Ethionamide

Ethionamide is a thioamide, a structural analogue of isoniazid, used as a companion drug in regimens for rifampicin-resistant and multidrug-resistant tuberculosis. It is poorly tolerated because of nausea, vomiting and metallic taste, and it causes hepatitis and hypothyroidism. Its role has diminished with newer oral drugs.

Class. Thioamide; second-line antituberculosis drug.

Mechanism. A prodrug activated by the monooxygenase EthA. The active form inhibits InhA and mycolic acid synthesis. inhA promoter mutations cause cross-resistance with isoniazid.

Pharmacokinetics. Well absorbed, peak at 1 to 3 hours, half life 2 to 3 hours, good tissue and cerebrospinal fluid penetration. Extensively hepatically metabolised, with inactive metabolites in urine.

Rifampicin-resistant and multidrug-resistant tuberculosis (adults).

• 15 to 20 mg/kg daily; usual 500 to 750 mg daily; maximum 1000 mg daily.
• Titration: start 250 mg daily and increase every 3 to 7 days to the target dose.
• Frequency: single bedtime dose or two divided doses.
• Loading dose: none. Maintenance dose: 500 to 750 mg daily.
• Duration: set by the regimen, often 18 to 20 months.

Children. 15 to 20 mg/kg daily, maximum 1000 mg daily.

Pyridoxine cover. Pyridoxine 50 mg daily to reduce neuropathy risk.

Main alternative. Prothionamide, which has near-identical activity; do not give both.

Antiemetic cover. An antiemetic before the dose, such as ondansetron, makes full doses tolerable.

Contraindications. Severe liver disease, hypersensitivity and first-trimester pregnancy where alternatives exist.

Serious adverse effects. Hepatitis, hypothyroidism (especially with para aminosalicylic acid), peripheral neuropathy, optic neuritis, depression and psychosis, gynaecomastia, hypoglycaemia and loss of glycaemic control in diabetes.

Common adverse effects. Nausea, vomiting, metallic taste, hypersalivation, anorexia and abdominal pain.

Interactions. Additive hepatotoxicity with isoniazid, rifampicin and pyrazinamide. Additive central nervous system toxicity with cycloserine. Para aminosalicylic acid raises hypothyroidism risk. Alcohol may cause psychosis.

Common prescribing errors. Starting at full dose, omitting thyroid checks, giving both ethionamide and prothionamide, and missing hypoglycaemia in diabetes.

Special groups.

• Pregnancy: avoid; animal teratogenicity and worsening nausea of pregnancy.
• Breastfeeding: limited data.
• Children: 15 to 20 mg/kg with antiemetic cover.
• Older adults: usual dose; monitor liver and thyroid tests.
• Kidney impairment: with CrCl under 30 mL/min, give 250 to 500 mg daily.
• Liver impairment: avoid in severe disease.

Formulations. Tablets 250 mg.

Administration. With food or at bedtime. Give the bigger dose at night.

Baseline. Liver tests, TSH, glucose and pregnancy test.

Monitoring. Liver tests monthly; TSH every 3 months (and symptoms); glucose in diabetes; neuropathy and mood at each visit.

Stopping thresholds. Stop for ALT over three times the upper limit of normal with symptoms, or over five times without; levothyroxine is started for overt hypothyroidism rather than stopping the drug.

Referral and escalation. Specialist review for hepatitis, uncontrolled vomiting, thyroid disease or psychiatric symptoms.