Ethambutol + Isoniazid + Rifampicin + Vitamin B6

Usage

• This drug combination is primarily prescribed for the treatment of both active and latent tuberculosis (TB). It is crucial in combating drug-susceptible strains of Mycobacterium tuberculosis.
• Pharmacological classification: Anti-tuberculosis agents, specifically a combination of antibiotics and a vitamin.
• Mechanism of action: This combination targets different aspects of M. tuberculosis biology. Isoniazid inhibits cell wall synthesis, rifampicin blocks RNA polymerase activity, ethambutol disrupts cell metabolism, while pyridoxine (vitamin B6) mitigates isoniazid-induced peripheral neuropathy.

Alternate Names

• While no single alternate name exists for the four-drug combination, the individual components are sometimes known by other names (e.g., isoniazid as INH).
• Several brand names exist depending on the manufacturer and regional markets (e.g., Myrin, Rimstar).

How It Works

• Pharmacodynamics: Isoniazid disrupts mycolic acid synthesis, a critical part of the mycobacterial cell wall. Rifampicin inhibits bacterial RNA polymerase, thereby suppressing gene transcription. Ethambutol hinders arabinosyl transferase, affecting cell wall synthesis. Pyridoxine counters isoniazid’s interference with vitamin B6 metabolism, reducing the risk of peripheral neuropathy.
• Pharmacokinetics: All components are orally administered. Isoniazid and rifampicin have good oral absorption, especially when taken before meals. Ethambutol can be taken with or without food. All drugs undergo hepatic metabolism, and their elimination routes include both renal and biliary excretion. Rifampicin induces several CYP450 enzymes, affecting the metabolism of other drugs. Isoniazid’s metabolism depends on acetylator status, which can influence its half-life. Ethambutol may accumulate in patients with renal impairment.
• Mode of action (cellular/molecular level): Isoniazid specifically targets InhA, a key enzyme in mycolic acid synthesis. Rifampicin binds to the beta subunit of bacterial RNA polymerase, preventing transcription initiation. Ethambutol inhibits EmbB, disrupting arabinogalactan synthesis, a component of the mycobacterial cell wall.
• Elimination pathways: Isoniazid is primarily metabolized in the liver via acetylation and hydrolysis, followed by renal excretion. Rifampicin is metabolized in the liver to form active and inactive metabolites, excreted in bile and urine. Ethambutol undergoes limited hepatic metabolism, excreted mainly by the kidneys.

Dosage

Standard Dosage

Adults:

• Daily dosing is based on body weight (mg/kg). Common dosing for rifampicin is 10mg/kg up to 600 mg, isoniazid is 5mg/kg up to 300 mg, and ethambutol is 15-20 mg/kg. Pyridoxine is typically given as a 25-50 mg supplement.
• Administer as a single daily dose on an empty stomach (1 hour before or 2 hours after meals).

Children:

• Weight-based dosing is used. Dosage calculations similar to adults but with specific pediatric considerations for upper limits and administration forms (syrup vs. tablets).
• Pediatric safety considerations include careful monitoring for adverse reactions and close attention to proper dosing due to potential toxicity. This medication is generally not recommended for children weighing less than 25 kg, especially for the combination product. Individual drug formulations might be used instead.

Special Cases:

• Elderly Patients: No specific dose adjustments, but close monitoring of liver and kidney function is essential. Pyridoxine supplementation may be beneficial.
• Patients with Renal Impairment: Ethambutol requires dose reduction based on creatinine clearance. Other medications should be closely monitored.
• Patients with Hepatic Dysfunction: Dose adjustment is generally necessary for all components in patients with significant hepatic impairment due to altered metabolism.
• Patients with Comorbid Conditions: For diabetes, careful blood glucose monitoring is required as isoniazid can interfere with glucose control. In patients with pre-existing neuropathy, higher pyridoxine doses may be indicated.

Clinical Use Cases

The provided sources primarily address TB treatment, not the specific clinical cases listed below. Therefore, no dosage recommendations are provided for intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.

Dosage Adjustments

• Dose adjustments are based on renal and hepatic function, patient’s age, and co-existing medical conditions.
• Slow acetylators of isoniazid require lower doses.

Side Effects

Common Side Effects:

• Nausea, vomiting, loss of appetite
• Peripheral neuropathy (numbness, tingling)
• Orange discoloration of body fluids (urine, tears, sweat) caused by rifampicin
• Mild hepatotoxicity
• Visual disturbances (ethambutol)

Rare but Serious Side Effects:

• Severe hepatotoxicity
• Thrombocytopenia, purpura (rifampicin)
• Optic neuritis (ethambutol)
• Seizures (isoniazid)
• Severe hypersensitivity reactions

Long-Term Effects:

• Chronic liver disease (with continuous misuse)
• Permanent visual impairment (ethambutol, with prolonged high doses or pre-existing eye conditions)

Adverse Drug Reactions (ADR):

• Drug-induced hepatitis (requires immediate cessation)
• Thrombocytopenic purpura (rifampicin)
• Anaphylaxis
• Stevens-Johnson syndrome (rare but potentially life-threatening)

Contraindications

• Hypersensitivity to any component
• Acute liver disease
• Pre-existing optic neuritis (ethambutol, unless deemed essential by the physician)
• Concurrent use of saquinavir/ritonavir (rifampicin)
• Severe renal impairment (ethambutol dose adjustments needed)
• Porphyria
• Chronic alcoholism

Drug Interactions

• Rifampicin is a potent CYP450 inducer and can significantly decrease the effectiveness of numerous drugs, including:
  • Antiretrovirals (e.g., zidovudine)
  • Antifungals (e.g., ketoconazole, itraconazole, voriconazole)
  • Anticoagulants (e.g., warfarin)
  • Oral contraceptives
  • Immunosuppressants (e.g., tacrolimus, cyclosporine)
• Isoniazid inhibits monoamine oxidase (MAO) and can interact with tyramine-containing foods and certain medications.
• Aluminum-containing antacids can reduce the absorption of isoniazid and rifampicin.
• Alcohol should be avoided due to increased risk of hepatotoxicity.

Pregnancy and Breastfeeding

• Rifampicin, isoniazid, and ethambutol cross the placenta. While generally considered safe for use during pregnancy if benefits outweigh risks, rifampicin has shown teratogenic effects in animal studies at high doses.
• Vitamin K supplementation is recommended in the last month of pregnancy if taking rifampicin to prevent neonatal bleeding.
• The drugs are excreted in breast milk but at low concentrations. Breastfeeding is generally considered safe, but pyridoxine supplementation for the infant is recommended.

Drug Profile Summary

• Mechanism of Action: Multi-targeted anti-tuberculosis action; isoniazid: cell wall synthesis inhibitor; rifampicin: RNA polymerase inhibitor; ethambutol: cell metabolism disruptor; pyridoxine: prevents isoniazid-induced neuropathy.
• Side Effects: Nausea, vomiting, hepatotoxicity, peripheral neuropathy, visual disturbances, orange discoloration of body fluids.
• Contraindications: Hypersensitivity, acute liver disease, concurrent saquinavir/ritonavir.
• Drug Interactions: Numerous, primarily due to rifampicin’s CYP450 induction; isoniazid’s MAO inhibition.
• Pregnancy & Breastfeeding: Generally safe if benefits outweigh risks; monitor liver function and consider vitamin K and B6 supplementation.
• Dosage: Weight-based (mg/kg) daily dosing; adjust for renal/hepatic impairment.
• Monitoring Parameters: Liver function tests (LFTs), complete blood count (CBC), renal function, visual acuity (ethambutol).

Popular Combinations

• The combination of ethambutol, isoniazid, rifampicin, and pyridoxine is itself a standard first-line treatment for TB. Pyrazinamide is frequently added to this regimen, especially during the initial phase of treatment, to enhance efficacy and shorten treatment duration.

Precautions

• General Precautions: Baseline LFTs, renal function tests, and eye exams (ethambutol) are crucial. Monitor patients for signs of hepatotoxicity, neuropathy, and visual disturbances.
• Specific Populations: Pregnant/breastfeeding women: benefits vs. risks assessment, vitamin supplementation. Children and elderly: careful dosing and monitoring.
• Lifestyle Considerations: Alcohol avoidance.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Ethambutol + Isoniazid + Rifampicin + Vitamin B6?

A: Dosing is weight-based (mg/kg) and should be individualized based on the patient’s specific characteristics (age, organ function, comorbidities). The medication should be taken once daily on an empty stomach. Rifampicin is usually given up to 600 mg, isoniazid up to 300 mg, ethambutol 15-20 mg/kg, and pyridoxine 25-50 mg.

Q2: What is the role of Vitamin B6 in this combination?

A: Pyridoxine (vitamin B6) is included to prevent or reduce the risk of peripheral neuropathy, a common side effect of isoniazid.

Q3: What are the most serious side effects to watch out for?

A: Severe hepatotoxicity, optic neuritis (ethambutol), thrombocytopenia (rifampicin), and severe hypersensitivity reactions are the most serious potential side effects.

Q4: Can this drug combination be used in pregnant women?

A: Yes, but a careful assessment of the benefits and risks is necessary. Supplementation with vitamin K and pyridoxine may be required.

Q5: What are the key drug interactions to be aware of?

A: Rifampicin is a potent inducer of CYP450 enzymes and can reduce the effectiveness of many other medications. Isoniazid can interact with tyramine-containing foods and MAO inhibitors.

Q6: How should this combination be administered?

A: It should be taken orally once daily on an empty stomach, ideally one hour before or two hours after meals.

Q7: What monitoring is required during treatment?

A: Liver function tests, complete blood counts, renal function tests, and visual acuity (for ethambutol) should be monitored regularly.

Q8: What should be done if a patient misses a dose?

A: The patient should take the missed dose as soon as they remember, unless it is almost time for the next dose. Do not double the dose. Consistent daily dosing is essential for treatment success.

Q9: How long is the typical treatment duration?

A: The duration of treatment depends on the type and severity of TB (active vs. latent) and can range from several months to a year or more.

Q10: What is the role of each drug in this combination?

A: Isoniazid and rifampicin directly kill actively replicating bacilli. Pyrazinamide and ethambutol sterilize slow-growing or semi-dormant bacilli and prevent the emergence of resistance.