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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
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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
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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
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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)
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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)
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