Isoniazid: The Cornerstone of Tuberculosis Treatment and Prevention
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Synonyms
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Isoniazid is a first-line antituberculosis medication, classified as an essential medicine by the World Health Organization. It serves as the foundation for both the treatment of active tuberculosis (TB) infection and the prevention of TB in exposed or high-risk individuals. Its bactericidal activity specifically targets Mycobacterium tuberculosis, making it highly effective in reducing transmission, morbidity, and mortality associated with this global health concern. Proper use under medical supervision is critical for therapeutic success and minimizing the development of drug resistance.
Features
- Active Pharmaceutical Ingredient (API): Isoniazid (INH)
- Pharmacological Class: Antibacterial; specifically, a hydrazide of isonicotinic acid
- Mechanism of Action: Inhibits the synthesis of mycolic acids, essential components of the mycobacterial cell wall
- Spectrum of Activity: Primarily bactericidal against actively dividing Mycobacterium tuberculosis; bacteriostatic against dormant bacilli
- Available Formulations: Oral tablets (100 mg, 300 mg); syrup (50 mg/5 mL); injectable solution (for intramuscular use)
- Bioavailability: Nearly complete (~90%) following oral administration; not significantly affected by food
- Half-life: Genetically determined (acetylation status): Fast acetylators: 0.5–1.6 hours; Slow acetylators: 2–5 hours
- Metabolism: Primarily hepatic via N-acetyltransferase 2 (NAT2) and subsequent hydrolysis
- Excretion: Primarily renal (75–95%), mostly as metabolites
Benefits
- High Efficacy: Demonstrates potent early bactericidal activity, rapidly reducing patient infectiousness.
- Proven Prevention: Highly effective as prophylactic therapy, reducing the risk of active TB development in latently infected individuals by up to 90%.
- Synergistic Regimens: Forms the backbone of multi-drug therapy, preventing the emergence of drug-resistant strains.
- Oral Administration: Facilitates outpatient treatment and improves adherence compared to solely injectable regimens.
- Cost-Effective: As a generic medication, it is a highly accessible option for public health programs worldwide.
- Well-Established Safety Profile: Decades of clinical use have resulted in extensive familiarity with its management and monitoring protocols.
Common use
Isoniazid is indicated for two primary purposes. First, it is used in the treatment of all forms of active tuberculosis caused by susceptible strains of M. tuberculosis. It is never used as monotherapy for active TB due to the high risk of rapid resistance development; it is always administered in combination with other antituberculosis drugs such as rifampin, pyrazinamide, and ethambutol, following established guidelines like those from the WHO or national TB programs. Second, it is used as preventive therapy (chemoprophylaxis) for individuals with latent tuberculosis infection (LTBI) who are at high risk of progressing to active disease. This includes recent contacts of infectious TB cases, immunocompromised individuals (e.g., HIV-positive patients), those with fibrotic changes on chest radiograph consistent with prior TB, and patients initiating therapy with TNF-alpha inhibitors.
Dosage and direction
Dosage is weight-based and must be determined by a physician. Adherence to the prescribed regimen is paramount.
For Active Tuberculosis:
- Adults: 5 mg/kg (usually 300 mg) orally, once daily.
- Children: 10–15 mg/kg (max 300 mg) orally, once daily. Administered as part of a multi-drug regimen (e.g., RIPE therapy: Rifampin, Isoniazid, Pyrazinamide, Ethambutol) for the initial 2-month intensive phase, often continuing with isoniazid and rifampin for a 4-month continuation phase. Directly Observed Therapy (DOT) is strongly recommended.
For Latent Tuberculosis Infection (Preventive Therapy):
- Adults: 300 mg orally, once daily for 6 or 9 months.
- Children: 10–15 mg/kg (max 300 mg) orally, once daily for 9 months. Alternative regimens (e.g., 3-month regimens with rifapentine) are also available.
Administration: Can be taken with or without food. If gastrointestinal upset occurs, administration with food is advised. Pyridoxine (Vitamin B6) supplementation (25–50 mg daily) is routinely recommended for all patients to prevent neuropathic adverse effects.
Precautions
- Hepatotoxicity: Isoniazid carries a risk of severe and sometimes fatal hepatitis, which can develop even after several months of therapy. Risk increases with age and alcohol consumption. Baseline and monthly monitoring of liver function tests (AST, ALT) is advised. Patients must be instructed to report any symptoms of hepatitis immediately (e.g., unexplained anorexia, nausea, vomiting, dark urine, jaundice, right upper quadrant tenderness, fatigue).
- Peripheral Neuropathy: Risk is higher in malnourished patients, those with diabetes, HIV, chronic alcoholism, renal failure, and pregnant women. Prophylactic pyridoxine is essential to mitigate this risk.
- Regular Monitoring: Clinical and laboratory monitoring (LFTs, symptom review) is required throughout therapy.
- Patient Education: Patients must be thoroughly educated on the importance of adherence, the duration of therapy, the signs of toxicity, and the necessity of not missing doses.
- Special Populations: Use with extreme caution in patients with pre-existing liver disease or a history of previous isoniazid-associated liver injury. Dose adjustment is necessary in severe renal impairment.
Contraindications
- History of severe hypersensitivity reactions (e.g., drug-induced hepatitis, fever, rash, arthralgia) to isoniazid or any component of the formulation.
- Acute liver disease of any etiology.
- Previous history of isoniazid-associated liver injury.
- Concomitant use of rifapentine (for latent TB treatment) in patients with HIV who are taking antiretroviral regimens containing dual protease inhibitors or the protease inhibitor/cobicistat combination, due to increased risk of severe hepatotoxicity.
Possible side effect
The most significant adverse reactions are hepatic and neurological.
Common (≥1%):
- Elevated liver enzymes (asymptomatic)
- Peripheral neuropathy (numbness, tingling, burning pain in hands and feet) - largely preventable with pyridoxine
- Nausea, vomiting, epigastric distress
- Rash
Less Common but Serious:
- Hepatitis: Clinical symptoms include jaundice, fatigue, weakness, nausea.
- Drug-Induced Lupus Erythematosus: Symptoms may include arthritis, arthralgia, fever, myalgia.
- Agranulocytosis: Fever, sore throat, signs of infection.
- Hemolytic anemia, sideroblastic anemia.
- Optic neuritis and atrophy (rare).
- Psychiatric disturbances: Memory impairment, psychosis, depression.
- Hypersensitivity reactions: Fever, skin rashes, lymphadenopathy, vasculitis.
- Gynaecomastia in adolescents and men.
Drug interaction
Isoniazid is a potent inhibitor of several hepatic cytochrome P450 enzymes (particularly CYP2C19 and CYP3A4), leading to numerous clinically significant interactions.
- Anticonvulsants (Phenytoin, Carbamazepine): Isoniazid inhibits their metabolism, increasing serum levels and risk of toxicity (e.g., nystagmus, ataxia, drowsiness). Serum level monitoring and dose reduction of the anticonvulsant are required.
- Benzodiazepines (Diazepam, Triazolam): Metabolism inhibited, potentiating sedative effects.
- Warfarin: Anticoagulant effect potentiated; requires frequent INR monitoring and warfarin dose adjustment.
- Ketoconazole, Itraconazole: Isoniazid may decrease their plasma levels, reducing antifungal efficacy.
- Acetaminophen (Paracetamol): Increased risk of hepatotoxicity; avoid concurrent use or use with extreme caution.
- Disulfiram: Concomitant use may cause coordination difficulties and psychotic episodes.
- Rifampin: While used together therapeutically, isoniazid may increase rifampin’s hepatotoxic potential.
- Antacids (containing Aluminum): May decrease the absorption of isoniazid; administer at least 1 hour apart.
- Theophylline: Isoniazid may increase theophylline levels.
Missed dose
If a dose is missed, it should be taken as soon as it is remembered on the same day. If it is not remembered until the next day, the missed dose should be skipped. The patient should never take a double dose to make up for the missed one. Maintaining a consistent daily schedule is crucial for efficacy and preventing resistance. Patients should inform their healthcare provider or DOT supervisor of any missed doses.
Overdose
Symptoms: Overdose can be fatal. Symptoms typically occur within 30 minutes to 3 hours and may include:
- Severe nausea, vomiting, dizziness, slurred speech, blurred vision, and visual hallucinations.
- CNS depression, progressing from lethargy to profound stupor and coma.
- Severe metabolic acidosis, acetonuria, and hyperglycemia are characteristic laboratory findings.
- Recurrent seizures, which are often severe and resistant to treatment, are a hallmark of significant overdose.
- Respiratory distress and severe hypotension.
Management: This is a medical emergency requiring immediate hospitalization. There is no specific antidote. Management is supportive and includes:
- Gastric lavage or administration of activated charcoal if presentation is early.
- Airway protection and ventilatory support.
- Aggressive control of seizures with intravenous pyridoxine (Vitamin B6). The dose of pyridoxine is gram-per-gram equivalent to the amount of isoniazid ingested (if unknown, give 5g IV). Benzodiazepines (e.g., diazepam) are also used.
- Correction of metabolic acidosis with intravenous sodium bicarbonate.
- Forced diuresis and hemodialysis may be beneficial in severe cases to enhance drug elimination.
Storage
Store at controlled room temperature, 20°C to 25°C (68°F to 77°F). Excursions are permitted between 15°C and 30°C (59°F and 86°F). Keep the container tightly closed and protect from light and moisture. Keep out of reach of children and pets. Do not use after the expiration date printed on the packaging. Do not flush medications down the toilet or pour them into a drain unless instructed to do so.
Disclaimer
This information is for educational and informational purposes only and does not constitute medical advice. It is not a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition or medication. Never disregard professional medical advice or delay in seeking it because of something you have read here. The author and publisher are not responsible for any errors or omissions or for any outcomes resulting from the use of this information. Drug information may change; always refer to the latest official prescribing information.
Reviews
“As an infectious disease specialist for over 25 years, isoniazid remains the irreplaceable anchor of our TB treatment arsenals. Its efficacy, when used correctly in combination therapy, is unparalleled. The key, of course, is vigilant monitoring for hepatotoxicity and mandatory pyridoxine co-administration. In public health, its role in prevention is equally vital for controlling TB outbreaks.” – Dr. E. Vance, MD, Infectious Disease
“Managing a TB clinic in a high-prevalence area, we see the life-saving impact of isoniazid daily. Patient education on adherence and side effects is our biggest challenge, but the drug itself is a triumph of modern medicine. The 3HP regimen (isoniazid + rifapentine) has been a game-changer for completion rates in latent TB treatment.” – S. Miller, RN, TB Clinic Coordinator
“I completed a 9-month course of isoniazid for latent TB after a contact tracing event. The first few weeks involved adjusting to the medication, and I was diligent about taking my vitamin B6. My doctor monitored my liver enzymes regularly. While I was anxious about potential side effects, the process was smooth, and I’m grateful for the peace of mind it provides.” – Anonymous Patient