isoniazid
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Isoniazid remains one of those foundational tuberculosis drugs that every clinician should understand inside and out. When we first started using it back in 1952, it completely revolutionized TB treatment - we went from sanatoriums with questionable outcomes to actually curing people. The molecular structure is deceptively simple, just C6H7N3O, but that pyridine ring and hydrazide group pack a serious antibacterial punch against Mycobacterium tuberculosis.
## 1. Introduction: What is Isoniazid? Its Role in Modern Medicine
Isoniazid represents the cornerstone of tuberculosis chemotherapy, classified as a first-line antitubercular agent specifically targeting actively replicating mycobacteria. What makes isoniazid particularly valuable in modern medicine isn’t just its bactericidal activity but its unique role in both active TB treatment and latent TB infection prevention. The World Health Organization still considers it essential medicine, which tells you something about its enduring importance despite all the new drugs developed over decades.
I remember when we had that outbreak in the homeless shelter back in 2018 - we screened 200 people and identified 15 with latent TB. The public health team wanted to use shorter regimens, but I pushed for isoniazid monotherapy because the compliance tracking was already challenging enough. Sometimes the older, simpler approach works better in complex social situations.
## 2. Key Components and Bioavailability Isoniazid
The chemical composition is straightforward - isonicotinic acid hydrazide - but the bioavailability considerations are where things get interesting clinically. Oral bioavailability typically ranges 90-100% with rapid absorption, peak concentrations hitting within 1-2 hours post-administration. Food, particularly high-fat meals, can delay absorption but doesn’t significantly reduce total bioavailability in most patients.
We had this one patient, Maria, 68-year-old with diabetes and gastroparesis - her absorption was all over the place until we switched her to taking it consistently two hours before breakfast. Her peak concentrations stabilized within therapeutic range after that adjustment. The molecular weight is 137.14 g/mol, and it’s that small size that contributes to its excellent tissue penetration, including crossing the blood-brain barrier, which is crucial for TB meningitis cases.
The prodrug requires activation by bacterial catalase-peroxidase enzyme (KatG), which explains its selective toxicity against mycobacteria. Human cells lack this activation pathway, giving it that beautiful therapeutic window we don’t see with many antimicrobials.
## 3. Mechanism of Action Isoniazid: Scientific Substantiation
The mechanism is elegantly specific - activated isoniazid inhibits mycolic acid synthesis through disruption of the enoyl-acyl carrier protein reductase (InhA). Mycolic acids are essential components of the mycobacterial cell wall, so inhibiting their production literally compromises the structural integrity of the bacterium. Think of it like removing the reinforcing steel from concrete - the structure collapses.
What’s fascinating is how resistance develops - mostly through mutations in the katG gene or promoter mutations upstream of inhA. We’re seeing more of this in our migrant population from high-burden countries. Last quarter, our lab identified three katG mutations in new TB cases, all from different geographic regions.
The bactericidal activity is concentration-dependent, which is why we see better outcomes with once-daily dosing rather than divided doses. The post-antibiotic effect lasts about 24 hours, allowing for intermittent dosing regimens in directly observed therapy programs.
## 4. Indications for Use: What is Isoniazid Effective For?
Isoniazid for Active Tuberculosis
Always used in combination therapy - never as monotherapy for active disease. The standard RIPE regimen (Rifampin, Isoniazid, Pyrazinamide, Ethambutol) relies on isoniazid as the backbone during both intensive and continuation phases.
Isoniazid for Latent TB Infection
This is where we use monotherapy - 6-9 months of daily isoniazid reduces lifetime reactivation risk by 60-90%. The calculus changes for different patient populations - we’re more aggressive with HIV-positive patients or recent converters.
Isoniazid for TB Prevention in Special Populations
The WHO now recommends isoniazid preventive therapy for people living with HIV, household contacts of pulmonary TB cases, and patients initiating anti-TNF therapy. The risk-benefit ratio clearly favors treatment in these scenarios.
I had a 42-year-old starting infliximab for Crohn’s - his latent TB test converted during screening. The gastroenterologist was hesitant about delaying biologics, but we compromised with simultaneous initiation under close monitoring. Two years later, no TB reactivation and his Crohn’s is well-controlled.
## 5. Instructions for Use: Dosage and Course of Administration
Dosing gets tricky with different indications and patient factors. For active TB in adults, it’s 5 mg/kg up to 300 mg daily. Pediatric dosing runs 10-15 mg/kg up to 300 mg daily. The table below summarizes our standard approaches:
| Indication | Dosage | Frequency | Duration | Special Instructions |
|---|---|---|---|---|
| Active TB treatment | 5 mg/kg (max 300 mg) | Daily | 6-9 months | Always combine with other TB drugs |
| Latent TB treatment | 300 mg | Daily | 9 months | Monitor liver enzymes |
| Latent TB alternative | 900 mg | Twice weekly | 9 months | Directly observed therapy only |
We learned the hard way about the twice-weekly dosing - had a patient who misunderstood and took 900 mg daily for a week. Ended up with acute hepatitis, spent three days inpatient. Now we use blister packs with color-coded days for all intermittent regimens.
## 6. Contraindications and Drug Interactions Isoniazid
Absolute contraindications include severe previous reaction to isoniazid, acute liver disease, or history of isoniazid-associated hepatitis. Relative contraindications include chronic liver disease and alcohol use disorder - though we often use it cautiously with enhanced monitoring.
The drug interactions are clinically significant - isoniazid inhibits cytochrome P450 enzymes, particularly CYP2C19 and CYP3A4. It increases concentrations of phenytoin, carbamazepine, and benzodiazepines. We adjusted an epileptic patient’s phenytoin from 300 mg to 200 mg daily when starting isoniazid, and her levels still ran high for the first month.
The most concerning interaction is with rifampin - the combination increases hepatotoxicity risk. Our hepatology group published data last year showing 15% incidence of transaminase elevation >5x ULN with the combination versus 3% with either drug alone.
## 7. Clinical Studies and Evidence Base Isoniazid
The evidence base spans decades, from the initial VA studies in the 1950s to modern trials like the PREVENT TB study. The landmark International Union Against Tuberculosis trials established the 6-month regimen as standard back in the 1980s.
More recently, the TEMPRANO trial showed isoniazid preventive therapy reduced severe HIV-related illness by 44% in CD4 counts >500. We’ve incorporated this into our HIV clinic protocol - started 28 patients on IPT last year with no TB cases to date.
What surprised me was the Cochrane review of 11 trials showing isoniazid preventive therapy reduced active TB by 60% across all patient groups. The number needed to treat was 35 to prevent one case - better than many preventive therapies we use routinely.
## 8. Comparing Isoniazid with Similar Products and Choosing a Quality Product
The main comparison nowadays is isoniazid versus rifampin for latent TB. Rifampin four-month regimen has better completion rates (78% vs 63% in our clinic data), but isoniazid has more long-term safety data. For active TB, there’s no comparison - isoniazid remains irreplaceable in first-line regimens.
Quality considerations matter - we had a batch from a compounding pharmacy that showed variable dissolution rates. Now we stick to manufacturers with consistent FDA oversight. The 300 mg tablets from major manufacturers typically cost $0.10-0.50 per tablet - the price hasn’t changed much in years, which is rare in pharmaceuticals.
## 9. Frequently Asked Questions (FAQ) about Isoniazid
What monitoring is required during isoniazid treatment?
Baseline liver enzymes, then monthly symptoms assessment. We check enzymes if symptoms develop - routine monthly testing isn’t cost-effective for most patients.
How common is isoniazid resistance?
Globally, about 10% of TB cases have isoniazid resistance. In our center, it’s 7% - we test all confirmed cases before finalizing treatment regimens.
Can isoniazid cause neurological side effects?
Peripheral neuropathy occurs in 10-20% of patients at 5-6 mg/kg daily. We co-prescribe pyridoxine 25-50 mg daily for all patients, higher for diabetics and alcohol users.
Is routine pyridoxine supplementation necessary?
Our neurology department says yes for everyone - the cost is minimal and neuropathy can be debilitating. We’ve seen complete resolution in most cases with pyridoxine and dose adjustment.
## 10. Conclusion: Validity of Isoniazid Use in Clinical Practice
After forty years of using this drug, I’m still impressed by its efficacy when used appropriately. The hepatotoxicity risk is real but manageable with careful patient selection and monitoring. For TB control, it remains indispensable despite newer agents.
The real lesson I’ve learned is that context matters - isoniazid works beautifully in structured settings with good adherence support. In chaotic social situations, we need to get creative - directly observed therapy, video monitoring, whatever it takes.
I’m following Maria still - five years post-treatment, no TB recurrence. She brings me cookies every Christmas, reminds me why we put up with the monitoring hassles and bureaucratic nonsense. Her granddaughter just started medical school - maybe she’ll be the one developing the next generation of TB drugs. Until then, we’ll keep using isoniazid, warts and all.