Usage
Ethionamide is a second-line antitubercular drug, classified as a thioamide antibiotic. It is primarily prescribed for the treatment of multi-drug resistant tuberculosis (MDR-TB) in patients who cannot tolerate or whose Mycobacterium tuberculosis strains are resistant to first-line antitubercular drugs like isoniazid and rifampin. Its pharmacological classification is antibiotic.
Ethionamide inhibits mycolic acid synthesis, a crucial component of the mycobacterial cell wall. This disruption leads to impaired cell wall integrity and ultimately bacterial death.
Alternate Names
While “ethionamide” is the universally accepted generic name, it’s marketed under various brand names such as Trecator and Trecator SC. There aren’t widely recognized international or regional variations of the generic name itself.
How It Works
Pharmacodynamics: Ethionamide exerts its bactericidal or bacteriostatic effects (depending on concentration and organism susceptibility) by targeting mycolic acid synthesis, a critical step in mycobacterial cell wall formation. This inhibition disrupts cell wall integrity, leading to bacterial death.
Pharmacokinetics:
- Absorption: Oral absorption is erratic and may be affected by gastrointestinal issues associated with the drug.
- Metabolism: Primarily metabolized in the liver.
- Elimination: Excreted mainly through the kidneys.
Mode of Action: Ethionamide is a prodrug activated by the bacterial enzyme EthA, a monooxygenase, within Mycobacterium tuberculosis. The activated form inhibits the enzyme InhA, involved in mycolic acid biosynthesis, ultimately disrupting the mycobacterial cell wall.
Receptor Binding/Enzyme Inhibition: The activated form of ethionamide specifically inhibits the enoyl-ACP reductase enzyme (InhA), an enzyme essential for the synthesis of mycolic acids.
Dosage
Standard Dosage
Adults:
Initial dose: 250 mg orally once daily for 1-2 days, then increase to 250 mg twice daily for 1-2 days. Gradually titrate up to the highest tolerated dose, typically 15-20 mg/kg/day, not exceeding a maximum of 1 g/day, usually divided into 3-4 doses. Concomitant administration of pyridoxine (vitamin B6) is recommended to prevent peripheral neuropathy.
Children:
10-20 mg/kg/day, up to a maximum of 1g/day, often divided into 2 or 3 doses, or 15 mg/kg/day as a single dose. Use in children younger than 12 is generally not recommended except in cases of resistance to first-line therapy and severe disease.
Special Cases:
- Elderly Patients: No specific dosage adjustment is required, but close monitoring for adverse effects, particularly liver and gastrointestinal issues, is crucial.
- Patients with Renal Impairment: No dosage adjustment is generally necessary due to minimal renal excretion.
- Patients with Hepatic Dysfunction: Contraindicated in severe hepatic impairment. Use with extreme caution in mild to moderate hepatic impairment with close monitoring of liver function.
- Patients with Comorbid Conditions: Use with caution in patients with diabetes mellitus, hypothyroidism, or psychiatric illness.
Clinical Use Cases Ethionamide isn’t typically used in situations like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Its role is specific to treating drug-resistant tuberculosis as part of a multi-drug regimen.
Dosage Adjustments Dosage adjustments might be necessary in patients with hepatic or gastrointestinal issues, diabetes, or psychiatric illnesses. Regular monitoring of liver enzymes, blood glucose, and mental status is essential. Therapeutic drug monitoring may be considered for optimizing the dose.
Side Effects
Common Side Effects
Nausea, vomiting, diarrhea, abdominal pain, metallic taste, increased salivation, loss of appetite, stomatitis.
Rare but Serious Side Effects
Hepatitis (with or without jaundice), peripheral neuropathy, optic neuritis, mental disturbances (depression, psychosis, seizures), hypersensitivity reactions (rash, fever, joint pain).
Long-Term Effects Long-term use may lead to chronic liver disease, peripheral neuropathy, and other neurological problems.
Adverse Drug Reactions (ADR)
Severe cutaneous adverse reactions (SCARs) like Stevens-Johnson syndrome and toxic epidermal necrolysis.
Contraindications
Severe hepatic impairment, hypersensitivity to ethionamide.
Drug Interactions
Isoniazid (increased risk of neurotoxicity), cycloserine (increased risk of neurotoxicity and seizures), other hepatotoxic drugs, alcohol (increased risk of hepatotoxicity and psychiatric effects).
Pregnancy and Breastfeeding
Ethionamide is generally avoided during pregnancy due to potential teratogenic effects observed in animal studies. If the benefits outweigh the risks, its use may be considered. Excretion in human milk isn’t well-established. If ethionamide is used during breastfeeding, infants should be closely monitored for adverse events.
Drug Profile Summary
- Mechanism of Action: Inhibits mycolic acid synthesis in Mycobacterium tuberculosis, disrupting cell wall integrity.
- Side Effects: Nausea, vomiting, diarrhea, hepatotoxicity, peripheral neuropathy, psychiatric effects.
- Contraindications: Severe hepatic impairment, hypersensitivity.
- Drug Interactions: Isoniazid, cycloserine, other hepatotoxic drugs, alcohol.
- Pregnancy & Breastfeeding: Generally avoided in pregnancy; use with caution during breastfeeding.
- Dosage: Adults: up to 1 g/day; Children: 10-20 mg/kg/day.
- Monitoring Parameters: Liver function tests, blood glucose, neurological assessment.
Popular Combinations
Ethionamide is typically used in combination with other second-line anti-TB drugs tailored to each patient’s resistance profile and tolerability.
Precautions
Assess for pre-existing liver disease, diabetes, and psychiatric conditions. Close monitoring of liver function, blood glucose, and mental status is essential. Avoid alcohol. Pyridoxine supplementation is recommended.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Ethionamide?
A: Adults: Start with 250 mg/day and gradually increase to a maximum of 1 g/day, based on tolerability, usually divided into 3-4 doses. Children: 10-20 mg/kg/day up to a maximum of 1g/day.
Q2: What is the mechanism of action of Ethionamide?
A: Ethionamide inhibits mycolic acid synthesis, a crucial component of the mycobacterial cell wall.
Q3: What are the common side effects of Ethionamide?
A: Nausea, vomiting, diarrhea, metallic taste, and gastrointestinal upset are common.
Q4: Is Ethionamide safe to use in patients with liver disease?
A: Ethionamide is contraindicated in patients with severe liver disease and should be used cautiously in those with mild to moderate hepatic impairment. Close monitoring of liver function is necessary.
Q5: Can Ethionamide be used during pregnancy?
A: Ethionamide should generally be avoided during pregnancy due to potential teratogenic effects. The decision to use it should be made on a case-by-case basis, considering the risks and benefits.
Q6: How should Ethionamide be administered?
A: Ethionamide is administered orally, typically with food to reduce gastrointestinal upset.
Q7: What are the signs of Ethionamide-induced hepatotoxicity?
A: Jaundice, dark urine, abdominal pain, and persistent nausea and vomiting.
Q8: Can Ethionamide be used in children?
A: Yes, it can, but use in children under 12 is usually restricted to cases of drug-resistant TB and severe disease.
Q9: Does Ethionamide interact with other medications?
A: Yes, ethionamide interacts with certain other drugs like isoniazid, cycloserine, and other hepatotoxic agents, potentially increasing side effects.
Q10: Should Ethionamide be used alone to treat TB?
A: No, ethionamide should always be used in combination with other antitubercular drugs to prevent the development of resistance.
