Isoniazid

Summary

Isoniazid (INH)  is an antibiotic commonly used to treat tuberculosis by inhibiting the synthesis of mycolic acid. It is activated in the body by the enzyme catalase-peroxidase, also called KatG. Remember that KatG is encoded upstream by a gene, also called KATG. Isoniazid is metabolized in the liver through acetylation, so the side effects of isoniazid will be more prevalent in slow acetylators. Isoniazid often causes a vitamin B6 deficiency, so vitamin B6 supplements are often taken along with the drug. Isoniazid inhibits CYP450 enzymes, so it can cause drug-to-drug interactions with other medications that are metabolized by the CYP enzymes, such as  warfarin and theophylline. Other adverse side effects include a lupus-like reaction, hepatotoxicity, and an anion gap metabolic acidosis.

Key Points

• Isoniazid (INH)
  • Mechanism
    • Impairs synthesis of mycolic acid
      • Mycolic acid is a key component of mycobacterial cell wall
    • Must be activated by bacterial catalase-peroxidase (encoded by KatG)
      • Isoniazid is an inactive pro-drug that must be converted into its active drug by an mycobacterial enzyme
  • Clinical Use
    • Mycobacteria (especially M. tuberculosis)
      • Major component of RIPE therapy for active TB
      • Monotherapy for latent TB, TB prophylaxis
  • Adverse Effects
    • Side effects more common in slow acetylators
      • INH is metabolized by acetylation, so drug has higher effective dosing and longer half-life in slow acetylators
    • Vitamin B6 (pyridoxine) deficiency
      • Isoniazid inhibits pyridoxine phosphokinase, which normally activates vitamin B6 into its active form (PLP)
      • Presents as peripheral neuropathy, sideroblastic anemia, seizures (in high doses)
      • Many patients on INH will require vitamin B6 supplementation
    • Inhibits CYP450 Enzymes
      • May lead to drug interactions (e.g. warfarin, theophylline)
    • Drug-induced lupus-like reaction
    • Hepatotoxicity
    • Anion gap metabolic acidosis
  • Resistance
    • Mutations cause underexpression of KatG
      • Reduces catalase-peroxidase, which prevents conversion of drug into active form
    • Mutations of binding site on mycolic acid synthase enzyme is also possible