ISONIAZID (INH)

Characteristic:
 Small molecular weight: 137, soluble in water, the structural similarity to pyridoxine.
 In vitro, isoniazid inhibits most tubercle bacilli in a concentration of 0.2 mcg/mL or less
and is bactericidal for actively growing tubercle bacilli.
 It is less effective against atypical mycobacterial species.
 Isoniazid penetrates into macrophages and is active against both extracellular and
intracellular organisms.

Mechanism of Action
 Isoniazid inhibits synthesis of mycolic acids, which are essential components of
mycobacterial cell walls.
 Isoniazid is a prodrug that is activated by KatG, the mycobacterial catalase-peroxidase.
 The activated form of isoniazid forms a covalent complex with an acyl carrier protein
(AcpM) and KasA, a beta-ketoacyl carrier protein synthetase, which blocks mycolic acid
synthesis and kills the cell.

Basis of Resistance
Resistance to isoniazid is associated with:
 mutations resulting in overexpression of inhA, which encodes an NADH-dependent acyl
carrier protein reductase  express low-level isoniazid resistance and cross-resistance to
ethionamide.
 mutation or deletion of the katG gene  express high-level isoniazid resistance and often
are not cross-resistant to ethionamide.
 promoter mutations resulting in overexpression of ahpC, a putative virulence gene
involved in protection of the cell from oxidative stress;
 mutations in kasA.
Pharmacokinetics
 absorbed from the gastrointestinal tract, diffuses readily into all body fluids and
tissues.
 300-mg oral dose (5 mg/kg in children) achieves peak plasma concentrations of 3–5
mcg/mL within 1–2 hours.
 The concentration in the central nervous system and cerebrospinal fluid ranges between
20% and 100% of simultaneous serum concentrations.
 Metabolism, especially acetylation, by liver N-acetyltransferase.
 excreted mainly in the urine.
 The dose need not be adjusted in renal failure.

Clinical Uses
 Administration: oral, but can be given parenterally in the same dosage.
 Isoniazid as a single agent is also indicated for treatment of latent tuberculosis. The
dosage is 300 mg/d (5 mg/kg/d) or 900 mg twice weekly for 9 months.
 usual dosage : 5 mg/kg/d , a typical adult dose is 300 mg given once daily.
 Up to 10 mg/kg/d may be used for serious infections or if malabsorption is a problem.
 A 15 mg/kg dose, or 900 mg, may be used in a twice-weekly dosing regimen in
combination with a second antituberculous agent (eg, rifampin 600 mg).
 Pyridoxine, 25–50 mg/d, is recommended for those with conditions predisposing to
neuropathy, an adverse effect of isoniazid.

Adverse Reactions
The incidence and severity of untoward reactions to isoniazid are related to dosage and duration of
administration.

IMMUNOLOGIC REACTIONS
Fever and skin rashes are occasionally seen. Drug-induced systemic lupus erythematosus has
been reported.

DIRECT TOXICITY
 Common major toxic effect: hepatitis.
 Peripheral neuropathy in 10–20% patients given dosages greater than 5 mg/kg/d, due to
a relative pyridoxine deficiency. (Isoniazid promotes excretion of pyridoxine).
 Increasing phenytoin blood level and toxicity, because Isoniazid reduce its metabolism.