Ethionamide, an antitubercular drug used to treat tuberculosis (TB), was developed in the mid-20th century and later introduced into clinical practice as a second-line agent, particularly for drug-resistant TB. Its history is characterized by its effectiveness against Mycobacterium tuberculosis, especially in cases resistant to first-line drugs, but also by its notable adverse effect profile, including gastrointestinal intolerance and hepatotoxicity, which limit its widespread use.
Ethionamide is a thioamide derivative that acts by inhibiting mycolic acid synthesis, an essential component of the mycobacterial cell wall. It is primarily used in multidrug-resistant tuberculosis (MDR-TB) regimens and is often included in combination therapy to prevent the development of resistance. Its clinical use requires careful monitoring due to side effects and the need for adherence in long-term TB treatment programs.
BRAND NAMES
Trecator – widely recognized internationally.
Ethion – used in some regions.
Etin – available in certain countries.
MECHANISM OF ACTION
Ethionamide is a prodrug that requires activation by the mycobacterial enzyme EthA, a flavin monooxygenase. Once activated, it inhibits the synthesis of mycolic acids, which are essential components of the mycobacterial cell wall. By disrupting mycolic acid production, ethionamide weakens the cell wall, impairing bacterial growth and survival.
PHARMACOKINETICS
Absorption
Ethionamide is well absorbed after oral administration, with bioavailability of approximately 70–80%. Peak plasma concentrations are usually reached 2–4 hours after ingestion.
Distribution
Ethionamide has a moderate volume of distribution, approximately 1–1.5 L/kg, indicating it distributes well into body tissues. It penetrates effectively into lungs, liver, kidneys, and spleen, which are key sites for Mycobacterium tuberculosis infection.
Metabolism
Ethionamide is extensively metabolized in the liver, primarily through oxidation and S-oxidation pathways. Its metabolism produces several inactive metabolites, which are then excreted mainly via the kidneys.
Elimination
Ethionamide and its metabolites are primarily excreted by the kidneys. Approximately 30–50% of the drug is eliminated unchanged, while the remainder is excreted as inactive metabolites.
PHARMACODYNAMICS
Ethionamide and its metabolites are primarily excreted by the kidneys. Approximately 30–50% of the drug is eliminated unchanged, while the remainder is excreted as inactive metabolites. The elimination half-life of ethionamide is roughly 2–3 hours, though it may be prolonged in patients with renal impairment, necessitating careful monitoring and possible dose adjustment. Minimal biliary excretion occurs.
ADMINISTRATION
Ethionamide is administered orally in the form of tablets, typically 250 mg per tablet. It is usually taken once or twice daily, depending on the prescribed dose and treatment regimen.
DOSAGE AND STRENGTH
Ethionamide is commonly available in 250 mg oral tablets and is typically prescribed at a dose of 15–20 mg/kg per day for adults, either as a single daily dose or divided into two doses, with a maximum of 1 g per day. Pediatric dosing is also weight-based, generally within the same range, and should be adjusted according to age and tolerance.
DRUG INTERACTIONS
Ethionamide can interact with other medications, primarily due to its effects on the liver and nervous system. Co-administration with hepatotoxic drugs such as isoniazid, rifampicin, pyrazinamide, or acetaminophen may increase the risk of liver injury, necessitating regular monitoring of liver function.
FOOD INTERACTIONS
Ethionamide can be taken with or without food, but taking it with meals may help reduce gastrointestinal discomfort, which is a common side effect. Food may slightly delay absorption, but it does not significantly affect the overall bioavailability of the drug.
CONTRAINDICATIONS
Ethionamide is contraindicated in patients with known hypersensitivity to the drug or any of its components. It should not be used in individuals with severe hepatic impairment, as the drug is extensively metabolized in the liver and may cause hepatotoxicity.
SIDE EFFECTS
Gastrointestinal effects: nausea, vomiting, abdominal pain, loss of appetite
Hepatotoxicity: elevated liver enzymes, liver injury (rare but serious)
Peripheral neuropathy: tingling, numbness, or burning sensation in hands and feet
Central nervous system effects: dizziness, depression, psychosis, headache
Endocrine effects: hyperglycemia, which may worsen diabetes
Allergic reactions: rash, itching, fever (uncommon)
Other effects: metallic taste, hypothyroidism (rare)
OVER DOSAGE
Overdosage of ethionamide can result in severe toxicity affecting multiple organ systems, including gastrointestinal symptoms such as nausea, vomiting, abdominal pain, and diarrhea; hepatic effects like elevated liver enzymes and, in rare cases, acute hepatotoxicity; and neurological manifestations such as peripheral neuropathy, dizziness, confusion, or even seizures and psychosis.
TOXICITY
Ethionamide toxicity is primarily dose-related and can affect multiple organ systems. The most significant toxicities include hepatotoxicity, which may present as elevated liver enzymes or, rarely, severe liver injury, and peripheral neuropathy, causing tingling, numbness.
