Pharmacology, Antimycobacterium

  1. Isoniazid (INH) (general info)
    • Interfere with mycolic acid synthesis
    • Most active drug against sensitive strains
    • Tab, syrup, injection
    • water soluble small molecule
    • similar to pyridoxine
    • In vitro bactericidal for most
    • Active against extra as well as intracellular
  2. INH-Mech of action
    prodrug --> activated form --> complex with AcpM and KasA --> mycolic acid

    • 1st enzyme: KatG mycobacterial catalase peroxidase from prodrug to active
    • INH blocks step to mycolic acid
  3. INH- resistance
    • mutations: over expression of inhA gene
    • mutation: KatG, no conversion of prodrug to active form)(often no cross resistance to ethionamide)
    • Mutation: in kasA
    • Possibility of mutant 1 in 10^6 single drug and 1 in 10^12 for 2 drugs
  4. INH-Pharmacokinetics
    • fast absorption in Gi
    • peak plasma 1-2 hr
    • CNS and CSF 20-100%
    • metabolized by acetylation (liver N-acetyl transferase) (depends on fast or slow acetylators
    • Excretion through urine
    • T1/2: 3 hr in slow acetylator (risk for neuropathy) 1 hr in rapid (risk for drug resistance)
  5. INH- toxicity
    • Fever and skin rashes
    • SLE: systemic lupus erythematosus
    • Isoniazid induced hepatitis (age dependent)
    • Peripheral neuropathy: with higher doses, more common in AIDS (avoid stavudine(NRTI)), malnourished, diabetes, slow acetylators. Fix with pyridoxine
    • CNS toxicity (very rare)
Card Set
Pharmacology, Antimycobacterium
Pharmacology, antimycobacterium