What are the side effects of tuberculosis (TB) medications?

Side Effects of Tuberculosis Medications

TB medications cause a range of organ-specific toxicities that require systematic monitoring, with hepatotoxicity being the most serious and common adverse effect across multiple first-line drugs, particularly when isoniazid, rifampicin, and pyrazinamide are used together. 1

First-Line TB Drug Side Effects

Isoniazid

• Hepatotoxicity is the primary concern, with incidence of 0.5-1% that increases significantly with age and is higher in females 1
• Peripheral neuropathy occurs and can be prevented with pyridoxine 10 mg daily 1
• Lupus erythematosus syndrome, drowsiness, and mood changes may develop 1
• Transient liver enzyme elevations during the first weeks of treatment are common but do not always progress to hepatitis 1
• Alcohol consumption and pre-existing hepatitis are major risk factors for hepatotoxicity 1
• Drug interactions include increased serum levels of phenytoin and carbamazepine, requiring dose adjustments 1

Rifampicin

• Drug interactions are the most clinically significant issue due to potent induction of hepatic enzymes, particularly CYP3A4 1, 2
• Reduces effectiveness of oral contraceptives, methadone, warfarin, corticosteroids, and other hepatically metabolized drugs 1, 2
• Hepatitis occurs but is less common than with isoniazid 1
• Thrombocytopenia, abdominal distress, and diarrhea may occur 1
• "Flu-like" syndrome (fever, chills, headache) is more common with intermittent dosing regimens 1
• Thrombocytopenic purpura, hemolysis, severe renal failure, and shock can occur, particularly with intermittent administration at doses >600 mg 1
• Orange discoloration of body fluids is expected 2

Pyrazinamide

• Hepatotoxicity is the most serious adverse effect, though rare, it can be lethal 1
• Pyrazinamide has the highest incidence of major adverse effects at 1.48 per 100 person-months of exposure compared to other first-line drugs 3
• Arthralgia or arthritis due to hyperuricemia is common but manageable 1
• Rash and abdominal distress occur 1
• Risk increases with age over 60 years and in patients born in Asia 3

Ethambutol

• Optic neuritis is the major concern, which is dose-dependent and can be irreversible 1, 4
• Monthly visual acuity testing is mandatory when dosing exceeds 15 mg/kg/day 4
• Patients must report any visual changes immediately, including blurred vision 4
• Abdominal distress may occur 1
• Testing should use Snellen eye charts with specific criteria for significant visual decline 4

Streptomycin

• Ototoxicity manifesting as hearing loss, ataxia, and nystagmus 1
• Nephrotoxicity with azotemia and proteinuria 1
• Eosinophilia and serum electrolyte abnormalities 1

Combined Hepatotoxicity Risk

When isoniazid and rifampicin are used together, hepatitis occurs in 3-4% of patients, typically appearing within the first 2 weeks of treatment 1

Second-Line TB Drug Side Effects

Cycloserine

• Psychosis and seizures occur in up to 16% at 500 mg twice daily 5
• Can exacerbate underlying mental illness 5
• Mood and cognitive deterioration are common 1
• Pyridoxine 100-200 mg/day should be added to reduce neurotoxic effects 5

Ethionamide

• Neurotoxicity including anxiety, depression, and psychosis in 1-2% with short courses, higher with prolonged treatment 5
• Makes diabetes more difficult to manage 5
• Hepatotoxicity requiring baseline and monthly liver function tests 5

Fluoroquinolones (Ofloxacin, Ciprofloxacin)

• Abdominal distress, nausea, bloating, diarrhea 1
• Rash and edema with ofloxacin 1
• Mood and cognitive deterioration, psychosis, and seizures with ciprofloxacin 1

Aminoglycosides (Amikacin, Kanamycin)

• Abdominal distress, headache, anxiety, tremulousness 1
• Thrush and drug interactions 1

Capreomycin

• Abdominal distress, dysgeusia, diarrhea 1
• Hepatitis and arthralgia 1

High-Risk Populations

Specific patient groups require heightened monitoring:

• Female sex increases risk with adjusted hazard ratio of 2.5 3
• Age over 60 years increases risk with adjusted hazard ratio of 2.9 3
• Asian birthplace increases risk with adjusted hazard ratio of 2.5 3
• HIV-positive status increases risk with adjusted hazard ratio of 3.8, particularly for rifabutin toxicity (arthralgias, uveitis, leukopenia) when combined with protease inhibitors or NNRTIs 1, 3
• HIV-infected patients have higher predisposition to isoniazid-related peripheral neuropathy 1

Monitoring Strategy

Monthly clinical evaluation is mandatory to monitor treatment response, adherence, and medication side effects 1

• During early therapy, evaluations should occur every 2 weeks 1
• Monthly liver function tests are essential, especially with hepatotoxic drug combinations 5
• Monthly visual acuity testing when ethambutol dose exceeds 15 mg/kg/day 4
• Weight should be recorded monthly 1
• Monthly cultures help identify early treatment failure 1

Critical Management Principles

Nausea and vomiting are common but not always treatment-limiting unless liver toxicity or increased intracranial pressure is present 1

• Can be managed by changing dosing schedule, giving medications with small snack, or premedicating with antiemetics (noting QT prolongation risk) 1

Drug discontinuation occurs in up to 10% of patients due to adverse effects 6

Side effects requiring immediate drug cessation:

• Progressive visual acuity decline with ethambutol 4
• Symptomatic hepatitis with unusual fatigue, anorexia, nausea, vomiting, dark urine, or jaundice 2
• Severe neuropsychiatric symptoms with second-line agents 5