What are the first-line antitubercular (anti-tuberculosis) drugs and their common side effects?

First-Line Antitubercular Drugs and Their Common Side Effects

The standard first-line antitubercular drugs are isoniazid, rifampin, pyrazinamide, and ethambutol, each with distinct and potentially serious side effects that require careful monitoring throughout treatment. 1

First-Line Antitubercular Drugs

1. Isoniazid (INH)

• Mechanism: Bactericidal agent with potent early bactericidal activity
• Dosage: 300 mg daily for adults (5-10 mg/kg) 1
• Common side effects:
  • Peripheral neuropathy (preventable with pyridoxine 25-50 mg/day) 1
  • Hepatotoxicity (major hepatotoxin) 2
  • Mental health changes (depression, psychosis) 3
  • Skin rash 3

2. Rifampin (RIF)

• Mechanism: Bactericidal agent that inhibits RNA synthesis
• Dosage: 600 mg daily for adults (10 mg/kg) 1
• Common side effects:
  • Orange discoloration of body fluids (urine, tears, sweat)
  • Hepatotoxicity (rare when used alone, but enhances isoniazid hepatotoxicity) 2
  • Drug interactions (potent inducer of cytochrome P450 enzymes) 3
  • Thrombocytopenia
  • Flu-like syndrome (rare)

3. Pyrazinamide (PZA)

• Mechanism: Bactericidal agent active in acidic environments
• Dosage: 15-30 mg/kg daily (maximum 2g/day) 4
• Common side effects:
  • Hepatotoxicity (major hepatotoxin, especially late-onset) 2
  • Hyperuricemia and gout 3
  • Arthralgias 3
  • Photosensitive dermatitis 3
  • Gastrointestinal upset 3

4. Ethambutol (EMB)

• Mechanism: Bacteriostatic agent that inhibits cell wall synthesis
• Dosage: 15-20 mg/kg daily 3, 1
• Common side effects:
  • Retrobulbar neuritis (dose-related, manifested as decreased visual acuity or red-green color discrimination) 3
  • Peripheral neuritis (rare) 3
  • Cutaneous reactions (0.2-0.7% of patients) 3

Monitoring for Side Effects

Hepatotoxicity Monitoring

• Two patterns of hepatotoxicity can occur during treatment 2:

  1. Early onset (within first 15 days): Likely due to rifampin-enhanced isoniazid toxicity
  2. Late onset (after 1 month): Possibly related to pyrazinamide toxicity, generally has poorer prognosis

• Recommended monitoring:

  • Baseline liver function tests before starting treatment
  • Regular monitoring of liver enzymes, especially in high-risk patients
  • Stop all hepatotoxic drugs (INH, RIF, PZA) if transaminases exceed 3x upper limit of normal with symptoms or 5x without symptoms 3

Visual Monitoring for Ethambutol

• Baseline visual acuity and color discrimination testing
• Monthly monitoring in patients on long-term therapy
• Risk of optic toxicity is minimal at standard dose of 15 mg/kg daily 3
• Use with caution in children whose visual acuity cannot be monitored (generally <5 years of age) 3

Special Considerations

Pregnancy

• Isoniazid, rifampin, and ethambutol are considered safe 3
• Pyrazinamide has limited safety data but is recommended by WHO when benefits outweigh risks 3
• Streptomycin should be avoided due to ototoxicity to the fetus 5
• Pyridoxine supplementation (10 mg/day) is recommended 5

Renal Disease

• Dose adjustments needed for ethambutol and metabolites of pyrazinamide 3
• For end-stage renal disease: PZA should be administered at reduced dose (25-35 mg/kg) three times weekly after dialysis 3
• Ethambutol should be given 8 hours before hemodialysis in acute renal failure 5

Hepatic Disease

• Patients with underlying liver disease require careful monitoring 3, 5
• Avoid pyrazinamide in patients with pre-existing liver test abnormalities 2
• Consider alternative regimens in severe liver disease

Pitfalls and Caveats

1. Never add a single drug to a failing regimen as this can lead to drug resistance 6

2. Rifampin interactions: As a potent enzyme inducer, rifampin can significantly affect the metabolism of many medications including oral contraceptives, antiretrovirals, and oral hypoglycemics 5

3. Pyridoxine supplementation: Always provide pyridoxine (vitamin B6) with isoniazid to patients at risk of neuropathy (pregnant women, HIV patients, diabetics, alcoholics, malnourished individuals, patients with chronic renal failure, and older adults) 1

4. Fixed-dose combinations may improve adherence but are not suitable for intermittent dosing regimens 3

5. Monitoring frequency: For hepatotoxicity, some experts recommend monitoring twice weekly during the first 2 weeks, every 2 weeks during the rest of the first 2 months, and monthly thereafter 2

By understanding these first-line drugs and their side effect profiles, clinicians can optimize tuberculosis treatment while minimizing adverse events and improving patient outcomes.