Isoniazid (Adverse effects)

Isoniazid is an antibiotic used in the treatment of tuberculosis, acting as a potent bactericidal agent of Mycobacterium tuberculosis. Its metabolism, especially related to NAT2 (N-acetyltransferase 2) genotype, may influence its efficacy and risk of adverse effects, such as hepatotoxicity.

Tuberculosis is one of the infectious diseases that causes the most deaths in the world, about 1.6 million annually. Treatments with first-line anti-tuberculosis drugs such as rifampicin, isoniazid, pyrazinamide and ethambutol are generally effective, however, the development of drug resistance has significantly affected the success of this treatment.

Introduced in 1952, isoniazid is characterized by its good tolerability and low cost. As previously described, antituberculosis drugs cause the death of the infectious agent and therefore have a bactericidal effect. In the case of isoniazid, the drug has a high early bactericidal activity, reducing the bacterial load by 90-95% in the first couple of days of treatment.

MECHANISM OF ACTION

Isoniazid is an antibiotic used mainly in the treatment and prevention of tuberculosis. This drug, one of the most effective first-line drugs against Mycobacterium tuberculosis, inhibits the synthesis of mycolic acid, an essential component of the bacterium's cell wall, resulting in its death.

CONTRAINDICATIONS

Isoniazid should not be used in patients with known hypersensitivity to the active ingredient or to any of its excipients. It should also not be used in patients with severe hepatic insufficiency.

This drug shows undesirable interactions with carbamazepine and disulfiram, so their simultaneous use is not recommended. In addition, caution is recommended in case of combining isoniazid with other compounds such as halogenated volatile anesthetics, coumarin anticoagulants, ketoconazole, glucocorticoids, phenytoin or rifampicin, among others.

SIDE EFFECTS

Although isoniazid is generally safe, it can cause adverse reactions, most of which are transient and low-grade. These include gastrointestinal effects, skin rashes and pruritus, and peripheral neuropathy, although the incidence of the latter is very low. However, one of the most serious adverse effects associated with antituberculosis drugs is hepatotoxicity, which can lead to treatment failure and increased mortality in patients with tuberculosis.

Isoniazid is metabolized in the liver primarily through acetylation by the enzyme N-acetyl transferase 2 (NAT2). The NAT2 gene, which encodes this enzyme, is highly polymorphic and shows wide variations in its expression and enzymatic activity among different individuals. Some genetic polymorphisms in the NAT2 gene have been associated with an increased plasma concentration of isoniazid and an increased risk of developing hepatotoxicity.

BRAND NAMES

Isoniazid is marketed under a multitude of names, including:

  • Isonarif®
  • Isaotamine®
  • Rifamate®
  • Rifater®

Genes analyzed

NAT2

Bibliography

O'Connor C, Patel P, Brady MF. Isoniazid. 2024 Feb 16. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan–. PMID: 32491549.

Pourmohamadi N, et al. Association of Cytochrome P450 2E1 and N-Acetyltransferase 2 Genotypes with Serum Isoniazid Level and Anti-Tuberculosis Drug-Induced Hepatotoxicity: A Cross-Sectional Study. Iran J Med Sci. 2023 Sep;48(5):474-483.

Sileshi T, Telele NF, Burkley V, et al. Correlation of N-acetyltransferase 2 genotype and acetylation status with plasma isoniazid concentration and its metabolic ratio in ethiopian tuberculosis patients. Sci Rep. 2023 Jul 15;13(1):11438.

Verma R, da Silva KE, Rockwood N, et al. A Nanopore sequencing-based pharmacogenomic panel to personalize tuberculosis drug dosing. medRxiv [Preprint]. 2023 Sep 10:2023.09.08.23295248.

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