Pharmacology of Isoniazid

Introduction/Overview

Isoniazid, also known by its abbreviation INH, represents a cornerstone chemotherapeutic agent in the global management of tuberculosis (TB). Since its introduction into clinical practice in the early 1950s, its potent bactericidal activity against Mycobacterium tuberculosis has rendered it indispensable for both the treatment of active disease and the prevention of latent infection. The enduring clinical relevance of isoniazid is underscored by its inclusion as a first-line agent in all standard TB regimens, a status maintained for over seven decades despite the development of newer antimycobacterial drugs. Its importance extends beyond individual patient care to public health strategies, where it serves as the primary agent for chemoprophylaxis, a critical component in TB eradication efforts. The pharmacology of isoniazid is characterized by a unique and specific mechanism of action, a generally favorable pharmacokinetic profile, and a distinct set of adverse effects that necessitate vigilant monitoring. A thorough understanding of its pharmacodynamics, pharmacokinetics, therapeutic applications, and toxicological profile is essential for clinicians and pharmacists involved in the management of tuberculosis.

Learning Objectives

• Describe the specific molecular mechanism of action of isoniazid, including its activation within Mycobacterium tuberculosis and its primary biochemical target.
• Outline the key pharmacokinetic properties of isoniazid, including its absorption, distribution, metabolism by N-acetyltransferase 2 (NAT2), and elimination, and explain how genetic acetylation status influences dosing and toxicity.
• Identify the primary therapeutic indications for isoniazid, distinguishing its role in active tuberculosis treatment from its use in latent tuberculosis infection (LTBI) prophylaxis.
• Recognize the major adverse effects associated with isoniazid therapy, particularly hepatotoxicity and peripheral neuropathy, and describe appropriate monitoring and preventive strategies.
• Analyze significant drug interactions involving isoniazid, with particular attention to those affecting anticonvulsant and antiretroviral therapies, and apply this knowledge to clinical management.

Classification

Isoniazid is classified pharmacotherapeutically as a first-line antitubercular agent. It is a core component of the standard multidrug regimens recommended by global health authorities, including the World Health Organization and the Centers for Disease Control and Prevention, for the treatment of drug-susceptible tuberculosis. From a chemical perspective, isoniazid is a synthetic derivative of nicotinic acid, specifically the hydrazide of isonicotinic acid. Its simple molecular structure, pyridine-4-carbohydrazide, belies its remarkable specificity and potency against mycobacteria. This structural relationship to nicotinamide is integral to its mechanism of action, as it serves as a prodrug that is activated by a bacterial enzyme to interfere with the synthesis of essential nicotinamide-derived cofactors.

Mechanism of Action

The antibacterial activity of isoniazid is exquisitely specific for members of the Mycobacterium tuberculosis complex, with minimal activity against other bacterial genera. This specificity arises from a requirement for bacterial enzyme activation and the presence of a unique bacterial target.

Molecular and Cellular Mechanisms

Isoniazid functions as a prodrug. Its activation is catalyzed by the mycobacterial enzyme catalase-peroxidase, encoded by the katG gene. This enzyme oxidizes isoniazid to form a range of reactive species, primarily an isonicotinoyl radical. This activated form then interacts with NAD⁺ or NADP⁺ to form a covalently bound adduct. The primary target of this isoniazid-NAD(P) adduct is the enzyme enoyl-acyl carrier protein reductase, known as InhA. InhA is an essential component of the type II fatty acid synthase (FAS-II) system in mycobacteria, which is responsible for the elongation of long-chain fatty acids. The adduct binds tightly to the active site of InhA, inhibiting its reductase activity. This inhibition disrupts the synthesis of mycolic acids, which are very long-chain, branched fatty acids that are critical constituents of the mycobacterial cell wall. Mycolic acids confer much of the characteristic impermeability, acid-fastness, and resilience of the mycobacterial envelope. Inhibition of their synthesis leads to a loss of cell wall integrity, bacterial cell lysis, and ultimately, cell death. The bactericidal effect of isoniazid is most pronounced against actively replicating mycobacteria, as cell wall synthesis is an ongoing process during division.

Resistance to isoniazid develops primarily through mutations in the katG gene, which impair the activation of the prodrug. Mutations in the promoter region of the inhA gene, leading to its overexpression, or within the inhA structural gene itself, can also confer resistance by reducing the binding affinity of the drug-adduct or by increasing the amount of target enzyme. Other, less common mechanisms involve mutations in genes such as ahpC and ndh.

Pharmacokinetics

The pharmacokinetic profile of isoniazid is characterized by good oral bioavailability, widespread tissue distribution, and metabolism that exhibits significant genetic polymorphism, which has profound clinical implications.

Absorption

Isoniazid is rapidly and nearly completely absorbed from the gastrointestinal tract following oral administration. Bioavailability typically exceeds 90% under fasting conditions. Peak plasma concentrations (C_max) are generally achieved within 1 to 2 hours post-dose. The presence of food, particularly high-fat meals, can delay and moderately reduce absorption; therefore, administration on an empty stomach is often recommended, though clinical practice may allow administration with food to improve tolerability if gastrointestinal upset occurs. Intramuscular administration is possible and results in comparable bioavailability but is rarely used in contemporary practice.

Distribution

Isoniazid distributes widely throughout body water and readily penetrates into various tissues and body fluids. It achieves therapeutic concentrations in pleural and cerebrospinal fluids, making it effective in the treatment of extrapulmonary tuberculosis, including tuberculous meningitis. The apparent volume of distribution is approximately 0.6 L/kg. The drug crosses the placenta and is also excreted into breast milk.

Metabolism

Hepatic metabolism represents the primary route of elimination for isoniazid. The most significant metabolic pathway is acetylation by the hepatic enzyme N-acetyltransferase 2 (NAT2). The activity of NAT2 is determined by genetic polymorphism, leading to a bimodal distribution of the population into rapid acetylators and slow acetylators. The frequency of these phenotypes varies among ethnic groups. Slow acetylators have a relative deficiency of functional NAT2 enzyme, leading to higher and more prolonged plasma concentrations of the parent drug. Rapid acetylators convert isoniazid to acetylisoniazid more quickly, which is then hydrolyzed to isonicotinic acid and monoacetylhydrazine. Monoacetylhydrazine can be further acetylated to diacetylhydrazine. This acetylation status significantly influences the plasma half-life, risk of certain toxicities, and potentially, dosing strategies. Other minor metabolic pathways include direct hydrolysis and conjugation with glycine.

Excretion

The metabolites of isoniazid, along with a small proportion of unchanged drug (which is higher in slow acetylators), are primarily excreted in the urine. Renal clearance accounts for approximately 75-95% of an administered dose within 24 hours. In patients with normal renal function, dosage adjustment is usually not required. However, in cases of severe renal impairment, accumulation of the parent drug may occur, particularly in slow acetylators, warranting cautious use and potential dose reduction.

Half-life and Dosing Considerations

The elimination half-life (t_1/2) of isoniazid is directly dependent on acetylation phenotype. In slow acetylators, the half-life ranges from 2 to 5 hours, whereas in rapid acetylators, it is typically between 0.5 and 1.5 hours. This difference historically led to recommendations for divided daily dosing. However, because the antibacterial effect of isoniazid is concentration-dependent and exhibits a significant post-antibiotic effect, once-daily dosing is now standard for both phenotypes in the treatment of active TB. The standard daily dose for adults is 5 mg/kg (maximum 300 mg) and for children is 10-15 mg/kg (maximum 300 mg). For intermittent therapy (e.g., twice or thrice weekly), doses are increased to 15 mg/kg (maximum 900 mg). For latent TB infection, a daily dose of 5 mg/kg (max 300 mg) or twice-weekly dose of 15 mg/kg (max 900 mg) is used.

Therapeutic Uses/Clinical Applications

Approved Indications

The therapeutic applications of isoniazid are centered on infections caused by Mycobacterium tuberculosis.

• Active Tuberculosis: Isoniazid is a fundamental component of all first-line, short-course regimens for drug-susceptible pulmonary and extrapulmonary tuberculosis. It is never used as monotherapy for active disease due to the rapid emergence of resistance. Standard regimens (e.g., 2 months of isoniazid, rifampin, pyrazinamide, and ethambutol, followed by 4 months of isoniazid and rifampin) rely on its potent early bactericidal activity to rapidly reduce the bacterial load.
• Latent Tuberculosis Infection (LTBI) Treatment: This represents a major public health use of isoniazid. Individuals with latent infection (positive tuberculin skin test or interferon-gamma release assay without active disease) are treated to prevent progression to active TB. Several regimens exist, with a classic course being isoniazid monotherapy daily for 9 months. Shorter regimens combining isoniazid with rifapentine once weekly for 3 months are also widely used.
• Preventive Therapy in Special Populations: Isoniazid is indicated for TB prophylaxis in specific high-risk groups, including close contacts of active TB cases, HIV-infected individuals with a positive LTBI test, patients with fibrotic lesions on chest radiograph consistent with old TB, and those initiating tumor necrosis factor-alpha inhibitor therapy.

Off-Label Uses

While its use is highly specific to mycobacteria, isoniazid has been investigated in other contexts with limited evidence. It is not recommended for infections caused by nontuberculous mycobacteria (NTM), as most species are inherently resistant.

Adverse Effects

The use of isoniazid is associated with a range of adverse effects, from common and benign to rare and life-threatening. Vigilant monitoring is a critical component of therapy.

Common Side Effects

• Gastrointestinal Disturbances: Nausea, vomiting, and epigastric discomfort may occur, especially with higher doses or if taken on an empty stomach.
• Neurotoxic Effects: Peripheral neuropathy, characterized by symmetrical numbness, tingling, and pain in the hands and feet, is a dose-related adverse effect. It results from isoniazid’s interference with pyridoxine (vitamin B₆) metabolism, leading to a functional deficiency. This effect is more common in slow acetylators, individuals with predisposing conditions (diabetes, alcoholism, malnutrition, HIV), and with higher doses.
• Mild Central Nervous System Effects: Dizziness, drowsiness, and headaches are occasionally reported.

Serious and Rare Adverse Reactions

• Hepatotoxicity: This is the most significant adverse effect of isoniazid. It can range from asymptomatic elevation of serum transaminases (occurring in 10-20% of patients) to clinically apparent hepatitis and, rarely, fulminant hepatic necrosis. The risk increases with age, pre-existing liver disease, concurrent alcohol use, and possibly in women, particularly in the postpartum period. The mechanism is believed to involve the formation of a toxic metabolite, possibly from monoacetylhydrazine, which can cause hepatocellular damage. Hepatotoxicity can occur at any time during therapy but is most frequent within the first three months.
• Hypersensitivity Reactions: Skin rashes, fever, and arthralgias can occur. Severe reactions like Stevens-Johnson syndrome are exceedingly rare.
• Hematologic Effects: Agranulocytosis, thrombocytopenia, and sideroblastic anemia have been reported. The anemia may also be related to pyridoxine deficiency.
• Autoimmune Phenomena: Isoniazid can induce a lupus-like syndrome, with positive antinuclear antibodies and symptoms such as arthritis and fever, which typically resolve upon drug discontinuation.
• Metabolic Effects: Pyridoxine deficiency can also lead to sideroblastic anemia and, in severe cases, seizures. Metabolic acidosis is a rare but serious event.

Black Box Warnings

Isoniazid carries a boxed warning from the U.S. Food and Drug Administration regarding severe and sometimes fatal hepatitis. The warning emphasizes that the risk increases with age and alcohol consumption, and it mandates that patients be informed of the symptoms of hepatitis (unexplained anorexia, nausea, vomiting, dark urine, jaundice, fatigue) and instructed to discontinue the drug and seek medical attention immediately if they occur. Regular clinical and laboratory monitoring of liver function is recommended, especially in high-risk patients.

Drug Interactions

Isoniazid is involved in several clinically significant drug interactions, primarily due to its metabolism via and inhibition of the cytochrome P450 enzyme system, particularly CYP2C19, CYP2C9, and CYP3A4.

Major Drug-Drug Interactions

• Anticonvulsants: Isoniazid inhibits the metabolism of phenytoin and carbamazepine, leading to increased serum concentrations and a heightened risk of toxicity (nystagmus, ataxia, drowsiness for phenytoin; dizziness, ataxia for carbamazepine). Serum level monitoring of these anticonvulsants is essential when isoniazid is initiated or discontinued.
• Warfarin: Isoniazid may potentiate the anticoagulant effect of warfarin by inhibiting its metabolism, increasing the risk of bleeding. More frequent monitoring of the International Normalized Ratio (INR) is required.
• Benzodiazepines: The metabolism of certain benzodiazepines (e.g., diazepam, triazolam) that undergo oxidative metabolism may be inhibited, potentially prolonging their sedative effects.
• Ketoconazole and Itraconazole: Isoniazid may reduce the bioavailability of these azole antifungals, potentially leading to therapeutic failure. The mechanism may involve increased gastric pH or other factors.
• Rifamycins (Rifampin, Rifapentine): While these are used together therapeutically, rifampin is a potent inducer of cytochrome P450 enzymes and may increase the metabolism of isoniazid, potentially lowering its levels. This interaction is usually managed by the standard combination dosing.
• Acetaminophen: There is a theoretical increased risk of hepatotoxicity when acetaminophen is used concomitantly with isoniazid, as both can be metabolized to hepatotoxic intermediates. While clinical evidence is not robust, caution is advised, particularly with chronic, high-dose acetaminophen use.
• Antiretroviral Drugs: Interactions with protease inhibitors and non-nucleoside reverse transcriptase inhibitors are complex due to overlapping effects on CYP enzymes. For instance, isoniazid may increase levels of ritonavir-boosted regimens. Expert consultation is mandatory in co-infected patients.
• Disulfiram: Concurrent use may cause coordination difficulties and psychotic episodes.
• Theophylline: Isoniazid may inhibit the metabolism of theophylline, increasing the risk of toxicity (nausea, vomiting, tachycardia, seizures).

Contraindications

Absolute contraindications to isoniazid therapy include severe previous hypersensitivity reactions to the drug (e.g., drug-induced hepatitis, Stevens-Johnson syndrome) and acute liver disease of any etiology. Its use in patients with severe hepatic impairment is contraindicated. A history of isoniazid-associated liver injury is also a strong relative contraindication to re-challenge.

Special Considerations

Use in Pregnancy and Lactation

Isoniazid is generally considered safe for use during pregnancy (Pregnancy Category C under the old FDA classification; no increased risk of teratogenicity has been demonstrated in large studies). Untreated tuberculosis poses a far greater risk to the pregnant person and fetus than does treatment. However, the risk of drug-induced hepatitis may be increased in the postpartum period. Pyridoxine supplementation (25-50 mg daily) is recommended for all pregnant individuals receiving isoniazid to protect both the patient and the fetus. Isoniazid is excreted into breast milk in low concentrations, but the amount ingested by the nursing infant is not considered harmful. The American Academy of Pediatrics considers it compatible with breastfeeding. Pyridoxine supplementation is also recommended for the breastfeeding infant if the mother is receiving high-dose isoniazid therapy.

Pediatric Considerations

Children tolerate isoniazid exceptionally well and are at much lower risk for hepatotoxicity compared to adults. Dosing is weight-based at 10-15 mg/kg/day (max 300 mg). Liquid formulations are available. Pyridoxine supplementation is not routinely required for children on standard doses unless they are malnourished or on concomitant medications that increase neurotoxicity risk.

Geriatric Considerations

The risk of isoniazid-induced hepatitis increases progressively with age, particularly after age 35, and is highest in those over 65. Baseline liver function tests are recommended, and patients should be monitored closely for clinical symptoms. Lower thresholds for investigating symptoms are warranted. Dose adjustment based on renal function may be necessary due to age-related decline in glomerular filtration rate, especially in slow acetylators.

Renal Impairment

Dosage adjustment is not usually necessary in mild to moderate renal impairment, as the parent drug and metabolites are adequately cleared. In patients with severe renal impairment (creatinine clearance < 30 mL/min) or those on hemodialysis, accumulation can occur. A dose reduction may be considered, or administration may be scheduled post-dialysis, as isoniazid is readily dialyzable. Monitoring for signs of neurotoxicity is prudent.

Hepatic Impairment

Isoniazid is contraindicated in acute liver disease and should be used with extreme caution, if at all, in patients with chronic liver disease or baseline transaminase elevations greater than three times the upper limit of normal. The risk of further hepatotoxicity is significantly increased. If use is deemed absolutely necessary, frequent monitoring of liver enzymes (e.g., every 2-4 weeks) is mandatory, and pyridoxine should be co-administered.

Summary/Key Points

• Isoniazid is a first-line, bactericidal antitubercular agent with specific activity against Mycobacterium tuberculosis. Its mechanism involves activation by bacterial KatG to form an adduct that inhibits mycolic acid synthesis, a critical component of the mycobacterial cell wall.
• Pharmacokinetics are marked by excellent oral absorption, wide distribution (including to CSF), and hepatic metabolism via N-acetyltransferase 2 (NAT2). Genetic polymorphism in NAT2 results in rapid and slow acetylator phenotypes, influencing plasma half-life and toxicity profiles.
• Its primary uses are as a core component of multidrug regimens for active drug-susceptible tuberculosis and as monotherapy for the treatment of latent tuberculosis infection (LTBI).
• The most significant adverse effect is dose- and age-related hepatotoxicity, which can range from asymptomatic transaminitis to fatal hepatitis. Peripheral neuropathy due to pyridoxine (B₆) deficiency is common and preventable.
• Major drug interactions involve inhibition of cytochrome P450 enzymes (particularly CYP2C19 and CYP3A4), leading to increased levels of phenytoin, carbamazepine, warfarin, and some benzodiazepines.
• Clinical monitoring for symptoms of hepatitis is paramount. Pyridoxine supplementation (25-50 mg daily) is recommended to prevent neuropathy in high-risk individuals (pregnant patients, those with diabetes, alcoholism, malnutrition, HIV, or renal failure).

Clinical Pearls

• Hepatotoxicity risk escalates with age; patients over 35 require clear education on hepatitis symptoms. Routine monthly symptom review is more practical than routine LFT monitoring in asymptomatic, otherwise healthy individuals, though baseline testing is advised.
• Always prescribe pyridoxine concomitantly with isoniazid for patients at risk for neuropathy (pregnancy, HIV, diabetes, alcoholism, renal failure, malnutrition).
• When a patient on stable phenytoin or warfarin starts isoniazid, anticipate the need to reduce the dose of the interacting drug and monitor levels or INR closely.
• For latent TB infection, completion of therapy is critical for efficacy. Directly observed therapy (DOT) or enhanced support strategies significantly improve completion rates for both the 9-month isoniazid and shorter rifapentine-based regimens.
• In patients presenting with unexplained hepatitis, a detailed medication history must include specific inquiry about isoniazid, as patients may not consider a “preventive” pill to be a significant medication.

References

1. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
2. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
3. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
4. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
5. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
6. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
7. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
8. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.