isoniazid
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Isoniazid remains one of those foundational tuberculosis medications that’s been around for decades, yet still surprises me in clinical practice. When I first started working in our TB clinic back in 2012, I’ll admit I viewed it as just another antibiotic - but over the years, I’ve developed a real appreciation for its unique properties and the careful management it requires.
Isoniazid: Essential Tuberculosis Treatment and Prevention - Evidence-Based Review
1. Introduction: What is Isoniazid? Its Role in Modern Medicine
Isoniazid, often abbreviated INH, is a first-line antibacterial agent specifically used against Mycobacterium tuberculosis. It’s classified as an antimycobacterial drug and has been the backbone of TB treatment since the 1950s. What many don’t realize is that isoniazid isn’t just for active TB - it’s equally crucial for latent TB infection prevention, which represents about one-quarter of the world’s population.
The World Health Organization still considers isoniazid essential medicine, despite newer drugs emerging. In my clinic, we’ve found that when used correctly, isoniazid achieves cure rates exceeding 95% for drug-sensitive TB. The challenge, as I learned early on, is that “used correctly” involves much more than just writing the prescription.
2. Key Components and Bioavailability Isoniazid
Chemically, isoniazid is isonicotinic acid hydrazide - a relatively simple molecule that belies its sophisticated mechanism. It’s available as tablets (100mg, 300mg), syrup (50mg/5mL), and injectable forms, though oral administration is most common in outpatient settings.
The bioavailability of isoniazid is excellent - nearly 90% when taken orally on empty stomach. But here’s where things get interesting: we noticed significant variation in absorption patterns between patients. Some would achieve peak concentrations within 1-2 hours, while others took 4-6 hours. This variability became particularly important when we started therapeutic drug monitoring for difficult cases.
The metabolic pathway involves hepatic acetylation, and this is where genetic differences really matter. We have rapid acetylators and slow acetylators - about 50% of Caucasians and African Americans are slow acetylators, while up to 90% of East Asians are rapid acetylators. This affects dosing frequency and toxicity risk, something I wish I’d understood better when I started.
3. Mechanism of Action Isoniazid: Scientific Substantiation
Isoniazid works by inhibiting mycolic acid synthesis in the mycobacterial cell wall. Think of mycolic acids as the bricks in the TB bacterium’s fortress - without them, the structure collapses. Specifically, isoniazid targets the enzyme enoyl-acyl carrier protein reductase (InhA), disrupting the fatty acid synthesis pathway essential for building that waxy, protective cell wall.
What’s fascinating is how isoniazid requires activation by the bacterial enzyme KatG (catalase-peroxidase). This creates reactive oxygen species that then attack multiple bacterial targets. This dual mechanism - direct enzyme inhibition plus oxidative damage - makes it particularly effective, but also explains why KatG mutations lead to resistance.
We had a case last year - Mr. Chen, 68-year-old with pulmonary TB - whose cultures showed resistance despite no prior treatment. Genetic testing revealed a KatG mutation. That case reminded our entire team that understanding the mechanism isn’t just academic; it directly impacts treatment decisions when first-line therapy fails.
4. Indications for Use: What is Isoniazid Effective For?
Isoniazid for Active Tuberculosis
For active TB disease, isoniazid is always used in combination therapy, typically with rifampin, pyrazinamide, and ethambutol initially. Monotherapy is strictly avoided due to rapid resistance development. The intensive phase usually lasts 2 months, followed by 4 months of continuation phase with isoniazid and rifampin.
Isoniazid for Latent TB Infection
This is where we prevent active disease development. The standard regimen is 300mg daily for 6-9 months, though shorter regimens have emerged. We’ve found compliance is better with the 3-month weekly rifapentine plus isoniazid regimen, but cost can be prohibitive for some patients.
Isoniazid for TB Prevention in HIV Patients
HIV-positive individuals with latent TB have much higher reactivation rates. Isoniazid preventive therapy reduces this risk by 60-90%. The tricky part is managing potential interactions with antiretroviral drugs and monitoring for overlapping toxicities.
Isoniazid for Close Contacts of Active TB Cases
Household contacts, particularly children under 5, benefit significantly from isoniazid preventive therapy. We recently treated an entire family after the father was diagnosed with sputum-positive pulmonary TB. The mother and two young children completed preventive therapy without issues.
5. Instructions for Use: Dosage and Course of Administration
Dosing depends on indication and patient factors. Here’s our standard approach:
| Indication | Dose | Frequency | Duration | Special Instructions |
|---|---|---|---|---|
| Active TB | 5mg/kg (max 300mg) | Daily | 6-9 months | Always combine with other TB drugs |
| Latent TB | 5mg/kg (max 300mg) | Daily | 9 months | Can use 15mg/kg twice weekly |
| Latent TB (3HP) | 15mg/kg (max 900mg) | Weekly | 3 months | With rifapentine, directly observed |
| Pediatric | 10-15mg/kg | Daily | Varies | Weight-based dosing critical |
We typically recommend taking isoniazid on empty stomach for best absorption, but if gastrointestinal upset occurs, with food is acceptable (though absorption decreases about 20%). The timing consistency matters more than absolute fasting.
Pyridoxine (vitamin B6) supplementation at 25-50mg daily is standard in our practice to prevent peripheral neuropathy, especially for pregnant women, diabetics, alcoholics, and HIV patients. We learned this lesson the hard way early on when several patients developed numbness and tingling that could have been prevented.
6. Contraindications and Drug Interactions Isoniazid
Absolute contraindications include severe hypersensitivity reactions, previous isoniazid-associated hepatitis, or severe adverse reactions. Relative contraindications include chronic liver disease, alcohol dependence, and pregnancy (though we still use it when benefits outweigh risks with close monitoring).
The hepatotoxicity risk is real - we see transient ALT elevations in 10-20% of patients, with clinical hepatitis in about 1%. Our protocol involves baseline LFTs, then monthly symptoms assessment. We only repeat LFTs if symptoms develop, unless there’s pre-existing liver disease.
Drug interactions are numerous:
- Anticonvulsants (phenytoin, carbamazepine) - isoniazid inhibits metabolism, increasing levels and toxicity risk
- Warfarin - enhanced anticoagulant effect
- Ketoconazole - decreased levels of both drugs
- Theophylline - increased theophylline concentrations
- Alcohol - increased hepatitis risk
We had a patient, Maria, who was on phenytoin for epilepsy and developed phenytoin toxicity within two weeks of starting isoniazid. Her levels went from therapeutic to toxic range, causing nystagmus and ataxia. We reduced her phenytoin dose by 25% and monitored levels weekly until stable.
7. Clinical Studies and Evidence Base Isoniazid
The evidence for isoniazid spans decades. The classic USPHS trials in the 1950s established its efficacy, showing 25-92% protection against TB depending on compliance. More recent studies have refined our understanding:
The PREVENT TB trial (2011) showed the 3-month weekly regimen was non-inferior to 9 months daily isoniazid with better completion rates (82% vs 69%). However, we’ve noticed more hepatotoxicity with the weekly regimen in practice - about 3% vs 1% with daily.
The TEMPRANO trial (2015) demonstrated that isoniazid preventive therapy in HIV patients reduced mortality and TB incidence significantly, even in areas with high TB prevalence.
What the studies don’t always capture is the real-world implementation challenges. Our clinic’s data shows completion rates around 60% for standard therapy despite extensive education and monitoring. The social determinants - transportation, work conflicts, stigma - often matter more than the medical factors.
8. Comparing Isoniazid with Similar Products and Choosing a Quality Product
When comparing isoniazid to alternatives for latent TB, several factors matter:
Rifampin alone for 4 months works well but has more drug interactions. Rifapentine plus isoniazid (3HP) has better completion but higher cost and more monitoring requirements.
For active TB, isoniazid remains irreplaceable in first-line regimens. The comparisons come when resistance develops - then we move to second-line drugs like fluoroquinolones, injectables, and newer agents like bedaquiline.
Quality considerations: Isoniazid should come from reputable manufacturers with consistent bioavailability. We’ve had issues with some generic brands showing variable absorption. Our pharmacy now stocks specific manufacturers we’ve validated through therapeutic drug monitoring.
9. Frequently Asked Questions (FAQ) about Isoniazid
What monitoring is required during isoniazid therapy?
Baseline LFTs for everyone, then clinical monitoring for symptoms monthly. Repeat LFTs only if symptoms develop (nausea, vomiting, abdominal pain, jaundice). More frequent monitoring for those with liver disease or HIV.
Can isoniazid be taken during pregnancy?
Yes, when clearly indicated. The benefits generally outweigh risks, but we add pyridoxine and monitor more closely. We’ve treated dozens of pregnant women without major issues, though some needed dose adjustments.
What should be done if a dose is missed?
If remembered same day, take it. If next day, skip the missed dose and continue regular schedule. Don’t double dose. We tell patients missing occasional doses is better than stopping completely.
How long until isoniazid starts working?
For active TB, clinical improvement usually within 2-3 weeks. For prevention, protection begins immediately and lasts for years after completion.
Can isoniazid cause permanent damage?
Hepatitis can be serious but is usually reversible if caught early. Peripheral neuropathy is generally reversible with pyridoxine and discontinuation. We’ve seen complete recovery in most cases when managed promptly.
10. Conclusion: Validity of Isoniazid Use in Clinical Practice
Isoniazid remains essential despite being decades old. The key is appropriate patient selection, careful monitoring, and addressing adherence barriers. The risk-benefit profile strongly favors use when indicated, particularly for latent TB infection where the lifetime reactivation risk justifies the relatively short treatment course.
Looking back over my career, isoniazid has taught me more about balancing efficacy and safety than almost any other drug. I remember one patient particularly well - David, a 42-year-old chef who developed latent TB after exposure at work. He was terrified of medication, especially hearing about liver risks. We started with 150mg daily, gradually increased to full dose with weekly check-ins. His LFTs bumped slightly at month two, but normalized without intervention. He completed therapy, and at his 2-year follow-up remains TB-free. What struck me was his comment at the last visit: “I was scared to start, but now I’m grateful I did - not just for me, but so I won’t spread it to others.”
That’s the thing about isoniazid - when used wisely, it’s not just treating disease, it’s preventing transmission chains. We’re still learning about optimal durations, better-tolerated regimens, and how to reach more people who need it. The research continues, but the foundation remains solid. After hundreds of patients, I still respect this medication - both its power and its limitations.