Prothionamide

Prothionamide is the propyl analogue of ethionamide and has the same activity, toxicity and role in regimens for rifampicin-resistant and multidrug-resistant tuberculosis. It is used where ethionamide is unavailable. It carries the same limiting nausea, vomiting, hepatitis and hypothyroidism.

Class. Thioamide; second-line antituberculosis drug.

Mechanism. A prodrug activated by EthA. The active form inhibits InhA and mycolic acid synthesis. Complete cross-resistance with ethionamide.

Pharmacokinetics. Well absorbed, peak at 1 to 3 hours, half life about 2 to 3 hours, extensive hepatic metabolism, good tissue and cerebrospinal fluid penetration.

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 target. - 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.

Main alternative. Ethionamide; do not give both.

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

Serious adverse effects. Hepatitis, hypothyroidism, neuropathy, optic neuritis, depression and psychosis, gynaecomastia and hypoglycaemia in diabetes.

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

Interactions. Additive hepatotoxicity with isoniazid, rifampicin and pyrazinamide; additive neurotoxicity with cycloserine; para aminosalicylic acid raises hypothyroidism risk.

Common prescribing errors. Starting at full dose, omitting thyroid and liver monitoring, and combining with ethionamide.

Special groups. - Pregnancy: avoid. - 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.

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

Monitoring. Liver tests monthly; TSH every 3 months; 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; treat overt hypothyroidism with levothyroxine.

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