Monograph of Isoniazid

Introduction

Isoniazid, a first‑line antitubercular agent, has maintained a pivotal role in the treatment of tuberculosis (TB) for several decades. As a hydrazide derivative of nicotinamide, it exerts its therapeutic effect by inhibiting mycolic acid synthesis, thereby compromising the integrity of the mycobacterial cell wall. The historical evolution of isoniazid, from its discovery in the 1950s to its current inclusion in standardized treatment regimens, underscores its significance in both clinical and pharmacological domains. Understanding the pharmacodynamic and pharmacokinetic properties of this drug, as well as its clinical implications, is indispensable for medical and pharmacy students seeking to grasp the intricacies of TB management.

• Define the pharmacological profile of isoniazid.
• Trace the historical development and clinical adoption of the drug.
• Explain the relevance of isoniazid within contemporary antitubercular therapy.
• Identify key pharmacokinetic parameters influencing dosing strategies.
• Recognize common adverse effects and strategies for mitigation.

Fundamental Principles

Core Concepts and Definitions

Is a hydrazide that functions as a bactericidal agent against Mycobacterium tuberculosis. The drug is typically administered orally in tablet or capsule form and is absorbed in the gastrointestinal tract. Its mechanism of action involves the inhibition of the enzyme mycolic acid synthase, which is essential for the synthesis of the mycobacterial cell wall. The resultant impairment of cell wall synthesis leads to cell death and clearance of the pathogen.

Theoretical Foundations

Pharmacodynamic models for isoniazid are often built upon the concept of time‑dependent killing. The concentration–time curve is a key determinant of therapeutic efficacy, with the area under the curve (AUC) and peak concentration (C_max) serving as pivotal pharmacokinetic indices. The relationship can be expressed as: C(t) = C₀ × e^‑k_elt, where k_el denotes the elimination rate constant. The elimination half‑life (t_1/2) is related to k_el by the equation t_1/2 = ln(2) ÷ k_el ≈ 0.693 ÷ k_el minutes.

Key Terminology

• Bioavailability – the proportion of the administered dose that reaches systemic circulation intact.
• First‑pass metabolism – hepatic metabolism occurring before the drug reaches systemic circulation, which can reduce bioavailability.
• Genotype‑driven variability – differences in drug response or toxicity due to genetic polymorphisms, notably in the N-acetyltransferase 2 (NAT2) enzyme.
• Therapeutic drug monitoring (TDM) – the clinical practice of measuring drug concentrations to optimize dosage.

Detailed Explanation

Mechanism of Action

Isoniazid’s bactericidal activity is primarily mediated through the inhibition of the enzyme enoyl‑acyl carrier protein reductase, which catalyzes a critical step in the biosynthesis of mycolic acids. By disrupting this pathway, the drug compromises the structural integrity of the mycobacterial cell wall, leading to cell lysis. The action is most effective during the logarithmic phase of bacterial growth, underscoring its suitability for active TB disease rather than latent infection alone.

Pharmacodynamics

Time‑dependent bactericidal activity is a hallmark of isoniazid. Research indicates that maintaining plasma concentrations above the minimum inhibitory concentration (MIC) for a sufficient duration is essential for optimal efficacy. The pharmacodynamic target (C_min ≥ MIC) is often expressed as the ratio of AUC to MIC (AUC/MIC). For isoniazid, an AUC/MIC ratio of > 25 h has been associated with favorable outcomes in standard treatment regimens.

Pharmacokinetics

Absorption

Following oral administration, isoniazid is rapidly absorbed, with peak plasma concentrations typically achieved within 1–2 hours. The absolute bioavailability is reported to be approximately 80 % under fasting conditions, although it may be reduced when taken with food. The absorption process is not significantly affected by gastric pH variations, making it relatively robust across different physiological states.

Distribution

Once absorbed, the drug distributes extensively into body tissues, including the central nervous system, where it achieves concentrations approximately 70 % of plasma levels. Protein binding is modest, around 10 %, which facilitates diffusion across membrane barriers. The volume of distribution (V_d) is approximately 1.5 L/kg, indicating a moderate tissue penetration profile.

Metabolism

Hepatic metabolism predominates, with the enzyme N-acetyltransferase 2 (NAT2) catalyzing acetylation to form acetylisoniazid. Genetic polymorphisms in the NAT2 gene lead to distinct acetylator phenotypes: rapid, intermediate, and slow. Fast acetylators exhibit a higher clearance of the drug, while slow acetylators retain higher plasma concentrations for extended periods. The kinetic equation for elimination can be expressed as: Clearance (CL) = k_el × V_d, and the AUC is calculated as Dose ÷ CL.

Excretion

Both unchanged isoniazid and its acetylated metabolite are excreted primarily via the kidneys. The renal clearance is approximately 0.15 L/min, with the majority of excretion occurring unchanged in the urine. Renal impairment may necessitate dose adjustment, particularly in patients with creatinine clearance below 30 mL/min.

Mathematical Relationships

The following equations are routinely employed in the pharmacokinetic analysis of isoniazid:

• C(t) = C₀ × e^‑k_elt
• t_1/2 ≈ 0.693 ÷ k_el
• AUC = Dose ÷ CL
• CL = V_d × k_el

Factors Affecting Pharmacokinetics

• Genetic polymorphisms – NAT2 acetylator status influences drug clearance and risk of hepatotoxicity.
• Hepatic function – Liver disease can reduce metabolic capacity, prolonging systemic exposure.
• Renal function – Impaired kidneys may accumulate the drug and its metabolites.
• Drug interactions – Concomitant use of rifampin can induce hepatic enzymes, increasing isoniazid clearance.
• Nutrition – Vitamin B6 deficiency may predispose patients to neurotoxicity, whereas vitamin supplementation can mitigate this risk.

Clinical Significance

Relevance to Drug Therapy

In the context of TB treatment, isoniazid is a cornerstone of both first‑line and preventive regimens. Its inclusion in combination therapy reduces the likelihood of resistance development. For latent TB infection (LTBI), a 6‑month daily course of isoniazid demonstrates superior efficacy compared to shorter regimens when adherence is maintained.

Practical Applications

Clinicians frequently adjust isoniazid dosing based on acetylator phenotype. For slow acetylators, a 300 mg daily dose may achieve therapeutic levels, whereas rapid acetylators may require 600 mg to reach comparable exposure. However, the potential for hepatotoxicity mandates careful monitoring, particularly in patients with preexisting liver disease or alcohol use disorder.

Clinical Examples

In a patient presenting with pulmonary TB and a normal liver function panel, a standard dose of 600 mg daily is typically initiated. Should the patient develop transaminase elevations exceeding 3 × the upper limit of normal, dose reduction to 300 mg or temporary discontinuation may be considered. Additionally, concurrent administration of pyridoxine (vitamin B6) at 25–50 mg daily reduces the incidence of peripheral neuropathy, particularly in populations at risk.

Clinical Applications/Examples

Case Scenario 1 – Rapid Acetylator with Hepatotoxicity

A 42‑year‑old male with newly diagnosed pulmonary TB is prescribed 600 mg isoniazid daily. After 4 weeks of therapy, alanine transaminase (ALT) levels rise from 22 U/L to 120 U/L, a 5.5‑fold increase. Genotyping reveals a rapid acetylator phenotype. The clinical decision may involve switching to a higher dose to achieve therapeutic levels while maintaining close monitoring of hepatic enzymes. Alternatively, a temporary interruption of therapy followed by re‑initiation at a reduced dose may be warranted, contingent upon the patient’s clinical status and risk assessment.

Case Scenario 2 – Slow Acetylator with Peripheral Neuropathy

A 55‑year‑old female with LTBI receives 300 mg isoniazid daily for 6 months. After 2 months, she reports tingling in the extremities. Screening reveals a slow acetylator genotype. Immediate initiation of pyridoxine 50 mg daily mitigates symptoms, and the therapy continues uninterrupted. This case illustrates the importance of genotype‑guided dosing and adjunctive vitamin supplementation.

Problem‑Solving Approaches

• Assess baseline hepatic and renal function before initiating therapy.
• Determine acetylator status when possible, particularly in populations with high prevalence of slow acetylators.
• Implement routine monitoring of liver enzymes at baseline, 2 weeks, and monthly thereafter.
• Administer pyridoxine prophylactically to reduce neurotoxicity risk.
• Adjust dosing or switch to alternative agents (e.g., ethambutol, pyrazinamide) if adverse effects persist.

Summary/Key Points

• Isoniazid is a hydrazide derivative that inhibits mycolic acid synthesis, essential for mycobacterial cell wall integrity.
• The drug exhibits time‑dependent bactericidal activity; maintaining plasma concentrations above the MIC for a sufficient duration is critical.
• Pharmacokinetic parameters: C_max achieved within 1–2 h, bioavailability ≈ 80 %, V_d ≈ 1.5 L/kg, t_1/2 ≈ 2–4 h in rapid acetylators, and longer in slow acetylators.
• Genetic polymorphisms in NAT2 significantly influence drug clearance and toxicity risk.
• Hepatotoxicity and peripheral neuropathy are the most common adverse effects; prophylactic pyridoxine reduces neurotoxicity incidence.
• Therapeutic drug monitoring can optimize efficacy and minimize toxicity, particularly in special populations.
• Combination therapy with other antitubercular agents reduces resistance emergence and improves treatment outcomes.

References

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