dose-independent): urticaria, flu-like syndrome, thrombocytopenia, haemolysis and renal failure — more frequent with intermittent dosing or when rifampicin is restarted after a long gap; NTEP advises such patients should never be rechallenged.
• Pregnancy: safe; give vitamin K to the newborn of a mother on rifampicin because of the risk of postnatal haemorrhage.
• Bedaquiline interaction: co-administration with rifampicin reduces bedaquiline exposure by about 52%.

Ethambutol eye toxicity is the reason for baseline and periodic visual acuity, colour vision and visual field testing. Early changes are reversible if the drug is stopped promptly, but irreversible blindness has been reported, so patients who cannot report visual symptoms (very young children, people with dementia) need particular caution. Ethambutol is considered safe in pregnancy.

Isoniazid, rifampicin and pyrazinamide are the hepatotoxic first-line drugs, and StatPearls also lists hepatotoxicity for ethambutol. Isoniazid liver injury is hepatocellular, with ALT and AST that can exceed 10 times the upper limit of normal; about 10% of such cases progress to acute liver failure.

1. Baseline LFTs in patients at higher risk — alcohol use, viral hepatitis B or C, abnormal baseline results — and repeat after 2–4 weeks; check LFTs promptly in anyone with symptoms of hepatitis.
2. If total bilirubin exceeds 3 mg/dL and liver enzymes exceed 5 times the upper limit of normal, stop isoniazid and the other anti-TB drugs.
3. If bilirubin is below 3 mg/dL and enzymes below 5 times normal, therapy can continue with enzymes rechecked in 3 days.
4. Once enzymes return to baseline (or below twice normal), reintroduce the potentially hepatotoxic drugs one at a time with careful monitoring.

Bedaquiline, a diarylquinoline, works on energy metabolism rather than the cell wall or nucleic acids: it binds subunit c of mycobacterial ATP synthase and stops ATP generation. It binds mycobacterial ATP synthase with more than 20,000 times the affinity it has for the human mitochondrial enzyme, which explains its selectivity. It is a core drug in the all-oral MDR-TB regimens used in India.

• QT prolongation is the main safety concern — additive with fluoroquinolones, macrolides and clofazimine, so ECG monitoring is needed.
• Metabolised by CYP3A4: rifampicin lowers bedaquiline exposure and strong CYP3A4 inhibitors such as ketoconazole raise it.
• Other reported effects include rash, pruritus, hyperuricaemia, haemoptysis and raised transaminases.