Isoniazid - Drug Monograph

Introduction

Isoniazid (INH) is a first-line antimycobacterial agent that has been a cornerstone of tuberculosis (TB) treatment since its introduction in 1952. This bactericidal antibiotic remains essential for both active TB treatment and latent TB infection prophylaxis. As a hydrazide derivative of isonicotinic acid, isoniazid demonstrates highly specific activity against Mycobacterium tuberculosis complex organisms.

Mechanism of Action

Isoniazid is a prodrug that requires activation by the mycobacterial catalase-peroxidase enzyme KatG. Once activated, it inhibits the synthesis of mycolic acids, which are essential components of the mycobacterial cell wall. Specifically, it targets the enoyl-acyl carrier protein reductase (InhA), disrupting the fatty acid synthesis pathway crucial for maintaining bacterial cell wall integrity. This mechanism leads to bactericidal activity against actively dividing organisms and bacteriostatic effects against dormant bacilli.

Indications

• Treatment of all forms of active tuberculosis (must be used in combination with other antituberculosis drugs)
• Preventive therapy for latent tuberculosis infection (LTBI)
• Treatment of infection caused by Mycobacterium kansasii (as part of combination therapy)

Dosage and Administration

• Active TB: 5 mg/kg (usual dose 300 mg) daily or 15 mg/kg (max 900 mg) 2-3 times weekly
• LTBI: 300 mg daily or 900 mg twice weekly for 6-9 months

• Active TB: 10-15 mg/kg/day (max 300 mg) daily or 20-30 mg/kg (max 900 mg) 2-3 times weekly
• LTBI: 10-15 mg/kg/day (max 300 mg) daily or 20-30 mg/kg (max 900 mg) twice weekly

• Renal impairment: No dosage adjustment required
• Hepatic impairment: Use with caution; consider reduced dosing or alternative regimens
• Dialysis: Administer after hemodialysis

Pharmacokinetics

• Absorption: Well absorbed orally (90% bioavailability); not affected by food
• Distribution: Widely distributed throughout body tissues and fluids, including cerebrospinal fluid
• Metabolism: Primarily hepatic via N-acetyltransferase (genetically determined acetylation status)
• Elimination: Renal excretion (75% as metabolites, 7-29% as unchanged drug)
• Half-life: Fast acetylators: 0.5-1.6 hours; Slow acetylators: 2-5 hours

Contraindications

• History of severe hypersensitivity reactions to isoniazid
• Previous isoniazid-associated hepatic injury or severe adverse reactions
• Acute liver disease of any etiology
• Concurrent use with rifapentine in HIV-positive patients receiving certain antiretroviral regimens

Warnings and Precautions

Additional precautions:

• Peripheral neuropathy risk (supplement with pyridoxine)
• Hypersensitivity reactions
• CNS effects (seizures, psychosis)
• Hematologic abnormalities
• Rheumatic syndromes (lupus-like syndrome)
• Hyperglycemia
• Ocular toxicity

Drug Interactions

• Carbamazepine, phenytoin: Increased levels of these anticonvulsants
• Disulfiram: Increased CNS effects
• Ketoconazole: Possible decreased ketoconazole levels
• Rifampin: Increased risk of hepatotoxicity
• Aluminum-containing antacids: Decreased isoniazid absorption
• Benzodiazepines: Increased effects and toxicity
• Theophylline: Increased theophylline levels

Adverse Effects

• Peripheral neuropathy
• Elevated liver enzymes
• Nausea, vomiting
• Rash
• Fever
• Dizziness

• Hepatitis (dose-related)
• Stevens-Johnson syndrome
• Agranulocytosis
• Aplastic anemia
• Seizures
• Psychosis
• Optic neuritis

Monitoring Parameters

• Liver function tests (ALT, AST, bilirubin)
• Complete blood count
• Renal function
• Visual acuity and color vision testing
• HIV status (increased hepatotoxicity risk)

• Monthly symptom assessment for hepatitis
• Liver enzymes monthly for first 3 months, then as clinically indicated
• Regular assessment for neuropathy symptoms
• Periodic visual testing with long-term use

Patient Education

• Take medication consistently, preferably on an empty stomach
• Report any signs of liver problems immediately: unusual fatigue, weakness, nausea, vomiting, dark urine, jaundice
• Report numbness, tingling, or burning in hands or feet
• Avoid alcohol consumption during therapy
• Take pyridoxine (vitamin B6) as prescribed to prevent neuropathy
• Complete full course of therapy even if feeling better
• Use sun protection due to increased photosensitivity risk
• Inform all healthcare providers about isoniazid therapy

References

1. American Thoracic Society, CDC, and Infectious Diseases Society of America. Treatment of Drug-Susceptible Tuberculosis. Clinical Infectious Diseases 2016;63(7):e147-e195. 2. Nahid P, et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clinical Infectious Diseases 2016;63(7):e147-e195. 3. CDC. Latent Tuberculosis Infection: A Guide for Primary Health Care Providers. 2020. 4. McIlleron H, et al. Isoniazid pharmacokinetics in children treated for respiratory tuberculosis. Archives of Disease in Childhood 2007;92:622-626. 5. Saukkonen JJ, et al. An official ATS statement: hepatotoxicity of antituberculosis therapy. American Journal of Respiratory and Critical Care Medicine 2006;174:935-952. 6. Package Insert: Isoniazid Tablets. Various manufacturers.