Antitubercular Drugs: Pharmacology and Clinical Application

Introduction/Overview

Mycobacterium tuberculosis remains a leading cause of morbidity and mortality worldwide, particularly in low‑ and middle‑income regions. Effective antitubercular therapy is essential for curative treatment and for preventing the emergence of drug‑resistant strains. This chapter provides a detailed examination of the pharmacological properties of antitubercular agents, with an emphasis on first‑line drugs and their clinical implications. The discussion is structured to support comprehension of drug selection, dosing, and monitoring in diverse patient populations.

Learning objectives:

• Describe the classification and chemical characteristics of principal antitubercular agents.
• Explain the mechanisms of action and pharmacodynamic principles underlying these drugs.
• Summarize pharmacokinetic parameters that influence dosing strategies.
• Identify common adverse effects, drug interactions, and special‑population considerations.
• Apply this knowledge to optimize therapeutic regimens for tuberculosis and related infections.

Classification

Drug Classes and Categories

Antitubercular agents can be grouped according to their temporal use in therapy and their mechanism of action:

• First‑line agents: isoniazid, rifampin, pyrazinamide, ethambutol, and streptomycin (historical).
• Second‑line agents: fluoroquinolones (moxifloxacin, levofloxacin), aminoglycosides (amikacin), cyclic peptidyl antibiotics (cycloserine), and linezolid.
• Adjunctive agents: ethionamide, para‑aminosalicylic acid, and bedaquiline (newer drug).

Chemical Classification

From a chemical standpoint, antitubercular drugs encompass a range of structures:

• Hydrazide derivatives: isoniazid, ethionamide.
• Phenolic compounds: pyrazinamide.
• Fluoroquinolones: levofloxacin, moxifloxacin (synthetic β‑lactam‑free antibiotics).
• Macrocyclic lactones: rifampin.
• Polypeptide antibiotics: streptomycin, amikacin.

Mechanism of Action

First‑Line Agents

Isoniazid: the prodrug undergoes activation by the bacterial catalase‑peroxidase enzyme KatG, yielding a reactive intermediate that inhibits mycolic acid synthesis by targeting the enoyl‑acyl carrier protein reductase (InhA) pathway. This interference compromises cell wall integrity, leading to bacterial death.

Rifampin: binds to the β‑subunit of RNA polymerase, blocking transcription initiation. The inhibition is sequence‑specific and results in a broad suppression of bacterial protein synthesis.

Pyrazinamide: is converted by the bacterial pyrazinamidase (PncA) into pyrazinoic acid, which accumulates in acidic intracellular compartments. The exact target remains partially understood, but disruption of membrane energetics and interference with fatty acid synthesis are implicated.

Ethambutol: interferes with arabinogalactan biosynthesis by competitively inhibiting arabinosyl transferases, thereby disrupting the cell wall’s peptidoglycan layer.

Streptomycin: binds to the 30S ribosomal subunit, inducing misreading of mRNA and inhibiting peptide bond formation. This results in defective protein synthesis.

Second‑Line and Adjunctive Agents

Fluoroquinolones inhibit DNA gyrase (type II topoisomerase) and topoisomerase IV, impeding DNA replication. Aminoglycosides, such as amikacin, bind to the 30S ribosomal subunit, causing erroneous protein synthesis. Linezolid inhibits the initiation of bacterial translation by binding to the 50S ribosomal subunit. Bedaquiline targets the mycobacterial ATP synthase, curtailing cellular energy production.

Pharmacokinetics

Absorption

Isoniazid: well absorbed orally; peak plasma concentrations occur within 1–2 h. Food does not significantly alter absorption. A small fraction is absorbed parenterally.

Rifampin: oral bioavailability is approximately 70 %; absorption is reduced when taken with high‑fat meals. Rapid absorption leads to peak levels at 2–4 h.

Pyrazinamide: readily absorbed; peak concentrations achieved in 2–3 h.

Ethambutol: oral bioavailability is around 60 %; peak levels are reached within 2–3 h.

Streptomycin: not absorbed orally; requires intramuscular or intravenous administration. Peak serum concentrations are achieved within 30 min to 1 h post‑dose.

Distribution

Isoniazid penetrates well into pulmonary tissues and cerebrospinal fluid. Rifampin distributes extensively into body fluids, including bile and urinary tract, but its penetration into the central nervous system is limited without adjunctive therapy.

Pyrazinamide achieves high concentrations in macrophage phagosomes, a crucial site of bacterial replication. Ethambutol demonstrates moderate distribution into tissues, with limited central nervous system penetration.

Streptomycin distributes into interstitial fluids but has limited penetration into lipid‑rich tissues.

Metabolism and Excretion

Isoniazid undergoes acetylation in the liver by N‑acetyltransferase 2; acetylation status influences plasma concentrations. Metabolites are excreted renally.

Rifampin is metabolized by hepatic conjugation and undergoes enterohepatic circulation; metabolites are excreted via bile and urine.

Pyrazinamide is primarily excreted unchanged by the kidneys; renal impairment necessitates dose adjustment.

Ethambutol is excreted unchanged in urine; dose modification is required for reduced renal clearance.

Streptomycin is eliminated by glomerular filtration; accumulation may occur in renal impairment.

Half‑Life and Dosing Considerations

Isoniazid half‑life ranges from 1.5 to 4.5 h, depending on acetylation status; standard dosing is 300 mg once daily. Rifampin has a half‑life of approximately 3–5 h; daily 600–900 mg dosing is typical. Pyrazinamide’s half‑life is 3–5 h; standard dose is 1500 mg daily. Ethambutol’s half‑life is 5–9 h; daily 15–25 mg/kg dosing is recommended. Streptomycin is dosed at 15–20 mg/kg daily, adjusted for renal function.

Therapeutic Uses/Clinical Applications

Approved Indications

First‑line agents constitute the backbone of standard tuberculosis therapy, typically administered for 6 months (2 months of intensive phase followed by 4 months of continuation phase). Combination regimens maximize bactericidal activity and mitigate resistance development.

Second‑line agents are reserved for multidrug‑resistant (MDR) or extensively drug‑resistant (XDR) tuberculosis, where first‑line agents are ineffective or contraindicated.

Off‑Label Uses

Ethambutol is occasionally employed in pulmonary nontuberculous mycobacterial infections, such as Mycobacterium avium complex, in combination with macrolides and rifamycins. Isoniazid has been investigated for prophylaxis in latent tuberculosis infection with varying efficacy. Fluoroquinolones are sometimes used in retreatment regimens for drug‑susceptible disease when adherence is problematic.

Adverse Effects

Common Side Effects

Isoniazid may cause peripheral neuropathy, hepatotoxicity, and hypersensitivity reactions; pyridoxine supplementation is often recommended. Rifampin is associated with hepatotoxicity, orange discoloration of bodily fluids, and gastrointestinal upset. Pyrazinamide frequently induces hyperuricemia and hepatotoxicity. Ethambutol commonly leads to optic neuropathy, characterized by decreased visual acuity and color vision deficits. Streptomycin may cause ototoxicity and nephrotoxicity.

Serious/Rare Adverse Reactions

Severe hepatotoxicity can occur with isoniazid, rifampin, and pyrazinamide, potentially leading to fulminant hepatic failure. Ototoxicity from streptomycin and ethambutol can be irreversible if not detected early. Linezolid may induce thrombocytopenia and neuropathy with prolonged use. Bedaquiline has been linked to QT interval prolongation and ventricular arrhythmias.

Black Box Warnings

Although not formally labeled in all jurisdictions, the combination of hepatotoxic agents warrants caution in patients with pre‑existing liver disease or alcoholism. Fluoroquinolone use in children is contraindicated due to potential cartilage damage.

Drug Interactions

Major Drug-Drug Interactions

Rifampin is a potent inducer of cytochrome P450 enzymes (CYP3A4, CYP2C9, CYP2C19), reducing plasma concentrations of numerous drugs including oral contraceptives, warfarin, and antiretroviral agents. Rifampin also induces P‑glycoprotein, affecting drug absorption. Isoniazid inhibits CYP2C19 and can elevate levels of drugs metabolized by this pathway.

Ethambutol does not significantly interact with other medications but may increase the risk of ocular toxicity when combined with other neurotoxic agents. Pyrazinamide can potentiate hyperuricemia when taken with allopurinol or colchicine.

Contraindications

Patients with severe hepatic impairment should avoid isoniazid, rifampin, and pyrazinamide. Streptomycin is contraindicated in patients with known hearing loss or renal dysfunction. Fluoroquinolones are contraindicated in individuals with a history of tendon rupture or in pregnancy.

Special Considerations

Pregnancy and Lactation

Isoniazid and rifampin are considered relatively safe during pregnancy, with benefits outweighing potential risks. Pyrazinamide is usually avoided in the first trimester due to limited data. Ethambutol is not teratogenic but may affect fetal ocular development; its use is reserved for severe disease. Streptomycin is contraindicated due to ototoxic risk to the fetus. Lactating mothers can generally continue first‑line agents, though breastfeeding may be discouraged with rifampin due to potential drug excretion in milk.

Pediatric/Geriatric Considerations

Children require weight‑based dosing and careful monitoring for optic neuropathy with ethambutol. Growth retardation can occur with prolonged isoniazid exposure. In geriatric patients, the risk of hepatotoxicity increases; renal function must be evaluated prior to streptomycin or aminoglycoside use. Dose adjustments are commonly required for both age groups due to altered pharmacokinetics.

Renal and Hepatic Impairment

Renal dosing adjustments are essential for ethambutol, pyrazinamide, and streptomycin. Hepatic function tests should guide the use of isoniazid, rifampin, and pyrazinamide, with careful tapering or discontinuation if transaminases rise >5 × upper limit of normal. Monitoring schedules should be intensified in patients with pre‑existing organ dysfunction.

Summary/Key Points

• First‑line antitubercular agents act via distinct mechanisms: cell wall synthesis inhibition (isoniazid, ethambutol), transcription blockade (rifampin), and membrane disruption (pyrazinamide).
• Combination therapy is essential to prevent resistance; dosing schedules are tailored to drug half‑lives and patient factors.
• Hepatotoxicity, neuropathy, and ocular toxicity are the most frequent adverse effects; vigilant monitoring and prophylactic measures (e.g., pyridoxine) mitigate risk.
• Rifampin’s enzyme‑inducing properties necessitate caution with concomitant medications; drug interactions can markedly alter therapeutic outcomes.
• Special populations—including pregnant women, children, the elderly, and those with organ impairment—require individualized dosing and monitoring to balance efficacy with safety.

Clinicians should remain cognizant of evolving resistance patterns and emerging therapies, integrating pharmacological knowledge with clinical judgment to optimize tuberculosis treatment outcomes.

References

1. Gilbert DN, Chambers HF, Saag MS, Pavia AT. The Sanford Guide to Antimicrobial Therapy. 53rd ed. Sperryville, VA: Antimicrobial Therapy Inc; 2023.
2. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
3. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
4. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
5. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
6. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
7. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.