Ethionamide

Ethionamide is a second-line antitubercular antibiotic derived from isoniazid. It is used as part of combination therapy for tuberculosis, particularly in cases of drug resistance or intolerance to first-line medications. Because of tolerability and safety concerns, it is generally reserved for regimens with other active agents.

Mechanism of action and spectrum: Ethionamide is a thioamide prodrug that is activated by the mycobacterial enzyme EthA to a reactive metabolite. The activated form inhibits the fatty acid synthesis pathway responsible for mycolic acid production, a key component of the Mycobacterium tuberculosis cell wall. This disruption impairs bacterial growth and enhances the effectiveness of companion drugs. It is active against M. tuberculosis but is used within multidrug regimens due to potential toxicity and resistance.

Administration and pharmacokinetics: Ethionamide is administered orally and is variably absorbed. It is primarily metabolized in the liver and excreted in urine and feces. Dosing is typically twice daily and may be adjusted based on tolerability, hepatic function, and concomitant medications. Drug interactions are common; rifampin, for example, can induce hepatic enzymes and reduce ethionamide levels, potentially requiring dose adjustments.

Adverse effects and safety: The drug is associated with gastrointestinal upset, anorexia, and a characteristic metallic taste. More serious adverse effects include hepatotoxicity and neurotoxicity, such as peripheral neuropathy or seizures. Long-term use can be associated with hypothyroidism or goiter. Patients require monitoring of liver function and, when indicated, thyroid status. Ethionamide’s toxicity profile limits its use, making it a consideration chiefly in resistant tuberculosis regimens.