## Most Common Adverse Effect of First-Line Antitubercular Drugs **Key Point:** Hepatotoxicity is the most common and clinically significant adverse effect among first-line antitubercular agents, occurring in 1–5% of patients on standard therapy. ### Causative Agents The three hepatotoxic first-line drugs are: 1. **Isoniazid (INH)** — most hepatotoxic; dose-dependent and idiosyncratic reactions 2. **Rifampicin (RIF)** — enzyme inducer; hepatotoxicity rare but severe when occurs 3. **Pyrazinamide (PZA)** — hyperuricemia and hepatotoxicity; risk increases with dose and duration **Clinical Pearl:** Drug-induced liver injury (DILI) from TB drugs typically manifests as: - Elevated transaminases (ALT > AST in most cases) - Jaundice (if severe) - Onset usually within first 2–8 weeks of therapy - Risk factors: age >35 years, female sex, malnutrition, concurrent HIV, alcohol use, pre-existing liver disease ### Monitoring Strategy | Baseline | During Therapy | Action | |----------|---|---| | LFTs (AST, ALT, bilirubin) | Monthly for first 2 months | Stop if ALT >3× ULN + symptoms | | HBsAg/Anti-HCV if risk factors | If jaundice develops | Investigate and modify regimen | **High-Yield:** Hepatotoxicity is the primary reason for treatment interruption and regimen modification in TB therapy. INH + RIF + PZA combination carries higher hepatotoxicity risk than any single agent. **Mnemonic: "HIP" drugs cause Hepatotoxicity** — Isoniazid, Pyrazinamide, plus Rifampicin (when combined). ### Why Other Options Are Less Common - **Peripheral neuropathy:** Primarily from INH (B6 deficiency); preventable with pyridoxine supplementation; less frequent than hepatotoxicity - **Ototoxicity:** Mainly from streptomycin (second-line agent, not first-line); rare with standard regimen - **Hyperuricemia:** Occurs with PZA but is asymptomatic in most; gout is rare; less clinically significant than hepatotoxicity
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