PHARMACOKINETICS

Isoniazid is usually given orally and is well absorbed from the gut. The drug is widely distributed to tissues and reaches intracellular concentrations sufficiently high to be effective against organisms inside cells and caseous lesions.

Isoniazid is extensively metabolized, and the parent compound and its metabolites are excreted in the urine. The primary metabolite, acetylisoniazid, is formed by conjugation of acetate with isoniazid in a reaction catalyzed by acetyltransferase, an enzyme whose activity is genetically determined. Slow acetylation is an autosomal recessive trait, and persons with the slow phenotype are homozygous for the slow allele. Persons with the fast phenotype are either heterozygous or autosomal dominant. Because of the different rates of acetylation of isoniazid, persons with the fast phenotype have lower plasma isoniazid concentrations than do persons with the slow phenotype (Fig. 41–1)

Figure 41–1 Bimodal distribution of plasma isoniazid concentrations. Plasma concentrations of isoniazid were measured 2 hours after the administration of a single 300-mg dose of isoniazid to each member of a general population of human subjects. Subjects with the fast acetylation phenotype showed lower plasma drug concentrations than did subjects with the slow acetylation phenotype.

The prevalence of phenotypes varies from population to population. The slow phenotype predominates in some Middle Eastern populations, whereas the fast phenotype predominates in Japanese populations. In the United States, about half the population exhibits each phenotype.

A small amount of acetylisoniazid is converted to isonicotinic acid and acetylhydrazine. Investigators believe that acetylhydrazine is responsible for the hepatic toxicity of the drug.

MECHANISM

Isoniazid acts by inhibiting the synthesis of mycolic acid. This acid is the mycobacterial cell wall component responsible for the acid-fast staining property of mycobacteria.

Isoniazid is activated by mycobacterial catalase-peroxidase, an enzyme encoded by the katG gene. The hydrazine moiety of isoniazid reduces the ferric component of catalase-peroxidase, and the reduced (ferrous) enzyme combines with oxygen to form an oxyferrous enzyme complex. This complex ultimately interacts with the target enzyme, a long-chain enoyl reductase involved in the synthesis of mycolic acid.

SPECTRUM AND INDICATIONS

Isoniazid is bactericidal against sensitive strains of M. tuberculosis and some strains of M. kansasii. It has little activity against M. avium-intracellulare and is not active against M. leprae or against most other bacteria.

Isoniazid is part of the standard four-drug regimen for TB for persons without known or suspected resistance to isoniazid (Table 41–2) These drugs are believed to kill different populations of TB bacilli, which include rapidly growing organisms and persistent nongrowing (stationary phase) bacteria. Isoniazid, together with rifampin and pyrazinamide, eradicates rapidly growing organisms during the first 2 months of therapy. During the next 4 months of treatment, isoniazid and rifampin act against persistent bacteria that revert to actively growing forms.

Table 41–2 Regimens for Treating Mycobacterial Infections

HIV = human immunodeficiency virus.

Isoniazid is also given to treat latent tuberculosis (formerly called prophylaxis) in persons with a positive reaction to the tuberculin skin test and who meet one of the following criteria: human immunodeficiency virus (HIV) positive; recently infected (conversion from a negative to a positive tuberculin skin test in the past 2 years); chest x-ray study showing nonprogressive tuberculous disease; predisposing conditions including illicit injected drug use, diabetes mellitus, immunosuppression, or certain diseases. The preferred duration of treatment for latent TB is 9 months, but 6 months may be sufficient in some cases. Rifampin can be used for prophylaxis if isoniazid is contraindicated or if the mycobacterial strain is known to be resistant to isoniazid (see Table 41–2).

Isoniazid is given to prevent TB in neonates and children who have had close contact with persons in whom active TB was recently diagnosed.

BACTERIAL RESISTANCE

Resistance to isoniazid is increasingly prevalent. This resistance is mediated primarily by mutations of the katG gene, which result in loss of the catalase-peroxidase enzyme required for activation of isoniazid.

ADVERSE EFFECTS

Isoniazid is fairly well tolerated by most patients, but it causes elevation of serum transaminase levels and potentially life-threatening hepatitis in some individuals. The risk of developing hepatitis during isoniazid therapy is low in persons under 35 years of age, is moderate in persons between 35 and 50 years of age, and is highest in persons over 50 years of age. Isoniazid treatment of latent TB (formerly called prophylaxis), however, appears to have a positive risk-benefit ratio in patients over 35 years of age if they are monitored appropriately for hepatotoxicity. Patients who have TB and are being treated with isoniazid should have their serum transaminase levels monitored periodically and should be told to inform their health care provider if they develop symptoms of hepatitis.

Isoniazid can also cause peripheral neuritis, with symptoms including paresthesias and numbness of the fingers and toes. This adverse effect is more likely to occur in individuals with the slow acetylator phenotype, because they have higher plasma concentrations of isoniazid. Peripheral neuritis is caused by a pyridoxine (vitamin B₆) deficiency resulting from direct inactivation of pyridoxine by the drug. It can be prevented or treated by administering pyridoxine supplements to patients who are taking isoniazid.

In rare circumstances, isoniazid causes toxic encephalopathy or seizures. Hematologic abnormalities, such as granulocytosis, anemia, or thrombocytopenia, can occur.