Isoniazid

Nomenclature
 Also known as INH
Structure

Chemical type and pharmacologic class

 Antibiotic
Uses
 Primary use is to treat tuberculosis, take for 9 months
 Almost always used in conjunction with another independently acting drug to combat
tuberculosis
Mechanism of action
Inhibits synthesis of mycolic acids, which are essential components of mycobacterial cell walls.
Drug-resistant mutants are present in susceptible mycobacterial populations at about 1/1million,
and since tuberculous lesions are often >10^8 bacilli, it is more effective and always
recommended to use two independently acting drugs.

Side effects
 Immunologic Reactions: Fever and skin rashes occasionally seen, induced systemic lupus
erythematosus has been reported
 Direct Toxicity: can induce hepatitis, the most common major toxic effect of isoniazid,
and this effect is more likely for older patients and patients who consume alcohol.
 Peripheral neuropathy: more likely to occur in slow acetylators and due to a relative
pyridoxine deficiency, can treat this by administration of pyridoxine
Contraindications
 Patients that develop severe hypersensitivity reactions, including drug-induced hepatitis
 Acute liver disease of any etiology
Clinically significant drug interactions
  Should not be administered with food, as bioavailability decreases with food
 Carbamazepine metabolism is slowed by isoniazid, so dosage adjustment should be made
 Ketoconazole: The AUC of ketoconazole may decrease up to 88% if co-administered
 Phenytoin: Isoniazid may increase serum levels of phenytoin
Pharmacokinetic considerations relevant to patient dosing

 Readily absorbed in the GI tract

 300 mg oral dose (5mg/kg in children) achieves peak plasma concentrations within 1-2
hours.
 Diffuses readily into all body fluids and tissues
 Metabolized by the liver via acetylation and dehydrazination
o Rapid acetylators have about 1/3 to ½ the plasma concentration of slow
acetylators
o This acetylation rate does not alter effectiveness when dosage is administered
daily
 Isoniazid metabolites are excreted in the urine.

Mycolic Acid Synthesis Pathway: Isoniazid inhibits FAS-II, a multi-unit, prokaryote-like

enzyme, so that long-chain fatty acid precursors for mycolic acid biosynthesis cannot occur.