Antitubercular Drug Adverse Effects
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Direct answer
Antitubercular drug adverse effects arise mainly from isoniazid, rifampicin and pyrazinamide, and drug-induced hepatotoxicity is the commonest serious reaction that prompts interruption. Isoniazid causes peripheral neuropathy that pyridoxine prevents, ethambutol causes optic neuritis that needs visual acuity and colour vision monitoring, and streptomycin causes eighth-nerve ototoxicity and nephrotoxicity. Management rests on identifying the offending drug, stopping the regimen during severe reactions and reintroducing agents one at a time under supervision.
What you must remember
- Isoniazid neuropathy: a peripheral neuropathy from interference with pyridoxine metabolism, prevented by pyridoxine supplementation and more likely in diabetes, alcohol use, malnutrition and renal failure.
- Rifampicin: orange body fluids, flu-like syndrome, thrombocytopenia and enzyme induction that reduces the efficacy of oral contraceptives and warfarin.
- Ethambutol: dose-related optic neuritis with loss of red-green colour discrimination; visual acuity and colour testing are done at baseline and during therapy.
- Pyrazinamide: hyperuricaemia that can precipitate gout and dose-related hepatotoxicity; the dose is adjusted in renal failure.
- Streptomycin: eighth-nerve ototoxicity, with vestibular damage more common than cochlear, and nephrotoxicity; it is contraindicated in pregnancy because it can damage the fetal eighth nerve.
- Hepatotoxicity thresholds: therapy is stopped when transaminases exceed about five times the upper limit of normal, or three times with symptoms or raised bilirubin, per national guidance.
- Rechallenge: drugs are reintroduced one at a time under monitoring, and books differ on the order, so the local programme protocol governs practice.
A worked example of drug-induced liver injury
A 40-year-old woman on the standard intensive-phase regimen of rifampicin, isoniazid, pyrazinamide and ethambutol develops nausea and jaundice on day 12. Her alanine transaminase is about eight times the upper limit of normal and bilirubin is raised.
- Stop the regimen: The regimen is stopped at once, and viral hepatitis serology, a liver ultrasound and an alcohol history are checked to exclude other causes.
- Hold the most hepatotoxic agent: Pyrazinamide is held until the cause is clarified, because it is the most hepatotoxic agent in the combination.
- Reintroduce agents one at a time: Once transaminases fall to normal, rifampicin and then isoniazid are reintroduced separately, with liver tests after each step, and pyrazinamide is reintroduced last, if at all.
- Document the sequence: Each step is documented, because the sequence determines the agent most likely to have caused the injury.
- Choose an alternative if needed: If a drug-resistant or alternative regimen is needed, the programme chooses agents such as a fluoroquinolone from its second-line options, and streptomycin is avoided if she is pregnant.
- Counsel the patient: She is told to report jaundice, dark urine or unexplained fatigue at once, since early reporting lets the injury be caught before it becomes severe.
Where the exam tries to catch you
Adverse-effect questions turn on which drug causes which reaction and how drugs are reintroduced.
- Trap: Treating isoniazid neuropathy with a steroid or ignoring it. Correct: Pyridoxine supplementation alone is the answer.
- Trap: Forgetting isoniazid hepatotoxicity in drinkers and older patients. Correct: Isoniazid hepatotoxicity is age-related and more frequent with alcohol use.
- Trap: Testing ethambutol toxicity in children who cannot report symptoms. Correct: Optic nerve monitoring needs a patient who can report colour changes and visual acuity, so ethambutol is used with caution in very young children who cannot be tested, and weight-band doses follow the national programme.
- Trap: Calling pyrazinamide arthralgia gout by default. Correct: Pyrazinamide arthralgia is often non-gouty, so serum urate and, if needed, joint aspiration decide the diagnosis.
Rifampicin turns body fluids orange and is harmless, although contact lenses may be permanently stained. Any new neuropathy or visual change should prompt a regimen review and a dose check against body weight and renal function, not automatic withdrawal of every drug.
Frequently asked questions
Which anti-tubercular drug causes peripheral neuropathy and how is it prevented?
Isoniazid causes peripheral neuropathy by interfering with pyridoxine metabolism, and it is prevented by supplementing pyridoxine alongside the regimen. The risk is higher in diabetics, alcohol users, malnourished patients, pregnant women and those with renal failure.
What eye test monitors ethambutol toxicity?
Visual acuity and red-green colour discrimination testing monitor ethambutol-induced optic neuritis, ideally with a baseline examination before starting. Ethambutol toxicity is dose-related and often reversible if the drug is stopped early.
When should anti-tubercular therapy be stopped for hepatotoxicity?
Anti-tubercular therapy is stopped when transaminases rise above about five times the upper limit of normal, or above three times with symptoms or raised bilirubin, following national guidance. The drugs are then reintroduced one at a time under monitoring.
Why should streptomycin be avoided in pregnancy?
Streptomycin crosses the placenta and can cause congenital eighth-nerve ototoxicity in the fetus. It is therefore contraindicated in pregnancy, and alternative agents are chosen when treating drug-resistant tuberculosis in a pregnant woman.