Pharmacology of Antitubercular Drugs

Introduction/Overview

Tuberculosis (TB) remains a major global health challenge, ranking among the leading causes of death from a single infectious agent. The pharmacology of antitubercular drugs constitutes a cornerstone of infectious disease therapeutics, characterized by unique principles such as prolonged combination therapy, the management of drug resistance, and the handling of complex pharmacokinetic and toxicological profiles. The therapeutic approach to tuberculosis is fundamentally different from that of most acute bacterial infections, necessitating a deep understanding of the specific pharmacodynamic and pharmacokinetic properties of these agents. Mastery of this subject is essential for the rational design and monitoring of effective treatment regimens, which are critical for achieving cure, preventing relapse, and curtailing the transmission of Mycobacterium tuberculosis.

Clinical Relevance and Importance

The global burden of tuberculosis, including multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains, underscores the critical importance of antitubercular pharmacology. Effective pharmacotherapy not only cures individual patients but also serves as a primary public health intervention to break chains of transmission. The complexity of treatment, which often involves multiple drugs administered for many months, demands a thorough knowledge of drug mechanisms, interactions, and adverse effect profiles to optimize outcomes and ensure patient adherence. The evolution of shorter regimens and new drug entities further highlights the dynamic nature of this field.

Learning Objectives

• Classify antitubercular drugs into first-line and second-line agents, and describe their respective roles in the treatment of drug-susceptible and drug-resistant tuberculosis.
• Explain the molecular mechanisms of action for major antitubercular drugs, including their specific targets within the mycobacterial cell.
• Analyze the key pharmacokinetic properties—absorption, distribution, metabolism, and excretion—of core antitubercular agents and their implications for dosing and therapeutic monitoring.
• Identify the major adverse effects, drug interactions, and contraindications associated with first-line and key second-line antitubercular drugs.
• Apply knowledge of pharmacologic principles to special clinical situations, including hepatic impairment, renal failure, pregnancy, and pediatric tuberculosis.

Classification

Antitubercular drugs are traditionally categorized based on their efficacy, potency, and role in standard treatment regimens. This classification guides therapeutic decision-making, particularly in distinguishing between treatment for drug-susceptible and drug-resistant disease.

First-Line Agents

First-line drugs form the backbone of treatment for drug-susceptible tuberculosis. They are characterized by high bactericidal or sterilizing activity and generally possess more favorable tolerability profiles compared to second-line agents. The core first-line agents are isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB). In many intensive phase regimens, streptomycin, an injectable aminoglycoside, is also considered a first-line agent, though its use has been supplanted by oral drugs in many settings.

Second-Line Agents

Second-line drugs are typically used for the treatment of drug-resistant tuberculosis (DR-TB) or when first-line drugs are not tolerated. They are often less potent, more toxic, or require more complex administration. This category is heterogeneous and includes:

• Fluoroquinolones: Later-generation agents like levofloxacin and moxifloxacin.
• Injectable Agents: Aminoglycosides (amikacin, kanamycin) and the polypeptide capreomycin.
• Oral Bacteriostatic Agents: Ethionamide, prothionamide, cycloserine, terizidone, and para-aminosalicylic acid (PAS).
• Newer and Repurposed Drugs: Bedaquiline (a diarylquinoline), delamanid and pretomanid (nitroimidazoles), linezolid (an oxazolidinone), and clofazimine.

Chemical Classification

From a chemical perspective, antitubercular drugs belong to diverse structural classes. Isoniazid is a hydrazide derivative of isonicotinic acid. Rifampin is a semisynthetic derivative of rifamycin B, a macrocyclic antibiotic. Pyrazinamide is a synthetic analogue of nicotinamide. Ethambutol is a synthetic diamine derivative. Fluoroquinolones are characterized by a fluorine-substituted quinolone core. Understanding chemical class can provide insights into mechanisms of action and cross-resistance patterns.

Mechanism of Action

The mechanisms of action of antitubercular drugs target essential and often unique biochemical pathways in Mycobacterium tuberculosis. These mechanisms underpin the concepts of bactericidal and sterilizing activity, which are crucial for effective regimen design.

Isoniazid

Isoniazid is a prodrug that requires activation by the mycobacterial catalase-peroxidase enzyme, KatG. The activated form, likely an isonicotinoyl radical, inhibits the synthesis of mycolic acids, which are long-chain fatty acids that are critical components of the mycobacterial cell wall. Primary targets include the InhA enzyme (enoyl-acyl carrier protein reductase) in the fatty acid synthase II system. Inhibition of mycolic acid synthesis compromises cell wall integrity, leading to bactericidal activity, particularly against actively replicating bacilli.

Rifampin

Rifampin exerts its bactericidal effect by inhibiting DNA-dependent RNA polymerase. It binds with high affinity to the beta subunit of the bacterial enzyme, thereby blocking the initiation of RNA transcription. This action suppresses protein synthesis and is lethal to mycobacteria. Rifampin’s ability to kill dormant or intermittently metabolizing bacilli (sterilizing activity) is a key attribute, allowing for shorter treatment durations.

Pyrazinamide

The precise mechanism of pyrazinamide remains a subject of investigation but is known to be pH-dependent. PZA, a prodrug, is converted to pyrazinoic acid (POA) by the mycobacterial pyrazinamidase enzyme, PncA. In an acidic environment, such as that found within macrophages, POA accumulates and is believed to disrupt membrane energy metabolism, possibly by inhibiting the enzyme fatty acid synthase I or by causing cytoplasmic acidification. Its unique sterilizing activity against semi-dormant bacilli within acidic inflammatory lesions is essential for six-month therapy.

Ethambutol

Ethambutol is a bacteriostatic agent that inhibits the synthesis of arabinogalactan, a vital polysaccharide in the mycobacterial cell wall. It specifically targets the arabinosyltransferases EmbA, EmbB, and EmbC, which are involved in the polymerization of arabinose into arabinan. Disruption of arabinogalactan synthesis weakens the cell wall and enhances the penetration of other antitubercular drugs, such as rifampin.

Fluoroquinolones

Fluoroquinolones like moxifloxacin and levofloxacin inhibit bacterial DNA synthesis by targeting two essential enzymes: DNA gyrase (topoisomerase II) and topoisomerase IV. They bind to the enzyme-DNA complex, stabilizing it and preventing the resealing of DNA breaks, which leads to rapid bactericidal activity.

Bedaquiline

Bedaquiline represents a novel class with a unique mechanism. It inhibits mycobacterial ATP synthase, the enzyme responsible for generating adenosine triphosphate (ATP). By binding to the c subunit of the ATP synthase proton pump, it disrupts the proton gradient necessary for ATP synthesis, depleting cellular energy and leading to bactericidal activity, including against non-replicating bacilli.

Delamanid and Pretomanid

These nitroimidazole prodrugs are activated by mycobacterial deazaflavin-dependent nitroreductase (Ddn). The activated metabolites inhibit the synthesis of methoxy- and ketomycolic acids, key components of the cell wall. They also generate reactive nitrogen species that are toxic to the bacterium, exhibiting activity against both replicating and dormant organisms.

Pharmacokinetics

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

Absorption

Most first-line oral agents are well absorbed from the gastrointestinal tract. The absorption of rifampin, isoniazid, and pyrazinamide is generally rapid and complete, with peak plasma concentrations (C_max) achieved within 1-2 hours. Ethambutol absorption is somewhat slower and less complete, at approximately 75-80%. Absorption can be significantly impaired by food, particularly for rifampin and fluoroquinolones, which are recommended to be taken on an empty stomach. Malabsorption, a common issue in advanced HIV co-infection or gastrointestinal pathology, can lead to subtherapeutic levels.

Distribution

Antitubercular drugs distribute widely into tissues and body fluids, a critical property for treating extra-pulmonary tuberculosis. Isoniazid, pyrazinamide, and fluoroquinolones achieve good penetration into cerebrospinal fluid (CSF), even in the absence of inflamed meninges. Rifampin penetrates adequately only when meninges are inflamed. Ethambutol and the injectable aminoglycosides have poor CSF penetration. Many agents, including isoniazid, rifampin, and pyrazinamide, achieve high concentrations within macrophages, the primary host cell for M. tuberculosis. Volume of distribution (V_d) is typically high for these drugs, often exceeding total body water.

Metabolism

Hepatic metabolism is a major route of elimination for several key agents. Isoniazid is metabolized primarily by hepatic N-acetyltransferase 2 (NAT2) to acetylisoniazid, which is then hydrolyzed to isonicotinic acid. Genetic polymorphisms in NAT2 give rise to rapid, intermediate, and slow acetylator phenotypes, influencing drug exposure and the risk of hepatotoxicity. Rifampin is a potent inducer of hepatic cytochrome P450 enzymes (particularly CYP3A4) and the drug transporter P-glycoprotein, which is the basis for numerous drug interactions. Pyrazinamide is hydrolyzed in the liver to pyrazinoic acid, its active moiety. Ethambutol undergoes partial hepatic metabolism.

Excretion

Renal excretion is the primary elimination pathway for ethambutol, pyrazinamide, and the fluoroquinolones. Dosing of these drugs requires adjustment in patients with renal impairment. Isoniazid and its metabolites are excreted renally, with slow acetylators excreting more parent drug. Rifampin and its metabolites are excreted predominantly via the bile into feces, with a minor renal component. The half-life (t_1/2) of these drugs varies: rifampin has a relatively short half-life (2-3 hours) but a prolonged post-antibiotic effect, while bedaquiline has an exceptionally long terminal half-life (≈5 months) due to extensive tissue distribution and slow release.

Therapeutic Uses/Clinical Applications

The application of antitubercular drugs follows standardized guidelines, which are periodically updated by organizations such as the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC).

Drug-Susceptible Pulmonary Tuberculosis

The standard regimen for adults with drug-susceptible pulmonary TB consists of a two-month intensive phase and a four-month continuation phase. The intensive phase typically employs four drugs: isoniazid, rifampin, pyrazinamide, and ethambutol. Ethambutol is discontinued once drug susceptibility to isoniazid and rifampin is confirmed. The continuation phase involves isoniazid and rifampin alone. This 6-month regimen is highly effective, achieving cure rates exceeding 95% with good adherence.

Extrapulmonary Tuberculosis

Most forms of extrapulmonary TB, including lymphatic, pleural, and bone/joint disease, are treated with the same 6-month regimen as pulmonary TB. Exceptions include tuberculosis meningitis and military (disseminated) tuberculosis, for which treatment is often extended to 9-12 months, and corticosteroids are frequently co-administered to reduce inflammatory complications.

Drug-Resistant Tuberculosis (DR-TB)

The treatment of DR-TB is complex and prolonged. For multidrug-resistant TB (MDR-TB: resistant to at least isoniazid and rifampin), regimens are constructed using a combination of second-line drugs. The WHO recommends all-oral regimens lasting 6-9 months for less complex MDR-TB cases, typically including bedaquiline, levofloxacin/moxifloxacin, linezolid, clofazimine, and cycloserine/terizidone. For more extensive resistance or XDR-TB (MDR plus resistance to a fluoroquinolone and a second-line injectable), individualized regimens of 18-20 months or longer may be required, incorporating newer agents like delamanid and pretomanid.

Latent Tuberculosis Infection (LTBI)

Treatment of LTBI aims to prevent progression to active disease. Preferred regimens include isoniazid monotherapy for 6-9 months, rifampin monotherapy for 4 months, or a 3-month regimen of weekly isoniazid plus rifapentine. The choice depends on patient factors, drug susceptibility of the likely source case, and local guidelines.

Adverse Effects

The adverse effect profiles of antitubercular drugs range from mild and common to severe and life-threatening. Vigilant monitoring is a critical component of TB management.

Hepatotoxicity

Hepatotoxicity is the most 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, and older age. Isoniazid hepatotoxicity may be due to reactive metabolites. Liver function tests (transaminases) are monitored at baseline and during treatment, with symptoms like nausea, vomiting, jaundice, and abdominal pain warranting immediate evaluation.

Peripheral Neuropathy

Isoniazid can cause dose-related peripheral neuropathy by inducing pyridoxine (vitamin B₆) deficiency, as it promotes renal excretion of pyridoxine. This effect is more common in slow acetylators, malnourished individuals, diabetics, and those with alcohol use disorder. Prophylactic pyridoxine supplementation (25-50 mg daily) is routinely recommended.

Optic Neuritis

Ethambutol can cause dose-dependent retrobulbar optic neuritis, presenting with blurred vision, decreased visual acuity, impaired red-green color discrimination, and central scotomas. The risk increases significantly with doses >15 mg/kg/day and with renal impairment. Baseline and periodic visual acuity and color vision testing are mandatory during treatment.

Hyperuricemia and Arthralgia

Pyrazinamide inhibits renal excretion of uric acid, leading to hyperuricemia. This can precipitate gouty arthritis in susceptible individuals, manifesting as arthralgias. The condition is usually manageable and does not typically require discontinuation of therapy.

Cutaneous Reactions and Flu-like Syndrome

Rifampin is associated with a variety of hypersensitivity reactions, including rash, pruritus, and a “flu-like” syndrome (fever, chills, myalgia) that may occur with intermittent dosing. It also causes a harmless orange-red discoloration of bodily fluids (urine, sweat, tears).

QTc Prolongation

Several drugs used for DR-TB, including fluoroquinolones (moxifloxacin), bedaquiline, and clofazimine, can prolong the QTc interval on the electrocardiogram. This increases the risk of torsades de pointes, a potentially fatal ventricular arrhythmia. Baseline and periodic ECG monitoring is required when these drugs are used in combination.

Other Notable Effects

• Gastrointestinal Intolerance: Nausea and abdominal discomfort are common with many agents, particularly pyrazinamide and ethionamide.
• Ototoxicity and Nephrotoxicity: Injectable aminoglycosides (streptomycin, amikacin) and capreomycin can cause irreversible vestibular/auditory toxicity and reversible renal impairment.
• Neuropsychiatric Effects: Cycloserine can cause a range of effects from headache and dizziness to psychosis, depression, and seizures. Isoniazid has also been associated with psychosis and seizures.
• Hematologic Toxicity: Linezolid is associated with myelosuppression (anemia, thrombocytopenia) and peripheral/optic neuropathy, especially with prolonged use (>28 days).

Drug Interactions

Drug interactions are a major consideration in tuberculosis pharmacotherapy, largely due to rifampin’s potent enzyme-inducing properties and the potential for overlapping toxicities.

Interactions Mediated by Rifampin

As a broad inducer of CYP450 isoenzymes and P-glycoprotein, rifampin accelerates the metabolism of numerous co-administered drugs, leading to subtherapeutic concentrations. This has profound clinical implications:

• Antiretroviral Drugs: Rifampin significantly reduces plasma concentrations of most protease inhibitors and some non-nucleoside reverse transcriptase inhibitors (NNRTIs). Rifabutin, a less potent inducer, is often substituted in HIV-TB co-treatment, or dose-adjusted regimens of efavirenz or dolutegravir are used with rifampin.
• Antifungals: Levels of azoles (ketoconazole, itraconazole, voriconazole) are markedly reduced.
• Cardiovascular Drugs: Concentrations of warfarin, digoxin, verapamil, diltiazem, and many antiarrhythmics are decreased.
• Immunosuppressants: Metabolism of cyclosporine, tacrolimus, and corticosteroids is enhanced.
• Hormonal Contraceptives: Rifampin reduces the efficacy of oral, implantable, and injectable contraceptives, necessitating alternative or additional contraceptive methods.

Interactions with Isoniazid

Isoniazid is a weak inhibitor of several CYP450 enzymes, including CYP2C19 and CYP3A4. It can increase plasma concentrations of drugs like phenytoin and carbamazepine, increasing the risk of toxicity. Concurrent use of acetaminophen may theoretically increase the risk of hepatotoxicity, though evidence is conflicting. Alcohol consumption should be avoided due to additive hepatotoxicity and the potential for disulfiram-like reactions.

Additive Toxicities

Combinations of drugs with similar toxicities require careful monitoring. Examples include:

• Concurrent use of aminoglycosides and capreomycin (both nephro- and ototoxic).
• Combination of ethambutol and linezolid (both associated with optic neuropathy).
• Use of multiple QTc-prolonging agents (e.g., bedaquiline, fluoroquinolones, clofazimine).

Contraindications

Absolute contraindications are relatively few but critical. 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 standard first-line regimens containing isoniazid, rifampin, and pyrazinamide until liver function improves. Ethambutol is relatively contraindicated in patients unable to report visual symptoms or undergo visual testing.

Special Considerations

The management of tuberculosis requires tailoring pharmacotherapy to specific patient populations and physiological conditions.

Pregnancy and Lactation

Active tuberculosis during pregnancy must be treated promptly. The standard first-line regimen (isoniazid, rifampin, ethambutol) is considered safe and is recommended for 9 months, with pyrazinamide often included depending on local guidelines. Streptomycin is contraindicated due to risk of fetal ototoxicity. For DR-TB, treatment decisions must weigh maternal benefit against fetal risk, with consultation from specialists. Most first-line drugs are excreted in breast milk in low concentrations, but breastfeeding is not contraindicated during maternal TB treatment, and the infant should receive prophylactic isoniazid if the mother is considered infectious.

Pediatric Considerations

Children generally tolerate first-line TB drugs well and have a lower risk of hepatotoxicity compared to adults. Dosing is weight-based (mg/kg). Ethambutol is used cautiously in young children who cannot report visual symptoms, though the risk of toxicity at recommended doses (15-20 mg/kg/day) is very low. Palatable, child-friendly fixed-dose combination dispersible tablets are available to improve adherence. Monitoring for growth and development is important during prolonged therapy.

Geriatric Considerations

Older patients have an increased risk of drug toxicity, particularly hepatotoxicity from isoniazid and pyrazinamide. Age-related decline in renal function necessitates dose adjustment for renally excreted drugs like ethambutol. Comorbid conditions and polypharmacy increase the risk of drug interactions, especially with rifampin. Visual and auditory function should be assessed carefully before and during treatment with ethambutol or injectable agents.

Renal Impairment

Drugs that are primarily renally excreted require dose reduction or interval extension in renal failure. These include ethambutol, pyrazinamide, the aminoglycosides, capreomycin, levofloxacin, and linezolid. Isoniazid and rifampin do not require adjustment in renal impairment, though metabolites may accumulate. Hemodialysis removes significant amounts of many antitubercular drugs; therefore, dosing is typically scheduled post-dialysis.

Hepatic Impairment

Hepatic impairment presents a significant challenge. Isoniazid, rifampin, and pyrazinamide are all potentially hepatotoxic and metabolized by the liver. In patients with stable chronic liver disease, treatment can often be initiated with close monitoring. In severe acute hepatitis or decompensated cirrhosis, a non-hepatotoxic regimen (e.g., streptomycin, ethambutol, a fluoroquinolone, and cycloserine) may be required initially until liver function improves, after which first-line drugs can be reintroduced cautiously.

HIV Co-infection

HIV co-infection complicates TB treatment due to drug interactions (primarily with rifamycins), immune reconstitution inflammatory syndrome (IRIS), higher rates of adverse drug reactions, and potential malabsorption. Rifabutin is often preferred over rifampin in patients on antiretroviral therapy due to fewer interactions. Clinical and microbiological monitoring should be intensified. The duration of TB treatment for patients with HIV is generally the same as for HIV-negative patients, provided there is a satisfactory clinical response.

Summary/Key Points

• The pharmacology of antitubercular drugs is defined by the principles of combination, long-duration therapy aimed at diverse bacterial populations (replicating, dormant, intracellular).
• First-line agents (isoniazid, rifampin, pyrazinamide, ethambutol) target unique mycobacterial structures and functions: mycolic acid synthesis, RNA polymerase, membrane energy metabolism, and arabinogalactan synthesis, respectively.
• Pharmacokinetic properties are crucial; rifampin is a potent enzyme inducer, isoniazid metabolism is genetically determined, and renal/hepatic function dictates the handling of many agents.
• Hepatotoxicity is the most significant class-wide adverse effect, requiring baseline and symptomatic monitoring. Other key toxicities include peripheral neuropathy (isoniazid), optic neuritis (ethambutol), hyperuricemia (pyrazinamide), and QTc prolongation (several second-line drugs).
• Rifampin’s induction of drug-metabolizing enzymes underlies numerous and clinically critical drug interactions, most notably with antiretroviral, antifungal, and cardiovascular medications.
• Treatment must be individualized for special populations: standard first-line regimens are generally safe in pregnancy and childhood, while dose adjustments are mandatory in renal impairment, and alternative regimens may be needed in severe hepatic disease.

Clinical Pearls

• Adherence is the single greatest predictor of treatment success and prevention of resistance. Directly Observed Therapy (DOT) is a cornerstone of public health management.
• Pyridoxine (vitamin B₆) supplementation (25-50 mg daily) should be given to all patients receiving isoniazid to prevent neuropathy.
• Visual acuity and color vision testing are mandatory before and periodically during ethambutol therapy, especially at doses >15 mg/kg/day or with renal impairment.
• In patients with HIV, careful coordination between TB and antiretroviral therapy is essential, often requiring substitution of rifabutin for rifampin or use of specific antiretroviral dosing schedules.
• Therapeutic drug monitoring, while not routinely required, can be invaluable in cases of treatment failure, suspected malabsorption, drug-drug interactions, or unusual pharmacokinetics (e.g., in critical illness).

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