Antitubercular Drugs — Classification, Mechanisms & NTEP Therapy

1. Classification of Antitubercular Drugs

A. Based on Efficacy (KDT/WHO Classification)

B. Based on Bactericidal vs. Bacteriostatic Action

C. Based on Activity on Bacterial Populations (Sterilizing Activity)

• Rapidly multiplying extracellular bacilli → Isoniazid (most active), Rifampicin
• Slow/intermittently multiplying bacilli (caseous lesions) → Rifampicin
• Intracellular bacilli (acidic environment of macrophages) → Pyrazinamide (most active), Rifampicin
• Dormant bacilli → Rifampicin (some activity)

The combination of INH + RIF + PZA targets all three bacterial populations, which is the rationale for the 6-month regimen.

2. Mechanisms of Action of First-Line Anti-TB Drugs

A. Isoniazid (INH / H)

• Class: Isonicotinic acid hydrazide (synthetic)
• Mechanism: INH is a prodrug activated by the mycobacterial catalase-peroxidase enzyme KatG. The activated form forms a covalent complex with acyl carrier protein (AcpM) and KasA (β-ketoacyl-ACP synthase), blocking mycolic acid synthesis — an essential component of the mycobacterial cell wall. Inhibition of InhA (NADH-dependent acyl carrier protein reductase) also contributes.
  • Bactericidal against rapidly dividing bacilli; bacteriostatic against dormant organisms
  • Active against both intracellular and extracellular organisms
• Resistance: Mutation/deletion of katG (most common, high-level resistance); overexpression of inhA; mutations in kasA or ahpC
• Key pharmacology:
  • Well absorbed orally (peak in 1–2 h, 3–5 µg/mL)
  • Penetrates all body fluids including CSF (20–100% of serum levels)
  • Metabolized by liver N-acetyltransferase (NAT2) — genetic polymorphism:
    • Slow acetylators: t½ ≈ 3–4 h → higher plasma levels → more neuropathy risk
    • Fast acetylators: t½ < 1 h → lower plasma levels
• Adverse effects:
  • Hepatotoxicity (most serious — age >35, daily alcohol, co-rifampicin increases risk)
  • Peripheral neuropathy (pyridoxine/B₆ deficiency — prevented by pyridoxine 10 mg/day)
  • CNS effects (seizures in predisposed patients)
  • Drug interaction: Inhibits CYP450 → potentiates phenytoin and carbamazepine toxicity

B. Rifampicin (Rifampin / R)

• Class: Rifamycin antibiotic (semisynthetic macrocyclic)
• Mechanism: Binds the β-subunit of mycobacterial DNA-dependent RNA polymerase, thereby blocking RNA transcription (inhibits initiation, not elongation). Bactericidal for both intracellular and extracellular organisms.
  • Active against M. tuberculosis, NTM, M. leprae, and many gram-positive/gram-negative bacteria
• Resistance: Point mutation in rpoB gene (encodes β-subunit of RNA polymerase) → reduced drug binding affinity. rpoB mutation = surrogate marker for MDR-TB.
• Key pharmacology:
  • Well absorbed orally; distributed widely including into CSF (10–20% of serum levels; higher with meningeal inflammation)
  • Undergoes enterohepatic recirculation; excreted mainly in bile/feces
  • Potent inducer of CYP1A2, 2C9, 2C19, 2D6, 3A4 → major drug interactions (reduces levels of OCP, antiretrovirals, warfarin, cyclosporine, methadone)
  • Autoinduction of its own metabolism (t½ shortens over first 1–2 weeks)
• Adverse effects:
  • Orange discoloration of urine, sweat, tears, saliva (harmless; may stain soft contact lenses permanently)
  • Hepatotoxicity (cholestatic jaundice, hepatitis)
  • Flu-like syndrome (if given less than twice weekly — intermittent dosing)
  • Thrombocytopenia, nephritis, rashes

C. Pyrazinamide (PZA / Z)

• Class: Synthetic analog of nicotinamide
• Mechanism: A prodrug hydrolyzed by mycobacterial pyrazinamidase to pyrazinoic acid (active form). Exact mechanism remains incompletely understood but it:
  • Disrupts membrane energy metabolism and the proton motive force
  • Inhibits fatty acid synthesis (FAS I system)
  • Active only in acidic pH (pH < 6) — therefore uniquely effective against intracellular bacilli in the acidic environment of macrophage phagolysosomes and caseous lesions
  • Sterilizing activity in this population allows shortening of treatment from 9 months to 6 months
• Resistance: Loss of pyrazinamidase enzyme activity (mutations in pncA gene)
• Pharmacology: Good oral absorption; penetrates CSF well; discontinued after 2 months of the 6-month regimen (most benefit early)
• Adverse effects:
  • Hepatotoxicity (dose-dependent)
  • Hyperuricemia (inhibits uric acid excretion) → arthralgia; rarely precipitates gout
  • Nausea, rash, flushing, photosensitivity

D. Ethambutol (EMB / E)

• Class: Synthetic ethylene diamine derivative
• Mechanism: Inhibits arabinosyl transferase (encoded by embB gene) — an enzyme essential for the synthesis of arabinogalactan, a key component of the mycobacterial cell wall. Disrupts cell wall integrity and allows other drugs better penetration.
  • Bacteriostatic (at standard doses); bactericidal at higher doses
  • Active only against multiplying mycobacteria
• Resistance: Mutations in embB gene
• Pharmacology: Well distributed; variable CSF penetration; excreted mainly in urine (reduce dose in renal failure)
• Adverse effects:
  • Retrobulbar (optic) neuritis — most important toxicity
    • Manifests as: decreased visual acuity, red-green colour blindness, central scotoma
    • Dose-dependent; reversible if stopped early
    • Baseline and monthly visual acuity + colour vision testing mandatory
  • Hyperuricemia (mild)
  • Avoid in children <5 years (cannot report visual symptoms reliably)

E. Streptomycin (S) — Historical First-Line; Still Used in Special Cases

• Class: Aminoglycoside
• Mechanism: Binds 30S ribosomal subunit (16S rRNA) → misreading of mRNA → faulty protein synthesis → bactericidal. Active only against extracellular bacilli (cannot penetrate macrophages; inactive in acidic pH).
• Route: IM only (not orally absorbed)
• Adverse effects: Ototoxicity (vestibular > cochlear), nephrotoxicity; contraindicated in pregnancy

Summary Diagram of Mechanisms

Lippincott Pharmacology — Standard 6-month TB treatment regimen

3. NTEP Antitubercular Therapy for Drug-Sensitive TB in Adults

Background & Principles

1. Daily directly observed treatment (DOT) — mandatory
2. Fixed-Dose Combinations (FDCs) — prescribed as per weight bands to ensure correct dosing
3. Universal Drug Susceptibility Testing (UDST) at diagnosis
4. Treatment in public or private sector follows the same regimen; FDCs supplied by NTEP

Standard Regimen for Drug-Sensitive TB (DS-TB)

Total duration: 6 months | Total doses: 168

FDC Composition

Weight-Band Dosing (Adults)

If patient's weight increases by >5 kg crossing a weight band during treatment → upgrade to next higher band

Standard Drug Doses (Reference)

Special Considerations Under NTEP

Rationale for 4-Drug Regimen

Pyridoxine (Vitamin B₆) Supplementation

• Malnourished patients
• Pregnant women
• Elderly
• Diabetics
• Alcoholics
• HIV-positive patients

Monitoring During NTEP Therapy

Uses of First-Line Antitubercular Drugs

1. Isoniazid (INH / H)

TB-Related Uses

Non-TB Uses

• M. kansasii infection (only NTM susceptible to INH at standard doses)

INH is not used as monotherapy for active TB — only for LTBI prophylaxis as a single agent.

2. Rifampicin (Rifampin / R)

TB-Related Uses

Non-TB Mycobacterial Uses

Non-Mycobacterial Uses

Rifampicin is never used as monotherapy for active TB — rapid resistance develops.

3. Pyrazinamide (PZA / Z)

Uses

Non-TB Uses

• No significant non-TB uses — PZA is highly specific for Mycobacterium tuberculosis
• No activity against M. bovis (intrinsically resistant — lacks pyrazinamidase)

Rationale for limiting PZA to 2 months: most clinical benefit is early; continued use increases hepatotoxicity risk without adding sterilizing benefit.

4. Ethambutol (EMB / E)

TB-Related Uses

Non-TB Mycobacterial Uses

Ethambutol is not used as monotherapy — it is bacteriostatic and serves primarily as a companion drug to prevent emergence of resistance.

5. Streptomycin (S)

TB-Related Uses

Non-TB Uses

Streptomycin is IM-only (not orally absorbed) and acts only against extracellular bacilli. Contraindicated in pregnancy (8th nerve damage in fetus) and avoided in renal failure and elderly.

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