Pharmacology of Antitubercular Drugs

Introduction/Overview

Tuberculosis remains a significant global health challenge, with an estimated 10 million new cases and 1.3 million deaths reported annually. The pharmacological management of tuberculosis is complex, requiring prolonged multidrug regimens to achieve cure and prevent the emergence of drug resistance. The unique pathophysiology of Mycobacterium tuberculosis, characterized by its slow replication rate, ability to persist in a dormant state, and complex cell wall structure, necessitates a specialized therapeutic approach. Antitubercular therapy has evolved from historical sanatorium-based care to modern, highly effective, though lengthy, outpatient chemotherapy. The development of drug-resistant strains, including multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) tuberculosis, presents ongoing therapeutic challenges and underscores the critical importance of understanding the pharmacology of these agents.

Learning Objectives

• Classify antitubercular drugs according to their clinical utility, mechanism of action, and chemical structure.
• Explain the molecular mechanisms by which first-line and second-line antitubercular drugs inhibit Mycobacterium tuberculosis.
• Analyze the pharmacokinetic profiles of key antitubercular agents, including absorption, distribution, metabolism, and excretion patterns.
• Evaluate the rationale for combination therapy in tuberculosis treatment and describe standard treatment regimens for drug-susceptible and drug-resistant disease.
• Identify major adverse effects, drug interactions, and special considerations for the use of antitubercular drugs in diverse patient populations.

Classification

Antitubercular drugs are systematically categorized based on their clinical efficacy, potency, and role in treatment regimens. This classification guides therapeutic decision-making, particularly in structuring phases of treatment and managing drug resistance.

Clinical Classification

The most clinically relevant classification divides agents into first-line and second-line drugs. First-line drugs form the cornerstone of treatment for drug-susceptible tuberculosis due to their high efficacy and generally acceptable toxicity profiles. This group includes isoniazid, rifampin, pyrazinamide, and ethambutol. Streptomycin, an aminoglycoside, was historically a first-line agent but is now more commonly reserved for specific cases due to toxicity and the need for parenteral administration. Second-line drugs are typically employed when first-line therapy fails due to drug resistance or intolerance. These agents often have lower efficacy, more complex pharmacokinetics, and less favorable toxicity profiles. The second-line category is broad and includes fluoroquinolones (e.g., levofloxacin, moxifloxacin), injectable agents (e.g., amikacin, capreomycin), and other oral bacteriostatic drugs (e.g., ethionamide, cycloserine, para-aminosalicylic acid).

Chemical Classification

From a chemical perspective, antitubercular drugs represent diverse structural classes. Isoniazid is a hydrazide derivative of isonicotinic acid. Rifampin is a semisynthetic derivative of rifamycin B, a macrocyclic antibiotic produced by Amycolatopsis rifamycinica. Pyrazinamide is a synthetic analogue of nicotinamide. Ethambutol is a synthetic diamine derivative. The fluoroquinolones are synthetic broad-spectrum antibiotics with a fluorine atom at the C-6 position. The injectable agents include aminoglycosides (amikacin, streptomycin) and the polypeptide capreomycin. Other second-line agents like ethionamide (a thioamide derivative of isonicotinic acid), cycloserine (an analogue of D-alanine), and para-aminosalicylic acid (a folate synthesis antagonist analogue) complete the chemical spectrum.

Classification by Activity

Drugs are also classified by their bactericidal activity against different bacterial populations within tuberculous lesions. Sterilizing drugs, such as rifampin and pyrazinamide, are particularly effective at killing dormant or slowly replicating bacilli within acidic environments like macrophages and caseous lesions, thereby shortening the total duration of therapy. Bactericidal drugs, like isoniazid, are most active against rapidly dividing extracellular bacilli. Bacteriostatic drugs, including many second-line agents like ethionamide and cycloserine, inhibit bacterial growth but do not reliably kill the organism, necessitating their use in combination with bactericidal agents.

Mechanism of Action

The mechanisms of action of antitubercular drugs target essential and unique biochemical pathways in Mycobacterium tuberculosis. Understanding these mechanisms provides insight into drug efficacy, the basis for combination therapy, and the development of resistance.

Inhibition of Cell Wall Synthesis

The mycobacterial cell wall is a complex, lipid-rich structure critical for virulence and survival. Several drugs target its synthesis. Isoniazid is a prodrug activated by the bacterial catalase-peroxidase enzyme KatG. The activated form inhibits the enzyme InhA (enoyl-acyl carrier protein reductase), a key component of the type II fatty acid synthase system responsible for synthesizing mycolic acids. Mycolic acids are long-chain fatty acids essential for the integrity and impermeability of the mycobacterial cell wall. Inhibition leads to a weakened cell wall, loss of acid-fastness, and bacterial death. Ethambutol specifically inhibits the arabinosyltransferases (EmbA, EmbB, EmbC) involved in the polymerization of arabinogalactan, a crucial polysaccharide in the cell wall matrix that links mycolic acids to the peptidoglycan layer. Cycloserine, a structural analogue of D-alanine, competitively inhibits two enzymes in the peptidoglycan synthesis pathway: alanine racemase (which converts L-alanine to D-alanine) and D-alanyl-D-alanine ligase.

Inhibition of Nucleic Acid Synthesis

Rifampin exerts its bactericidal effect by binding to the β-subunit of bacterial DNA-dependent RNA polymerase. This binding occurs with high affinity in a deep pocket of the enzyme, blocking the elongation step of RNA transcription after the first few phosphodiester bonds are formed. This inhibition of mRNA synthesis is lethal to the bacterium. The fluoroquinolones, such as moxifloxacin and levofloxacin, target DNA gyrase (topoisomerase II) and topoisomerase IV. By stabilizing the DNA-enzyme cleavage complex, they introduce double-stranded DNA breaks, inhibiting DNA replication and transcription.

Disruption of Protein Synthesis

The injectable aminoglycosides (streptomycin, amikacin) and the polypeptide capreomycin inhibit protein synthesis by binding to the 16S ribosomal RNA of the 30S ribosomal subunit. This binding induces misreading of the genetic code and inhibits the initiation of translation. Streptomycin’s binding site is distinct from that of other aminoglycosides, which influences cross-resistance patterns.

Other Mechanisms

Pyrazinamide’s mechanism is unique and not fully elucidated. It is a prodrug converted to pyrazinoic acid by the bacterial pyrazinamidase enzyme (PncA). Pyrazinoic acid is then exported by a weak efflux pump. The subsequent futile cycling of protonated pyrazinoic acid back into the cell is thought to deplete cellular energy (ATP) and lower intracellular pH, disrupting membrane potential and inhibiting vital enzymes like fatty acid synthase I. This activity is particularly potent in the acidic environment of macrophages. Para-aminosalicylic acid acts as a competitive antagonist of dihydropteroate synthase, inhibiting folate synthesis. Ethionamide, like isoniazid, is a prodrug activated by the monooxygenase EthA and also inhibits InhA, though through a different binding site, providing a potential alternative pathway for mycolic acid inhibition.

Pharmacokinetics

The pharmacokinetic properties of antitubercular drugs significantly influence dosing regimens, therapeutic efficacy, and toxicity. Considerable inter-individual variability exists, often necessitating therapeutic drug monitoring in complex cases.

Absorption and Distribution

Most first-line oral agents are well absorbed from the gastrointestinal tract. Isoniazid, rifampin, and pyrazinamide achieve peak plasma concentrations (C_max) within 1-2 hours post-administration. Ethambutol absorption is somewhat slower and less complete, with a C_max at approximately 2-4 hours. Food can significantly impair the absorption of rifampin and isoniazid; therefore, these drugs are typically administered on an empty stomach. Pyrazinamide absorption is less affected by food. Distribution is generally wide, with most drugs achieving adequate concentrations in tissues and body fluids, including lungs, kidneys, and caseous lesions. Rifampin and isoniazid penetrate well into cerebrospinal fluid, especially when meninges are inflamed, making them cornerstones of tuberculous meningitis treatment. Pyrazinamide exhibits exceptional penetration into macrophages and acidic environments, which underpins its sterilizing activity.

Metabolism and Excretion

Metabolic pathways are drug-specific and a major source of pharmacokinetic variability and drug interactions. Isoniazid is primarily metabolized in the liver by N-acetyltransferase 2 (NAT2). Genetic polymorphism in the NAT2 gene results in populations of rapid and slow acetylators, leading to variable plasma half-lives (t_1/2 ≈1-4 hours) and influencing both efficacy and the risk of hepatotoxicity. Rifampin is a potent inducer of hepatic cytochrome P450 enzymes (particularly CYP3A4) and the drug transporter P-glycoprotein. It undergoes deacetylation in the liver to an active metabolite, and both parent and metabolite are excreted primarily in bile, undergoing enterohepatic recirculation. Pyrazinamide is hydrolyzed in the liver to pyrazinoic acid, its active moiety, and further metabolized before renal excretion. Ethambutol is partially metabolized in the liver, but a significant portion is excreted unchanged in urine.

Renal excretion is the primary route of elimination for ethambutol, the fluoroquinolones, and the injectable agents. Dose adjustment is critical in renal impairment for these drugs. In contrast, isoniazid, rifampin, and pyrazinamide are predominantly hepatically cleared or have active metabolites; their dosing requires careful adjustment in hepatic impairment but not typically in renal dysfunction.

Key Pharmacokinetic Parameters

The elimination half-life (t_1/2) influences dosing frequency. Rifampin has a relatively short t_1/2 (≈3 hours) but induces its own metabolism, and its prolonged post-antibiotic effect allows for once-daily dosing. Isoniazid’s t_1/2 varies by acetylator status. Pyrazinamide’s t_1/2 is approximately 9-10 hours. The area under the concentration-time curve (AUC) and the ratio of C_max to minimum inhibitory concentration (MIC) are important pharmacodynamic predictors of efficacy for many antitubercular drugs, particularly fluoroquinolones and aminoglycosides.

Therapeutic Uses/Clinical Applications

The application of antitubercular drugs follows standardized guidelines designed to maximize cure rates and minimize the development of drug resistance. Treatment is always initiated with a combination of drugs.

Treatment of Drug-Susceptible Tuberculosis

The standard regimen for active, drug-susceptible pulmonary tuberculosis consists of two phases: an intensive (bactericidal) phase and a continuation (sterilizing) phase. The intensive phase typically lasts two months and employs four drugs: isoniazid, rifampin, pyrazinamide, and ethambutol. This multi-drug approach rapidly reduces the bacterial load, minimizes the emergence of resistant mutants, and addresses the possibility of initial isoniazid resistance. The continuation phase lasts four months and involves isoniazid and rifampin only, aiming to eliminate persistent, dormant bacilli. The total duration is therefore six months. Ethambutol can be discontinued if drug susceptibility testing confirms susceptibility to isoniazid and rifampin. Treatment for extrapulmonary tuberculosis generally follows the same regimen, though durations may be extended for sites like bone/joint or meningeal disease.

Treatment of Latent Tuberculosis Infection

To prevent progression to active disease, latent tuberculosis infection is treated with a single drug or a short combination regimen. The most common regimens include nine months of daily isoniazid, three months of weekly isoniazid plus rifapentine (a long-acting rifamycin), or four months of daily rifampin. The choice depends on patient factors, drug availability, and potential for hepatotoxicity.

Treatment of Drug-Resistant Tuberculosis

Management of MDR-TB (resistance to at least isoniazid and rifampin) and XDR-TB (MDR-TB plus resistance to any fluoroquinolone and at least one second-line injectable) requires individualized regimens based on drug susceptibility testing. Regimens are longer (often 18-24 months), more complex, and more toxic. They typically include a later-generation fluoroquinolone (e.g., levofloxacin), a second-line injectable agent (e.g., amikacin), and multiple other second-line oral drugs (e.g., linezolid, clofazimine, cycloserine). Recently, shorter (9-12 month) all-oral regimens for MDR-TB have been recommended by the World Health Organization, incorporating newer agents like bedaquiline (a diarylquinoline that inhibits ATP synthase) and pretomanid (a nitroimidazole).

Off-Label and Investigational Uses

Rifampin is sometimes used off-label for the treatment of serious staphylococcal infections, particularly in prosthetic device-related infections, due to its potent activity against biofilms. However, rapid resistance development necessitates its use only in combination with other antistaphylococcal agents. Several antitubercular drugs are under investigation for repurposing in other infectious or non-infectious conditions.

Adverse Effects

The adverse effect profiles of antitubercular drugs range from mild and common to severe and life-threatening. Vigilant monitoring is an integral component of tuberculosis management.

Hepatotoxicity

Hepatotoxicity is the most clinically significant adverse effect associated with first-line therapy. Isoniazid, rifampin, and pyrazinamide are all potentially hepatotoxic. The risk is increased with combination therapy, pre-existing liver disease, alcohol use, older age, and female gender. Isoniazid hepatotoxicity may be due to the formation of a toxic hydrazine metabolite. Presentation ranges from asymptomatic elevation of transaminases to clinical hepatitis with nausea, vomiting, jaundice, and, rarely, fulminant hepatic failure. Regular monitoring of liver function tests is recommended, and patients should be educated to report symptoms promptly.

Neurological and Ophthalmological Effects

Peripheral neuropathy is a dose-related adverse effect of isoniazid, resulting from interference with pyridoxine (vitamin B₆) metabolism. It is more common in slow acetylators, malnourished individuals, and patients with diabetes or HIV. Prophylactic pyridoxine supplementation is standard. Optic neuritis is the hallmark toxicity of ethambutol, presenting as blurred vision, decreased visual acuity, and impaired red-green color discrimination. It is dose- and duration-dependent, and baseline visual acuity and color vision testing are recommended. Cycloserine can cause a range of central nervous system effects, including headache, dizziness, psychosis, and seizures, related to its structural similarity to neurotransmitters.

Gastrointestinal and Cutaneous Reactions

Gastrointestinal intolerance, including nausea, vomiting, and abdominal discomfort, is common with many antitubercular drugs, particularly pyrazinamide and para-aminosalicylic acid. Rifampin frequently causes a benign orange-red discoloration of bodily fluids (urine, sweat, tears). Cutaneous reactions, from mild rash to severe Stevens-Johnson syndrome, can occur with any agent but are notably associated with isoniazid and rifampin. A flu-like syndrome (fever, chills, myalgia) can occur with intermittent rifampin dosing.

Other Serious Reactions

Pyrazinamide inhibits renal urate excretion, leading to hyperuricemia, which can precipitate gouty arthritis. Rifampin is associated with rare but serious hematological reactions, including thrombocytopenia and hemolytic anemia. The injectable aminoglycosides and capreomycin carry significant risks of nephrotoxicity and irreversible ototoxicity (vestibular and auditory). Ethionamide is frequently associated with severe gastrointestinal upset and endocrine disturbances like hypothyroidism and gynecomastia.

Drug Interactions

Drug interactions are a major consideration in antitubercular therapy, primarily due to the potent enzyme-inducing properties of rifampin and the metabolic pathways of other agents.

Interactions Mediated by Rifampin

As a broad-spectrum inducer of CYP450 enzymes and P-glycoprotein, rifampin decreases the plasma concentrations and efficacy of numerous co-administered drugs. This has profound clinical implications. Key interactions include reduced efficacy of antiretroviral drugs (particularly protease inhibitors and non-nucleoside reverse transcriptase inhibitors), oral contraceptives, warfarin, corticosteroids, many anticonvulsants, and immunosuppressants like cyclosporine and tacrolimus. Management requires dose adjustments, alternative drug choices, or close therapeutic monitoring. Rifabutin, a related rifamycin, is a less potent inducer and is often substituted for rifampin in patients requiring concomitant antiretroviral therapy.

Interactions with Isoniazid

Isoniazid is a weak inhibitor of several CYP450 enzymes, including CYP2C19 and CYP3A4. It can increase plasma levels of drugs like phenytoin and carbamazepine, potentially leading to toxicity. Concurrent administration of isoniazid with rifampin may increase the risk of hepatotoxicity beyond that of either drug alone. Alcohol consumption can potentiate isoniazid hepatotoxicity and should be avoided.

Other Notable Interactions

Fluoroquinolones can chelate with polyvalent cations (e.g., aluminum, magnesium, calcium, iron), found in antacids, sucralfate, and mineral supplements, leading to drastically reduced absorption. Administration should be separated by at least 2-4 hours. The nephrotoxic and ototoxic effects of injectable aminoglycosides are additive with other drugs possessing similar toxicities, such as loop diuretics and vancomycin. Ethambutol may reduce renal excretion of aluminum, a consideration in patients also receiving aluminum-containing phosphate binders.

Contraindications

Absolute contraindications are relatively few but important. A history of severe hypersensitivity reaction (e.g., anaphylaxis, Stevens-Johnson syndrome) to a specific drug precludes its reuse. Severe hepatic impairment is a contraindication to the use of isoniazid, rifampin, and pyrazinamide until liver function improves. Ethambutol is contraindicated in patients unable to report visual symptoms or undergo visual testing, such as young children, due to the difficulty in monitoring for optic neuritis.

Special Considerations

The use of antitubercular drugs requires careful adaptation to specific patient populations and physiological conditions to balance efficacy and safety.

Pregnancy and Lactation

Active tuberculosis in pregnancy must be treated to protect both mother and fetus. The first-line regimen of isoniazid, rifampin, and ethambutol is considered safe and recommended. Pyrazinamide is also used in many guidelines worldwide, though its safety data are less extensive; it is routinely included in WHO recommendations. Streptomycin is contraindicated due to risk of fetal ototoxicity. For latent infection, treatment is generally deferred until postpartum unless the mother is at high risk for progression. Most first-line drugs are excreted in breast milk in low concentrations, but breastfeeding is not contraindicated during maternal treatment; the benefits of breastfeeding and treating active disease outweigh the minimal risk to the infant. Pyridoxine supplementation is essential for breastfeeding mothers on isoniazid.

Pediatric and Geriatric Considerations

Children generally tolerate first-line drugs well and have a lower risk of hepatotoxicity compared to adults. Dosing is weight-based (mg/kg). Ethambutol is often avoided in very young children due to the challenge of monitoring vision, though it can be used with appropriate monitoring if needed. In elderly patients, age-related declines in renal and hepatic function increase the risk of drug accumulation and toxicity. Lower doses or extended dosing intervals may be required, especially for renally excreted drugs like ethambutol. The risk of isoniazid-induced peripheral neuropathy and hepatotoxicity is also higher in older adults.

Renal and Hepatic Impairment

In renal impairment, dose adjustment is critical for drugs primarily excreted unchanged by the kidneys: ethambutol, the fluoroquinolones, and all injectable agents (aminoglycosides, capreomycin). Isoniazid, rifampin, and pyrazinamide do not typically require dose reduction in renal failure, though accumulation of active metabolites may occur. In hepatic impairment, the use of first-line hepatotoxic drugs (isoniazid, rifampin, pyrazinamide) becomes problematic. For mild impairment, they may be used with very close monitoring. For moderate to severe impairment, a non-hepatotoxic regimen must be constructed, often consisting of a fluoroquinolone, ethambutol, and an injectable agent, with later introduction of first-line drugs as liver function permits.

HIV Co-infection

Pharmacokinetic and toxicodynamic interactions between antitubercular and antiretroviral drugs are complex. Rifampin’s enzyme induction significantly lowers levels of many antiretrovirals. Rifabutin is the preferred rifamycin for patients on protease inhibitor-based regimens. Conversely, some antiretrovirals can alter levels of antitubercular drugs. The risk of immune reconstitution inflammatory syndrome (IRIS) is elevated when antiretroviral therapy is initiated during tuberculosis treatment. Furthermore, HIV-positive patients have an increased incidence of adverse drug reactions, particularly rash and hepatotoxicity.

Summary/Key Points

• Antitubercular therapy is fundamentally based on combination, long-duration regimens to cure active disease and prevent the emergence of drug resistance.
• First-line drugs (isoniazid, rifampin, pyrazinamide, ethambutol) target unique mycobacterial structures and pathways: mycolic acid synthesis, RNA transcription, energy metabolism within acidic environments, and arabinogalactan polymerization, respectively.
• Pharmacokinetic properties, particularly the enzyme-inducing effect of rifampin and the acetylation polymorphism affecting isoniazid, are major determinants of dosing, efficacy, and drug interaction potential.
• Hepatotoxicity is the most significant class-wide adverse effect, requiring vigilant monitoring. Other agent-specific toxicities include peripheral neuropathy (isoniazid), optic neuritis (ethambutol), hyperuricemia (pyrazinamide), and nephro-/ototoxicity (injectable agents).
• Treatment must be individualized for special populations, including those with HIV co-infection, hepatic or renal impairment, and pregnant patients, often requiring regimen modification and intensive monitoring.

Clinical Pearls

• Directly Observed Therapy (DOT) is a cornerstone of tuberculosis management to ensure adherence and completion of the lengthy treatment course.
• Baseline and periodic monitoring should include liver function tests (for patients on first-line therapy), visual acuity and color vision testing (for patients on ethambutol), and renal function and audiometry (for patients on injectable agents).
• Pyridoxine (25-50 mg daily) should be administered prophylactically with isoniazid to all patients to prevent peripheral neuropathy.
• The management of drug-resistant tuberculosis is evolving rapidly with the introduction of new agents like bedaquiline and pretomanid, allowing for shorter, all-oral regimens.
• Collaboration between clinicians, pharmacists, and public health authorities is essential for successful tuberculosis treatment and the prevention of community transmission.

References

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