Isoniazid + Rifampicin

Usage

• Medical Conditions: Isoniazid + Rifampicin is primarily prescribed for the treatment of tuberculosis (TB), both active and latent. It is a crucial component of multi-drug regimens used to combat this bacterial infection. The combination is particularly important for preventing the development of drug-resistant TB.
• Pharmacological Classification: Antimycobacterial, Antitubercular, Antibiotic.
• Mechanism of Action: Isoniazid inhibits the synthesis of mycolic acids, essential components of the mycobacterial cell wall. Rifampicin inhibits bacterial DNA-dependent RNA polymerase, preventing RNA synthesis and subsequent protein synthesis in susceptible bacteria. The combination exhibits synergistic activity against Mycobacterium tuberculosis.

Alternate Names

• International/Regional Variations: No widely recognized international variations exist for the combination. Individual components are sometimes referred to as isonicotinylhydrazide (INH) for isoniazid and rifampin for rifampicin.
• Brand Names: Rifamate, IsonaRif, Rifinah (for combined tablets). Numerous generic formulations are also available.

How It Works

• Pharmacodynamics: Isoniazid acts primarily on actively growing mycobacteria by disrupting cell wall formation. Rifampicin also targets actively replicating bacteria by suppressing RNA synthesis.
• Pharmacokinetics:
  • Absorption: Both drugs are well-absorbed orally, ideally administered on an empty stomach. Food can reduce rifampicin absorption.
  • Metabolism: Isoniazid is metabolized primarily by N-acetyltransferase (NAT) in the liver, with genetic polymorphisms influencing the rate of acetylation (fast vs. slow acetylators). Rifampicin is metabolized in the liver and undergoes enterohepatic circulation. It is a potent inducer of several cytochrome P450 enzymes (CYP450).
  • Elimination: Isoniazid metabolites are excreted renally. Rifampicin is eliminated primarily in bile and feces, with a smaller portion excreted in urine.
• Mode of Action: Isoniazid inhibits the InhA enzyme, responsible for mycolic acid synthesis, crucial for mycobacterial cell wall integrity. Rifampicin binds to the β-subunit of bacterial RNA polymerase, blocking transcription initiation.
• Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: Isoniazid inhibits InhA. Rifampicin inhibits bacterial DNA-dependent RNA polymerase. Isoniazid can also inhibit monoamine oxidase (MAO).
• Elimination Pathways: Isoniazid - primarily renal excretion of metabolites. Rifampicin - primarily biliary/fecal excretion, some renal excretion. Rifampicin induces CYP450 enzymes (CYP2C9, CYP2C19, CYP3A4), significantly impacting the metabolism of other drugs.

Dosage

Standard Dosage

Adults:

• 300 mg Isoniazid + 600 mg Rifampicin once daily, on an empty stomach (at least 1 hour before or 2 hours after meals). Two capsules of Rifamate or IsonaRif are typically prescribed.
• Maximum Dose: Isoniazid: 300 mg/day. Rifampicin: 600 mg/day (in combination).

Children:

• Dosage is weight-based:
  • Isoniazid: 10-20 mg/kg daily (max 300 mg/day).
  • Rifampicin: 10-20 mg/kg daily (max 600 mg/day).
• Pediatric dispersible formulations are available to ensure accurate dosing.
• Monitor closely for adverse effects.

Special Cases:

• Elderly Patients: Monitor liver function closely. May require dose adjustments based on renal/hepatic function.
• Patients with Renal Impairment: Closely monitor renal function and for signs of isoniazid toxicity. Dose reduction may be necessary in severe renal impairment.
• Patients with Hepatic Dysfunction: Monitor closely for hepatotoxicity. Dose adjustments, or discontinuation, may be needed. Contraindicated in active liver disease.
• Patients with Comorbid Conditions: Caution is advised in patients with diabetes, HIV infection, or other conditions affecting drug metabolism. Vitamin B6 supplementation is often recommended for patients at risk of peripheral neuropathy (e.g., diabetes, malnutrition, HIV).

Clinical Use Cases

The provided sources primarily focus on the use of Isoniazid + Rifampicin for tuberculosis treatment and prophylaxis. Dosing in the context of intubation, surgical procedures, mechanical ventilation, ICU use, and emergency situations is not specifically addressed.

Dosage Adjustments

• Renal/Hepatic Dysfunction: Adjust doses based on the severity of impairment, as detailed in the “Special Cases” section.
• Metabolic Disorders/Genetic Polymorphisms: Slow acetylators may require dose adjustments for isoniazid to avoid toxicity.

Side Effects

Common Side Effects:

• Red-orange discoloration of body fluids (urine, tears, sweat, saliva).
• Peripheral neuropathy (numbness, tingling).
• Nausea, vomiting, abdominal discomfort.
• Loss of appetite.
• Headache, dizziness.
• Mild rash.
• Flu-like symptoms.

Rare but Serious Side Effects:

• Hepatotoxicity (jaundice, liver failure).
• Drug-induced hepatitis.
• Severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis).
• Thrombocytopenia.
• Acute renal failure.
• Seizures.

Long-Term Effects:

• Peripheral neuropathy (if not managed).
• Liver damage (with chronic, unmanaged hepatotoxicity).

Adverse Drug Reactions (ADR):

• Hepatotoxicity requiring immediate discontinuation.
• Severe skin reactions necessitating urgent intervention.

Contraindications

• Hypersensitivity to isoniazid or rifampicin.
• Active liver disease (acute hepatitis, cirrhosis).
• Previous isoniazid-induced liver injury.
• Concurrent use with saquinavir/ritonavir.

Drug Interactions

• Rifampicin is a potent inducer of CYP450 enzymes, leading to decreased efficacy of numerous drugs, including:
  • Oral contraceptives.
  • Warfarin.
  • Some antiretrovirals.
  • Corticosteroids.
  • Anticonvulsants.
• Isoniazid can inhibit the metabolism of certain drugs, such as phenytoin.
• Antacids can reduce rifampicin absorption.
• Alcohol increases the risk of hepatotoxicity.
• Tyramine-containing foods (cheese, red wine) and histamine-rich foods (tuna, skipjack) may interact with isoniazid due to its MAO-inhibiting activity.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: C (consult a specialist).
• Fetal Risks/Teratogenicity: Potential risks, although generally considered safe when benefits outweigh risks. Adequate folate supplementation is recommended.
• Breastfeeding: Generally considered compatible with breastfeeding. Monitor infants for jaundice. Mothers taking isoniazid should receive pyridoxine (vitamin B6) supplementation.

Drug Profile Summary

• Mechanism of Action: Isoniazid inhibits mycolic acid synthesis; rifampicin inhibits bacterial RNA polymerase.
• Side Effects: Hepatotoxicity, peripheral neuropathy, rash, discoloration of body fluids.
• Contraindications: Active liver disease, hypersensitivity.
• Drug Interactions: Numerous, mainly due to rifampicin’s CYP450 induction.
• Pregnancy & Breastfeeding: Use with caution; monitor infant.
• Dosage: Adults: 300 mg INH + 600 mg RIF daily. Children: weight-based.
• Monitoring Parameters: Liver function tests, signs of hepatitis, peripheral neuropathy symptoms.

Popular Combinations

• Isoniazid + Rifampicin + Pyrazinamide + Ethambutol (for initial TB treatment).
• Isoniazid + Rifapentine (for latent TB infection).

Precautions

• General Precautions: Monitor liver function regularly. Screen for pre-existing liver disease, renal impairment, diabetes, HIV infection.
• Specific Populations:
  • Pregnant Women: Careful risk-benefit assessment.
  • Breastfeeding Mothers: Monitor infant; vitamin B6 supplementation for mother.
  • Children & Elderly: Weight-based dosing for children; monitor elderly for toxicity.
• Lifestyle Considerations: Avoid alcohol. Caution with tyramine/histamine-rich foods.

FAQs (Frequently Asked Questions)

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

A: Adults: 300 mg Isoniazid + 600 mg Rifampicin daily. Children: Weight-based (10-20mg/kg/day for both drugs).

Q2: What are the most serious side effects?

A: Hepatotoxicity (liver damage), severe skin reactions, peripheral neuropathy.

Q3: Can this combination be used during pregnancy?

A: It can be used if benefits outweigh risks. Consult a specialist. Folate supplementation is crucial.

Q4: How does Rifampicin affect other medications?

A: Rifampicin induces CYP450 enzymes, potentially reducing the efficacy of other drugs metabolized by this pathway.

Q5: Why is it important to take Isoniazid + Rifampicin on an empty stomach?

A: Food, especially high-fat meals, can reduce Rifampicin absorption, impacting its effectiveness.

Q6: What are the signs of peripheral neuropathy?

A: Numbness, tingling, burning sensation in the hands and feet.

Q7: What should I do if a patient develops jaundice while taking this medication?

A: Discontinue the medication immediately and consult a specialist. Jaundice can indicate hepatotoxicity.

Q8: What are the treatment options for latent TB infection with this drug combination?

A: Three months of daily isoniazid plus rifampin (3HR) is one of the recommended regimens. Other options include three months of weekly isoniazid plus rifapentine (3HP), and four months of daily rifampin (4R).

Q9: How should I counsel patients about the red-orange discoloration of body fluids?

A: Reassure patients that this side effect is harmless and temporary. It can stain soft contact lenses, so advise against wearing them during treatment.

Q10: How is dosing adjusted for patients with renal impairment?

A: Close monitoring is needed. A dose reduction might be considered in cases of severe renal dysfunction, especially for isoniazid.