Usage
- Ethambutol + Isoniazid is prescribed for the treatment of drug-susceptible pulmonary and extrapulmonary tuberculosis (TB), primarily during the continuation phase. It is crucial to administer this combination alongside other antitubercular drugs in the initial phase of treatment to prevent the development of drug resistance.
- Pharmacological Classification: Antitubercular agents, specifically antibacterial agents.
- Mechanism of Action: Ethambutol inhibits arabinosyl transferases in mycobacteria, disrupting cell wall synthesis. Isoniazid inhibits mycolic acid synthesis, another essential component of the mycobacterial cell wall. The combination provides dual action against Mycobacterium tuberculosis.
Alternate Names
- This combination is not widely recognized by a specific international nonproprietary name (INN). It’s most commonly referred to as Ethambutol + Isoniazid or by the active ingredients’ names.
- Brand Names: Myrin™, Rifinah® (in combination with Rifampicin). Various other brand names may exist regionally.
How It Works
- Pharmacodynamics: Both drugs act synergistically to disrupt mycobacterial cell wall formation, leading to bacterial death. They are most effective against actively replicating bacilli.
- Pharmacokinetics:
- Ethambutol: Absorbed orally, reaching peak serum concentrations in 2-4 hours. It is primarily excreted renally, requiring dose adjustment in renal impairment.
- Isoniazid: Well-absorbed orally. Metabolized by acetylation in the liver, with significant interindividual variability in acetylation rates (“fast” and “slow” acetylators). Excreted in urine.
- Mode of Action: Ethambutol hinders arabinogalactan synthesis, a key component of mycobacterial cell walls, through inhibition of arabinosyl transferases. Isoniazid blocks mycolic acid synthesis, another crucial cell wall constituent, by interfering with the enoyl-acyl carrier protein reductase (InhA) enzyme. There is no direct receptor binding or neurotransmitter modulation.
- Elimination Pathways: Ethambutol is primarily excreted unchanged in urine. Isoniazid undergoes hepatic acetylation and is subsequently excreted in urine as metabolites.
Dosage
Standard Dosage
Adults:
- Ethambutol: 15-25 mg/kg orally once daily (max dose 2.5g/day).
- Isoniazid: 5 mg/kg orally once daily (max dose 300mg/day) or 15 mg/kg two or three times per week.
- Combination products such as Myrin™ exist with fixed doses, necessitating precise weight-based adjustments for individualized therapy.
Children:
- Ethambutol: 15-20 mg/kg orally once daily (not established for children under 6)
- Isoniazid: 10-15 mg/kg orally once daily (max 300mg/day) or 20-40 mg/kg twice weekly (max 900mg/dose).
Special Cases:
- Elderly Patients: Renal and hepatic function should be assessed, and dosage adjusted accordingly. Monitor for adverse reactions.
- Patients with Renal Impairment: Ethambutol dose reduction is necessary depending on creatinine clearance. Isoniazid dose may need adjustment for severe impairment.
- Patients with Hepatic Dysfunction: Close monitoring for hepatotoxicity is crucial for both drugs. Dosage adjustments may be needed, particularly for isoniazid.
- Patients with Comorbid Conditions: Diabetes, HIV, malnutrition, and alcoholism can increase the risk of adverse effects. Careful monitoring and dose modification may be required.
Clinical Use Cases
- Intubation, Surgical Procedures, Mechanical Ventilation, ICU Use, and Emergency Situations: Dosage adjustments are not specifically indicated for these scenarios. Standard TB treatment regimens should be followed, with individualized dosing and careful monitoring based on patient factors.
Dosage Adjustments:
- Renal and hepatic function must be assessed, and adjustments made as per guidelines. Slow acetylator status requires lower isoniazid doses. Concomitant medications may necessitate dosage modifications. Genetic polymorphisms influencing drug metabolism may also warrant personalized dosing.
Side Effects
Common Side Effects:
- Ethambutol: Ocular toxicity (blurred vision, color vision changes, optic neuritis), gastrointestinal upset.
- Isoniazid: Peripheral neuropathy (numbness, tingling), hepatotoxicity (nausea, vomiting, jaundice), drug-induced lupus.
Rare but Serious Side Effects:
- Ethambutol: Severe vision loss, allergic reactions.
- Isoniazid: Severe hepatitis, seizures, psychosis.
Long-Term Effects:
- Ethambutol: Permanent vision loss (rare).
- Isoniazid: Chronic liver damage.
Adverse Drug Reactions (ADR):
- Ethambutol: Optic neuritis, hypersensitivity reactions.
- Isoniazid: Hepatotoxicity, severe cutaneous reactions.
Contraindications:
- Hypersensitivity to ethambutol or isoniazid.
- Ethambutol: Pre-existing optic neuritis (unless clinically justified).
- Isoniazid: Acute liver disease, previous isoniazid-induced hepatitis.
Drug Interactions:
- Ethambutol: Aluminum hydroxide-containing antacids.
- Isoniazid: Disulfiram, para-aminosalicylic acid, cycloserine, tyramine-containing foods, alcohol, aluminum antacids. CYP450 enzyme interactions are possible.
Pregnancy and Breastfeeding:
- Both ethambutol and isoniazid cross the placenta and are present in breast milk.
- Generally considered safe for use during pregnancy and breastfeeding when benefits outweigh risks.
- Monitor infants for potential adverse effects.
- Pyridoxine supplementation is recommended for breastfeeding women taking isoniazid to prevent neonatal neuropathy.
Drug Profile Summary
- Mechanism of Action: Inhibits mycobacterial cell wall synthesis.
- Side Effects: Vision changes (ethambutol), peripheral neuropathy, hepatotoxicity (isoniazid).
- Contraindications: Hypersensitivity, optic neuritis (ethambutol), acute liver disease (isoniazid).
- Drug Interactions: Antacids, certain medications (e.g., disulfiram).
- Pregnancy & Breastfeeding: Generally safe, monitor infant.
- Dosage: Weight-based. See detailed section above.
- Monitoring Parameters: Liver function tests, visual acuity, color vision (for ethambutol), signs of peripheral neuropathy.
Popular Combinations:
- Ethambutol + Isoniazid is often used in combination with rifampicin and pyrazinamide, especially during the initial phase of TB treatment. This combination is essential for combating drug resistance.
Precautions:
- Baseline and periodic monitoring of liver function and vision (for ethambutol).
- Consider pyridoxine supplementation for patients taking isoniazid.
- Monitor patients with renal or hepatic impairment closely.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Ethambutol + Isoniazid?
A: Refer to the detailed dosage guidelines above. Dosing is weight-based and requires adjustment for children, renal/hepatic impairment, and slow acetylators.
Q2: What are the most common side effects?
A: Ethambutol: Optic neuritis (vision changes). Isoniazid: Peripheral neuropathy (numbness/tingling) and hepatotoxicity.
Q3: What are the contraindications for this drug combination?
A: Hypersensitivity to either drug, pre-existing optic neuritis (ethambutol), acute liver disease (isoniazid).
Q4: Can this combination be used during pregnancy and breastfeeding?
A: Generally considered safe, but requires careful monitoring of the mother and infant. Pyridoxine supplementation is recommended for breastfeeding mothers on isoniazid.
Q5: How should I manage a patient with renal impairment?
A: Ethambutol dosage reduction is necessary. Isoniazid dosage may need adjustment in severe renal impairment.
Q6: What are the key drug interactions to be aware of?
A: Aluminum hydroxide-containing antacids (both drugs), disulfiram, para-aminosalicylic acid (isoniazid). Consult drug interaction resources for a comprehensive list.
Q7: Are there specific monitoring parameters for this combination?
A: Monitor liver function tests for both drugs. Regularly assess visual acuity, color vision, and signs of peripheral neuropathy in patients receiving ethambutol and isoniazid, respectively.
Q8: What are the indications for drug level monitoring?
A: Drug level monitoring is generally not routinely recommended. It may be considered in cases of poor treatment response, suspected malabsorption, or in specific clinical situations where pharmacokinetic variability is a concern.
Q9: What should I do if a patient experiences vision changes while on ethambutol?
A: Discontinue ethambutol immediately and consult an ophthalmologist. Vision changes can be a sign of optic neuritis and may be irreversible if the drug is continued.
A: Isoniazid is metabolized by acetylation in the liver. Patients can be either “fast” or “slow” acetylators. Slow acetylators are at increased risk of toxicity due to higher drug levels. Dosage adjustment may be necessary for these individuals.
