Isoniazid

Introduction Overview

Generic Name

isoniazid

Brand Name

Nydrazid

Dosage Form

oral syrup (50 mg/5 mL), oral tablet (100 mg; 300 mg)

Drug Class

Hydrazide derivatives

Pharmacokinetics

Absorption:
Isoniazid is rapidly and almost completely absorbed from the gastrointestinal tract, primarily through passive diffusion. Following oral administration, peak plasma concentrations are usually reached within 1 to 2 hours. Absorption is not significantly affected by food; however, to maximize absorption and reduce gastric irritation, isoniazid is commonly recommended to be taken on an empty stomach, at least one hour before or two hours after meals. The bioavailability ranges near 100%, indicating excellent oral absorption. Various factors may influence absorption, including gastrointestinal pH and motility, but clinical data suggest these effects are minimal.

Distribution:
Isoniazid is widely distributed throughout body tissues and fluids, including lung, liver, kidneys, and cerebrospinal fluid at therapeutic concentrations, making it effective against intracellular Mycobacterium tuberculosis. It crosses the placenta and is excreted in breast milk. Its volume of distribution approximates total body water, reflecting extensive distribution into body compartments. The drug binds minimally to plasma proteins (about 10-20%), which facilitates its penetration into most tissues. Distribution may vary in patients with altered physiology, such as those with hepatic impairment, which may further influence both efficacy and toxicity.

Metabolism:
Isoniazid undergoes extensive hepatic metabolism primarily by acetylation, catalyzed by the N-acetyltransferase enzyme system. Genetic polymorphisms result in categorization of patients as 'slow' or 'fast' acetylators, significantly impacting plasma half-life and susceptibility to toxicity or treatment failure. Slow acetylators experience higher plasma concentrations and prolonged drug exposure, increasing risk of adverse effects, notably hepatotoxicity and peripheral neuropathy. Metabolic pathways also include hydrolysis and conjugation with glycine to form acetylhydrazine and diacetylhydrazine, metabolites implicated in hepatotoxicity. Drug interactions affecting hepatic enzymes, such as cytochrome P450s, can alter isoniazid metabolism and necessitate careful monitoring.

Elimination:
Isoniazid and its metabolites are primarily eliminated via the kidneys through glomerular filtration and tubular secretion. Renal excretion accounts for approximately 75-95% of the administered dose within 24 hours, with less than 10% excreted unchanged. The elimination half-life varies depending on acetylation status: approximately 1 hour in fast acetylators and 3 hours in slow acetylators. Impaired renal function may prolong elimination and warrant dose adjustment. Minor biliary excretion may occur, but its clinical significance is limited. The pharmacokinetic profile informs dosing intervals and the need for monitoring in special patient populations such as those with renal or hepatic impairment.

Dosage Forms

Available Dosage Forms:
Isoniazid is supplied in several oral formulations to accommodate patient needs and dosing requirements:
- Oral Syrup: 50 mg/5 mL
- Oral Tablets: 100 mg and 300 mg strengths
These dosage forms allow flexible dosing strategies especially for pediatric patients or those unable to swallow tablets.

Dosages for Adults and Adolescents:
The standard adult dosage for latent tuberculosis infection prophylaxis is typically 5 mg/kg daily (up to 300 mg daily) for 6 to 9 months. In active tuberculosis treatment regimens, isoniazid is used at 5 mg/kg (up to 300 mg) daily in combination with other antitubercular drugs. Alternatively, intermittent dosing regimens (twice or thrice weekly) may be employed under directly observed therapy (DOT) programs. Dosage adjustments may be necessary based on acetylator status, age, hepatic and renal function, and coadministered medications.

Specific Patient Populations:
In pediatric patients, dosing is weight-based at 10-15 mg/kg daily (maximum 300 mg/day). Patients with hepatic impairment require monitoring and possible dose adjustments due to increased risk of hepatotoxicity. Elderly patients should be monitored closely for liver enzyme elevations and neuropathy. Patients with renal impairment generally do not require dose adjustment but should be monitored for toxicity.

Clinical guidelines stress administration on an empty stomach to optimize absorption and advise supplementation with pyridoxine (vitamin B6) to prevent isoniazid-induced peripheral neuropathy, especially in malnourished, diabetic, pregnant, or HIV-infected patients who are at higher risk.

Mechanism Of Action

Isoniazid is a prodrug that requires activation by the bacterial enzyme catalase-peroxidase (encoded by the katG gene) within Mycobacterium tuberculosis. Once activated, isoniazid forms reactive species that interfere with the synthesis of mycolic acids—essential components of the mycobacterial cell wall responsible for maintaining structural integrity and impermeability.

Biochemically, activated isoniazid inhibits the NADH-dependent enoyl-ACP reductase (InhA), a critical enzyme in the fatty acid synthase II system of mycolic acid biosynthesis. This inhibition halts the elongation of mycolic acid chains, leading to defective cell wall formation, increased cell permeability, and ultimately bacterial cell death. The bactericidal activity is most pronounced against actively replicating tubercle bacilli.

In addition, isoniazid exerts a mycobactericidal effect by generating reactive oxygen species and modulating bacterial metabolism, contributing to intracellular killing. Resistance mechanisms commonly involve mutations in katG, reducing prodrug activation, or mutations in inhA, decreasing drug binding affinity.

Clinically, the specificity of isoniazid for mycobacteria underpins its critical role in tuberculosis treatment regimens. Comparative to other antitubercular agents, isoniazid's unique mechanism complements drugs like rifampin (a RNA polymerase inhibitor) and pyrazinamide (active in acidic environments), providing synergistic effects that reduce the emergence of resistance and shorten therapy duration. Numerous clinical trials have validated isoniazid's efficacy and tolerability when used in combination therapy for latent and active tuberculosis.

Pharmacological Actions

Potent bactericidal activity against Mycobacterium tuberculosis by inhibiting mycolic acid synthesis.
Selective inhibition of NADH-dependent enoyl-ACP reductase (InhA) enzyme in mycobacterial cell wall biosynthesis.
Activated intracellularly by bacterial catalase-peroxidase (katG), producing reactive species.
Disruption of mycobacterial cell wall integrity resulting in increased permeability and cell death.
Effective against actively dividing mycobacterial bacilli, with limited activity against dormant organisms.
Synergistic action when combined with other first-line antitubercular agents (e.g., rifampin).
Potential modulation of bacterial metabolism through reactive oxygen species generation.
Minimal effect on normal human flora due to specific targeting of mycobacterial enzymes.
Demonstrates low protein binding facilitating extensive tissue and intracellular penetration.
Metabolized by acetylation with pharmacogenetic variability impacting drug exposure and toxicity.
Therapeutic effect enhanced when combined with pyridoxine (vitamin B6) to reduce neurotoxicity.
Lack of cross-resistance with other antituberculosis drugs except those impacting katG or inhA.
Capable of crossing blood-brain barrier, making it effective in tuberculous meningitis.
Exhibits a short half-life, necessitating daily or intermittent dosing in clinical practice.

Therapeutic Or Clinical Uses

Treatment of active tuberculosis in combination with other antitubercular drugs to prevent resistance.
Prophylaxis for latent tuberculosis infection in individuals at high risk of progression to active disease.
Management of tuberculosis caused by Mycobacterium kansasii as part of multi-drug regimens.
Use in preventive therapy among immunocompromised patients, including those with HIV/AIDS.
Post-exposure prophylaxis following contact with active tuberculosis cases in susceptible populations.
Adjunct therapy in tuberculosis meningitis and miliary tuberculosis due to excellent CNS penetration.
Used in multidrug regimens for both pulmonary and extrapulmonary tuberculosis infection.
Treatment of tuberculosis in pediatric patients with weight-based dosing to ensure efficacy and safety.
Component of directly observed therapy (DOT) programs to improve treatment adherence and outcomes.
Preventive therapy in patients undergoing immunosuppressive treatments such as TNF-alpha inhibitors.
Management strategy in tuberculous pleuritis and bone/joint tuberculosis cases.
Medication employed in combination regimens to reduce treatment duration and minimize resistance.
Utilized in drug-susceptibility guided therapy to tailor treatment for resistant tuberculosis strains.
Occasionally used off-label for certain non-tuberculous mycobacterial infections in combination therapy.
Part of standard treatment protocol recommended by WHO and CDC for tuberculosis control.

Side Or Adverse Effects

Peripheral neuropathy presenting as numbness, tingling, or burning sensations in extremities.
Hepatotoxicity ranging from asymptomatic elevation of liver enzymes to severe liver failure.
Hypersensitivity reactions including rash, fever, and, rarely, severe skin reactions such as Stevens-Johnson syndrome.
Gastrointestinal symptoms such as nausea, vomiting, and abdominal discomfort.
Central nervous system effects including dizziness, ataxia, seizures, and memory impairment in rare cases.
Optic neuritis leading to changes in vision or pain behind the eyes.
Hematological effects such as anemia, thrombocytopenia, and leukopenia.
Systemic lupus erythematosus-like syndrome with arthralgia, fever, and skin manifestations.
Hyperglycemia or impaired glucose tolerance particularly in diabetic patients.
Psychiatric manifestations potentially including confusion, hallucinations, or depression.
Elevated serum uric acid levels leading to gout exacerbations in predisposed patients.
Drug-induced fever and flu-like symptoms.
Unusual bruising or bleeding due to thrombocytopenia or altered coagulation.
Allergic hepatitis or cholestatic jaundice especially in patients with previous liver disease.
Rare reports of seizure disorders or encephalopathy associated with overdose or toxicity.

Precautions

Baseline and periodic monitoring of liver function tests are essential due to risk of hepatotoxicity.
Concomitant alcohol consumption should be avoided to reduce additive liver injury risk.
Supplementation with pyridoxine (vitamin B6) is recommended to prevent peripheral neuropathy.
Use caution in patients with pre-existing liver disease or a history of isoniazid-induced hepatitis.
Monitor closely in elderly patients who have higher susceptibility to adverse hepatic effects.
Careful assessment in patients with diabetes or malnutrition who are more vulnerable to neuropathy.
Evaluate acetylator status or adjust dosing in populations known for slow acetylation to prevent toxicity.
Avoid use in patients with known hypersensitivity or previous severe adverse reactions to isoniazid.
Cautious use and monitoring warranted in HIV-infected individuals due to increased risk of toxicity.
Inform patients about signs of liver injury and neuropathy and instruct prompt reporting of symptoms.
Caution in those taking other hepatotoxic or neurotoxic medications to minimize additive risks.
Close monitoring required during pregnancy and breastfeeding, with potential benefit-risk assessment.
Use with care in patients with renal impairment, although routine dose adjustments are generally not needed.
Avoid abrupt discontinuation to prevent emergence of resistant mycobacteria or disease relapse.
Educate patients to adhere strictly to prescribed dosing schedules and not to double doses if missed.

Warnings

Contraindicated in active liver disease or a history of severe hepatic reactions to isoniazid.
Serious and sometimes fatal hepatotoxicity may occur, particularly in patients aged 35-65 years.
Monthly liver function monitoring is recommended during prolonged treatment courses.
Discontinue isoniazid immediately if signs of liver dysfunction (nausea, vomiting, jaundice, fatigue) occur.
Avoid alcohol consumption during therapy to reduce risk of liver damage.
Risk of peripheral neuropathy necessitates vitamin B6 supplementation in high-risk groups.
May cause severe hypersensitivity reactions including anaphylaxis and severe skin reactions.
Use caution in patients with a history of peripheral neuropathy or seizure disorders.
Monitor for signs of neurotoxicity such as confusion, memory loss, or hallucinations.
Potential for drug interactions that increase toxicity or reduce efficacy.
Not recommended in patients with a history of severe allergic reactions or multiple drug intolerances.
Possible hematologic toxicity requires vigilance for symptoms of bleeding or bruising.
Pregnancy and breastfeeding require risk-benefit assessment; limited data on safety available.
Risk of lupus-like syndrome with prolonged use, warranting clinical monitoring for autoimmune manifestations.
Avoid use as monotherapy in active tuberculosis to prevent development of drug-resistant strains.

Contraindication

Known hypersensitivity to isoniazid or any component of the formulation.
Active liver disease or hepatic impairment with significant transaminase elevations.
History of isoniazid-induced hepatitis, liver failure, or severe adverse reactions.
Previous occurrence of severe allergic reactions such as anaphylaxis or Stevens-Johnson syndrome with isoniazid.
Concurrent use with other hepatotoxic medications where risks outweigh benefits without monitoring.
Patients with suspected or confirmed acute phase of tuberculosis without combination therapy.
Severe peripheral neuropathy unresponsive to pyridoxine supplementation.
Individuals with a history of severe lupus-like syndrome triggered by isoniazid.
Use in patients with unexplained persistent fever or rash during treatment.
Use with caution or contraindicated in individuals with significant alcohol abuse or dependence.
Known acetylation status causing excessive toxicity without monitoring or dose adjustment.
Presence of severe renal impairment without ability to monitor for toxicity.
Contraindicated in patients unwilling or unable to adhere to strict monitoring and therapy guidelines.
Children under prescribed age or weight criteria without appropriate dosing adjustments.
Pregnant women only if clearly needed and benefits justify potential risks after medical evaluation.

Drug Interactions

Increased risk of hepatotoxicity when combined with other hepatotoxic drugs such as rifampin, pyrazinamide, or phenytoin.
Isoniazid inhibits cytochrome P450 enzymes (notably CYP2C19, CYP3A4, and CYP2E1), affecting metabolism of many drugs.
Potentiation of the effects and toxicity of carbamazepine, leading to increased serum levels and seizures.
Enhanced anticoagulant effect with warfarin, requiring close monitoring of INR to avoid bleeding complications.
Increased plasma concentrations of phenytoin, potentially causing toxicity including nystagmus and ataxia.
Possible increase in levels and toxicity of theophylline and caffeine due to P450 inhibition.
Reduced metabolism of benzodiazepines such as diazepam and triazolam, leading to sedation and prolonged effects.
Interaction with rifampin reduces isoniazid plasma levels due to enzyme induction, necessitating dose adjustments.
Potential antagonistic interaction with levodopa, reducing its efficacy in Parkinson’s disease management.
Increased risk of peripheral neuropathy when used with cycloserine or ethionamide without pyridoxine supplementation.
Concurrent use with alcohol significantly raises hepatotoxicity risk and should be avoided.
Interference with metabolism of sulfonylureas may lead to hypoglycemia or hyperglycemia.
May alter the efficacy of antiretroviral agents; careful monitoring required in HIV patients.
Concomitant use with valproic acid may of increased neurotoxicity and necessitates dose monitoring.
Potential interaction with anticonvulsants requiring adjustment of dosages.
Herbal products like St. John's Wort may alter isoniazid metabolism and effectiveness.

Preparations Of The Drug

Oral syrup formulation: 50 mg/5 mL concentration suitable for pediatric and patients unable to swallow tablets.
Oral tablets available in 100 mg and 300 mg strengths for flexible dosing and ease of administration in adults and children.
Combination formulations with pyridoxine designed to mitigate risk of peripheral neuropathy.
Injectable formulations available under specialized circumstances but rarely used compared to oral forms.
Commercially marketed under the brand name Nydrazid among others internationally.
Packaged with detailed patient information regarding administration on empty stomach and adherence importance.
Storage recommendations specify room temperature, protection from moisture, heat, and light to maintain stability.
Unit dose packaging and blister packs facilitate accurate dosing and reduce medication errors.
Formulations manufactured according to stringent quality control to ensure bioequivalence and purity.
Parenteral forms are primarily reserved for patients unable to tolerate oral therapy or with severe disease.
Some preparations incorporate flavoring agents to improve palatability particularly for pediatric use.
Dosage forms are included in tuberculosis treatment programs and directly observed therapy (DOT) kits.
Bulk powder forms exist for compounding but are restricted to specialized pharmacy settings.
Available preparations comply with regulatory and pharmacopoeial standards for antitubercular agents.
Commercial products come with prescribing information including contraindications, warnings, and interactions.