Pharmacology of Antitubercular Drugs

Introduction/Overview

Mycobacterium tuberculosis remains a leading cause of morbidity and mortality worldwide, despite advances in public health and diagnostic technologies. Effective pharmacologic therapy is central to disease control, with multidrug regimens designed to eradicate the bacillus, prevent resistance, and achieve cure. This monograph aims to provide a detailed, evidence-based review of antitubercular pharmacology, tailored for medical and pharmacy students preparing for clinical practice or advanced study.

Learning Objectives

• Identify the principal drug classes used in tuberculosis treatment and their chemical classifications.
• Explain the molecular mechanisms by which antitubercular agents inhibit bacterial growth.
• Describe key pharmacokinetic parameters influencing dosing strategies for different patient populations.
• Recognize common adverse effects and major drug–drug interactions associated with first‑line and second‑line agents.
• Apply pharmacologic principles to special patient groups, including pregnant women, children, and individuals with organ impairment.

Classification

Antitubercular drugs are traditionally grouped into first‑line and second‑line agents, reflecting their position in standard treatment regimens and resistance profiles. Chemical classification further distinguishes these agents by core structural motifs.

First‑Line Drugs

• Isoniazid – hydrazide derivative, nitroimidazole analog.
• Rifampicin – macrocyclic lactone, rifamycin class.
• Ethambutol – quinoline carboxylate, hydroxybenzoic acid derivative.
• Pyrazinamide – pyrazine carboxamide, pyrazinamide class.

Second‑Line Drugs

• Fluoroquinolones – e.g., levofloxacin, moxifloxacin; fluoroquinolone core.
• Amikacin – aminoglycoside, 2,6‑diaminopurine scaffold.
• Ethionamide – thioamide derivative of ethionamide.
• Cycloserine – cyclic β‑alanine analog.
• Streptomycin – aminoglycoside with a 4‑thio‑4‑aminobutyryl side chain.

Mechanism of Action

Antitubercular agents exert bactericidal or bacteriostatic effects through diverse cellular targets, often interfering with essential biosynthetic pathways or membrane integrity.

Isoniazid

Converted intracellularly by catalase–peroxidase (KatG) to a reactive species that inhibits mycolic acid synthesis by blocking the enoyl‑acyl carrier protein reductase (InhA). This disrupts cell wall lipid biosynthesis, leading to bactericidal activity, particularly against actively dividing bacilli.

Rifampicin

Binds to the β‑subunit of RNA polymerase, preventing initiation of mRNA synthesis. The inhibition is reversible but potent, resulting in bactericidal effects. Resistance typically arises via mutations in the rpoB gene encoding the RNA polymerase β‑subunit.

Ethambutol

Interferes with arabinosyl transferases (Emb proteins) involved in arabinogalactan synthesis, an essential component of the mycobacterial cell wall. The effect is bacteriostatic, requiring combination with other agents to prevent resistance.

Pyrazinamide

Prodrug activated by pyrazinamidase (PncA) to pyrazinoic acid, which accumulates in acidic environments within macrophages. The exact target remains incompletely defined but is believed to disrupt membrane transport and energy metabolism, yielding bactericidal activity against dormant bacilli.

Fluoroquinolones

Bind to DNA gyrase (GyrA/GyrB) and topoisomerase IV, inhibiting DNA replication and transcription. The activity is concentration‑dependent and is particularly useful against multidrug‑resistant strains.

Amikacin and Streptomycin

Bind to the 30S ribosomal subunit, causing misreading of mRNA and inhibiting protein synthesis. They exhibit bactericidal activity and are employed in severe or resistant disease.

Ethionamide, Cycloserine, and Other Second‑Line Agents

Ethionamide is a prodrug activated by EthA to an active metabolite that inhibits mycolic acid synthesis via InhA inhibition. Cycloserine targets D‑alanine racemase and D‑alanine–D‑alanine ligase, disrupting peptidoglycan cross‑linking. Their mechanisms are bacteriostatic or bactericidal depending on concentration.

Pharmacokinetics

Understanding absorption, distribution, metabolism, and excretion (ADME) is essential for optimizing dosing and minimizing toxicity.

Isoniazid

Orally absorbed with rapid and complete bioavailability. Metabolized primarily by hepatic acetylation via N‑acetyltransferase 2 (NAT2). Slow acetylators exhibit higher plasma concentrations and prolonged half‑life (≈5–6 h), whereas fast acetylators display shorter t_1/2 (~1–2 h). Dose adjustments are typically unnecessary, but therapeutic drug monitoring may be considered in slow acetylators to reduce neurotoxicity risk.

Rifampicin

Well absorbed from the gastrointestinal tract; oral bioavailability is approximately 70%. Metabolized in the liver by glucuronidation. A half‑life of about 3–5 h permits daily dosing. Rifampicin is a potent inducer of CYP450 enzymes (particularly CYP3A4) and P‑glycoprotein, leading to reduced plasma concentrations of concomitant drugs.

Ethambutol

Rapid absorption with peak plasma concentrations reached within 1–2 h. Distribution is limited to extracellular fluid; penetration into the central nervous system is modest. Renally excreted unchanged; dosage adjustment is required in patients with creatinine clearance <50 mL min^-1. Half‑life is approximately 5–7 h.

Pyrazinamide

Rapidly absorbed, with peak concentrations at 1–2 h post‑dose. Metabolized in the liver to pyrazinoic acid and further to the monophosphate. Excretion is predominantly renal. The elimination half‑life is roughly 2–3 h, allowing once‑daily dosing.

Fluoroquinolones

Oral formulations exhibit high bioavailability (~80–90%). Distribution is extensive, with good penetration into lung tissue and pleural fluid. Renal excretion accounts for 30–50 % of the dose; dosage adjustments are necessary in renal impairment. The half‑life ranges from 6–12 h depending on the agent (e.g., levofloxacin t_1/2 ≈6 h, moxifloxacin t_1/2 ≈12 h).

Amikacin and Streptomycin

Administered intravenously or intramuscularly due to poor oral absorption. Distribution is primarily extracellular; peak concentrations occur rapidly. Renal clearance is the main elimination pathway; dosage reduction or extended dosing intervals are required in patients with decreased glomerular filtration rate. Half‑life of amikacin is 2–3 h in normal renal function.

Cycloserine and Ethionamide

Cycloserine is absorbed orally with peak levels at 1–2 h. Metabolized by the liver; half‑life is ~6–8 h. Ethionamide is also absorbed orally; its half‑life is 1–3 h. Both agents undergo renal excretion, necessitating dose adjustments in renal impairment.

Therapeutic Uses/Clinical Applications

Antitubercular drugs are employed in various regimens, tailored to disease severity, drug susceptibility, and patient factors.

First‑Line Regimens

Standard treatment for drug‑susceptible pulmonary tuberculosis involves a 2‑month intensive phase with isoniazid, rifampicin, pyrazinamide, and ethambutol, followed by a 4‑month continuation phase with isoniazid and rifampicin. This regimen achieves cure rates exceeding 90 % in most settings.

Second‑Line Regimens

For multidrug‑resistant (MDR) and extensively drug‑resistant (XDR) tuberculosis, regimens incorporate fluoroquinolones, aminoglycosides (amikacin, kanamycin, capreomycin), and other second‑line agents such as cycloserine, ethionamide, and PAS. Regimen design is guided by susceptibility testing and patient tolerance. Newer agents, including bedaquiline and delamanid, are increasingly incorporated into MDR/XDR protocols.

Off‑Label and Adjunctive Uses

Rifampicin’s potent CYP inducer activity is exploited in anti‑HIV therapy to accelerate the metabolism of antiretroviral agents. Isoniazid has been used experimentally for prophylaxis in latent tuberculosis infection (LTBI) in high‑risk populations, although newer regimens (e.g., 3 months of once‑weekly isoniazid and rifapentine) have supplanted it in many guidelines.

Adverse Effects

Adverse effect profiles vary across drug classes, influencing monitoring and management strategies.

Isoniazid

• Peripheral neuropathy – dose‑dependent; mitigated by pyridoxine supplementation.
• Hepatotoxicity – asymptomatic transaminase elevations; severe hepatotoxicity is rare but may require discontinuation.
• Acute hypersensitivity – rash, fever, eosinophilia.
• Seizures – uncommon, more likely in patients with renal impairment or concomitant neurotoxins.

Rifampicin

• Hepatotoxicity – typically reversible; monitoring of liver function tests is recommended.
• Orange discoloration of bodily fluids – benign, cosmetic concern.
• Gastrointestinal upset – nausea, vomiting.
• Drug interactions – due to CYP3A4 induction, potentially reducing efficacy of oral contraceptives, warfarin, and other agents.

Ethambutol

• Optic neuritis – visual acuity loss, color vision changes; dose‑dependent; reversible upon discontinuation.
• Gastrointestinal disturbances – nausea, vomiting.
• Rash – mild, self‑limited.

Pyrazinamide

• Hepatotoxicity – higher risk compared to other first‑line drugs; requires liver function monitoring.
• Hyperuricemia – gout flares; prophylaxis with allopurinol may be considered.
• Gastrointestinal discomfort – nausea, diarrhea.

Fluoroquinolones

• Gastrointestinal upset – nausea, diarrhea.
• Central nervous system effects – headache, dizziness.
• Peripheral neuropathy – rare but documented, especially in high doses.
• Tendonitis and tendon rupture – heightened risk with corticosteroid co‑administration.

Amikacin and Streptomycin

• Ototoxicity – irreversible hearing loss with prolonged use.
• Nephrotoxicity – dose‑dependent; requires monitoring of serum creatinine.
• Neuromuscular blockade – may precipitate respiratory failure in susceptible individuals.

Cycloserine

• Central nervous system effects – insomnia, mood changes, psychosis.
• Gastrointestinal upset – nausea, vomiting.
• Hepatotoxicity – rare.

Ethionamide

• Gastrointestinal disturbances – nausea, vomiting, abdominal pain.
• Hepatotoxicity – elevation of transaminases; monitoring required.
• Skin rash – mild to moderate.

Drug Interactions

Drug–drug interactions are frequent with antitubercular therapy, necessitating vigilance, especially in polypharmacy contexts.

Rifampicin

• Strong inducer of CYP3A4, CYP2C9, and CYP1A2; reduces plasma levels of oral contraceptives, antiretrovirals (e.g., protease inhibitors), warfarin, and statins.
• Inhibitor of P‑glycoprotein, potentially increasing concentrations of drugs like digoxin.
• Metabolite of rifampicin is rifapentine, which shares similar interaction profiles but with extended half‑life.

Isoniazid

• Inhibits CYP2E1, impacting metabolism of ethanol and certain antiepileptics.
• Can potentiate hepatotoxicity when combined with other hepatotoxic drugs.

Fluoroquinolones

• Reduced absorption when co‑administered with antacids containing divalent or trivalent cations (e.g., calcium, magnesium, aluminum).
• Potential nephrotoxicity when combined with other nephrotoxic agents (e.g., aminoglycosides).

Amikacin and Streptomycin

• Synergistic ototoxicity with other aminoglycosides or loop diuretics.
• Additive nephrotoxicity with nonsteroidal anti‑inflammatory drugs.

Cycloserine

• Increases CNS effects when combined with other CNS depressants (e.g., benzodiazepines).
• Potential interaction with antiepileptics leading to altered seizure thresholds.

Special Considerations

Antitubercular therapy must be individualized for patient subgroups to balance efficacy and safety.

Pregnancy and Lactation

Rifampicin and isoniazid are considered category B drugs; they are generally regarded as safe during pregnancy. Ethambutol and pyrazinamide have limited data but are usually continued if benefits outweigh risks. Amikacin and streptomycin are category D due to potential ototoxicity in the fetus; use is restricted to severe disease. Breastfeeding mothers may excrete low concentrations into breast milk; the benefits of therapy typically justify continuation, but monitoring of infant hearing and growth is advised.

Pediatric Considerations

Children require weight‑based dosing, often with liquid formulations. Isoniazid acetylator status varies by ethnicity; slow acetylators may require dose adjustment. Monitoring of growth, neurodevelopment, and liver function is essential. Fluoroquinolone use in pediatrics is limited due to concerns of cartilage damage; however, newer agents (e.g., levofloxacin) have shown minimal adverse effects in short courses.

Geriatric Considerations

Age‑related pharmacokinetic changes, such as reduced renal clearance, necessitate dose adjustment for aminoglycosides and ethambutol. Polypharmacy increases interaction risk, particularly with rifampicin. Vigilant monitoring of liver function and hearing is recommended.

Renal Impairment

Ethambutol, cycloserine, and aminoglycosides require dose reduction proportional to creatinine clearance. Isoniazid and rifampicin are primarily hepatically cleared; however, hepatic dysfunction should be monitored. Pharmacokinetic modeling indicates that a 50 % dose reduction in amikacin may suffice in moderate renal impairment, but therapeutic drug monitoring is preferable.

Hepatic Impairment

Isoniazid and pyrazinamide are hepatotoxic; dosing in cirrhosis may involve lower doses and more frequent liver function testing. Rifampicin is contraindicated in severe hepatic failure due to extensive metabolism and risk of worsening liver injury. Alternative regimens that spare hepatotoxic drugs are considered in this population.

Summary/Key Points

• First‑line antitubercular drugs target essential cell wall synthesis and protein transcription, providing high efficacy against susceptible strains.
• Second‑line agents extend therapeutic options for drug‑resistant disease but carry higher toxicity profiles and require careful monitoring.
• Pharmacokinetic variability, particularly acetylator status for isoniazid and CYP induction by rifampicin, necessitates individualized dosing and interaction assessment.
• Hepatotoxicity and neurotoxicity are prominent adverse effects; routine laboratory monitoring and patient education mitigate complications.
• Special populations—including pregnant women, children, the elderly, and those with renal or hepatic impairment—require dose adjustments and intensified surveillance.

Adopting a systematic approach to the pharmacologic management of tuberculosis, grounded in an understanding of drug mechanisms, kinetics, and patient‑specific factors, enhances therapeutic success and minimizes harm. Continuous education and adherence to evolving guidelines remain pivotal as treatment paradigms evolve in response to emerging drug resistance and novel therapeutic agents.

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. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
6. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
7. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
8. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.