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Anti-Tubercular Drugs - 2nd MBBS Pharmacology

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Classification

• Streptomycin (S)
• Ethionamide / Prothionamide
• Cycloserine / Terizidone
• Para-aminosalicylic acid (PAS)
• Fluoroquinolones: Levofloxacin, Moxifloxacin (now Group A for MDR-TB)
• Bedaquiline (Group A for MDR-TB)
• Delamanid, Pretomanid
• Amikacin, Capreomycin, Kanamycin

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First-Line Drugs - Detailed

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1. Isoniazid (INH / H)

• Prodrug - enters bacilli by passive diffusion
• Activated inside the bacterium by KatG (multifunctional catalase-peroxidase), which produces an isonicotinoyl radical
• The radical reacts with mycobacterial NAD and NADP to form adducts:
  • Nicotinoyl-NAD isomer → inhibits InhA (enoyl-ACP reductase) and KasA (β-ketoacyl-ACP synthase) → blocks mycolic acid synthesis (cell wall component)
  • Nicotinoyl-NADP isomer → inhibits dihydrofolate reductase (DHFR) → interferes with nucleic acid synthesis
• KatG also generates superoxide, H₂O₂, and NO radicals, contributing to bactericidal activity

• Bactericidal to rapidly dividing bacilli (best against actively replicating organisms)
• Highly specific for mycobacteria; no activity against other genera
• MIC for M. tuberculosis: 0.025-0.05 mg/L (very low)
• Active against M. kansasii; poor against MAC

• Well absorbed orally; food slightly reduces absorption (take on empty stomach)
• Widely distributed including CSF, pleural, peritoneal fluids, and caseous material
• Penetrates well into macrophages (active against intracellular bacilli)
• Metabolized in liver by N-acetyltransferase 2 (NAT2) - acetylation polymorphism:
  • Slow acetylators (50-60% of Caucasians/Africans): higher plasma levels → more peripheral neuropathy risk
  • Fast acetylators (majority of Asians): lower plasma levels, need adequate dosing
• Excreted in urine (partly as acetyl-INH)
• Half-life: ~1 hour in fast acetylators; ~3 hours in slow acetylators

• Adults: 5 mg/kg/day (max 300 mg/day) - daily
• Children: 10-15 mg/kg/day
• Intermittent regimen: 10 mg/kg 3x/week

• Mutation/deletion of katG gene → can't activate INH (most common, causes high-level resistance - Ser315Asn mutation)
• Overexpression of inhA → low-level resistance; cross-resistance with ethionamide
• Overexpression of ahpC (alkyl hydroperoxide reductase) → survival under oxidative stress
• Efflux pump induction

• Latent TB infection: INH 5 mg/kg/day × 6-9 months (alone)
• Close contacts of TB patients, HIV+ individuals with positive tuberculin test

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2. Rifampicin (R)

• Inhibits DNA-dependent RNA polymerase (binds β-subunit of bacterial RNAP)
• Blocks chain initiation of RNA synthesis → bactericidal
• Highly specific for bacterial RNAP (mammalian RNAP is 10,000x less sensitive)
• Active against both intracellular and extracellular bacilli, and against dormant organisms in caseous material (sterilizing activity)

• Bactericidal - one of the most potent sterilizing drugs
• Broad spectrum: M. tuberculosis, M. leprae, atypical mycobacteria, Staph. aureus, Neisseria, H. influenzae
• Critical for shortening TB treatment (from 18 months to 6 months)

• Oral absorption good; food reduces absorption - take on empty stomach
• Excellent tissue penetration including CSF (especially when meningitis inflames meninges), macrophages, caseous lesions
• Metabolized in liver → desacetylrifampicin (active metabolite)
• Potent inducer of CYP450 enzymes (3A4, 2C9, 2C19) - major drug interaction source
• Undergoes enterohepatic circulation; secreted in bile
• Half-life: 2-5 hours (shortened with continued use due to autoinduction)
• Excreted in bile/feces (mainly) and urine
• Imparts orange-red color to urine, tears, sweat, sputum - patients must be warned

• 10 mg/kg/day (450-600 mg/day in adults)
• Intermittent: 10 mg/kg 3x/week

• Mutation in rpoB gene (β-subunit of RNAP) - single mutation can confer resistance
• Rifampicin resistance is a surrogate marker for MDR-TB (since resistance to both INH and RIF = MDR-TB)

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3. Pyrazinamide (Z / PZA)

• Prodrug - converted to pyrazinoic acid by pyrazinamidase (encoded by pncA gene) inside M. tuberculosis
• Active only at acidic pH (pH 5.0-5.5) → uniquely active against intracellular organisms within macrophage phagolysosomes
• Pyrazinoic acid disrupts membrane potential and inhibits mycobacterial energy metabolism
• Also inhibits fatty acid synthase I (FAS-I), blocking mycolic acid synthesis

• Bactericidal in acidic environments (inside macrophages)
• Active against persisters (slowly or non-replicating bacilli in acidic pH)
• No activity at neutral pH or against M. kansasii
• Allows shortening of TB treatment to 6 months when added to INH+RIF regimen

• Oral absorption: excellent
• Good tissue and CSF penetration
• Metabolized by liver (xanthine oxidase)
• Half-life: ~10 hours
• Mainly excreted renally; hemodialysis removes it (redose after session)

• Mutations in pncA gene (pyrazinamidase) - prevents activation

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4. Ethambutol (E)

• Inhibits arabinosyl transferases (encoded by embB gene) → blocks arabinan synthesis
• Arabinan is a component of arabinogalactan (cell wall polysaccharide linking peptidoglycan to mycolic acids)
• Disrupts cell wall integrity
• Bacteriostatic at standard doses; bactericidal at high doses

• Oral absorption: 75-80%
• Distributed to most tissues including CSF (when meninges inflamed)
• Renal excretion - dose reduction required in renal failure
• Half-life: ~4 hours

• Contraindicated in young children (can't report visual changes reliably) and in pre-existing optic neuritis

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Second-Line Anti-TB Drugs

5. Streptomycin (S)

• First anti-TB drug discovered (1943, Waksman)
• Aminoglycoside - inhibits 30S ribosomal subunit → misreads mRNA → defective protein synthesis → bactericidal
• Cannot penetrate cells - only active against extracellular bacilli
• Does not penetrate caseous material well; poor CSF penetration
• Given IM or IV (not absorbed orally)
• Adverse effects: Ototoxicity (vestibular > cochlear), nephrotoxicity, neuromuscular blockade
• Resistance: Mutations in rpsL (S12 protein) and rrs (16S rRNA) genes

6. Ethionamide / Prothionamide

• Structural analogue of INH; also a prodrug activated by EtaA (monooxygenase)
• Inhibits InhA (same target as INH) → blocks mycolic acid synthesis
• Cross-resistance with INH (inhA mutations)
• Adverse effects: GI intolerance (most limiting), hepatotoxicity, hypothyroidism, peripheral neuropathy, CNS effects

7. Cycloserine

• Structural analogue of D-alanine
• Inhibits alanine racemase (converts L-Ala → D-Ala) and D-Ala-D-Ala ligase → blocks cell wall (peptidoglycan) synthesis
• Adverse effects: Neuropsychiatric (50% at 1g/day) - headache, psychosis, seizures, suicidal ideation; called "psychoserine"
• Contraindicated in epilepsy; use with caution in depression

8. Para-aminosalicylic Acid (PAS)

• Structural analogue of PABA → inhibits dihydropteroate synthase (folate synthesis)
• Weak bacteriostatic activity; used mainly to prevent resistance
• Adverse effects: Severe GI intolerance (nausea, vomiting, diarrhea), hepatotoxicity, hypothyroidism

9. Bedaquiline (newer drug)

• FDA approved 2012 for MDR-TB
• Mechanism: Inhibits subunit c of ATP synthase → disrupts proton pump → depletes ATP → bactericidal (including dormant organisms)
• Group A drug for MDR-TB (now standard of care)
• Adverse effects: QTc prolongation (major concern - avoid with other QT-prolonging drugs), hepatotoxicity

10. Fluoroquinolones (Levofloxacin, Moxifloxacin)

• Inhibit DNA gyrase (topoisomerase II) and topoisomerase IV → block DNA replication
• Group A drugs for MDR-TB
• Bactericidal; good tissue penetration
• Adverse effects: QTc prolongation, tendinopathy, GI effects

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Standard Treatment Regimens

Drug-Susceptible TB (Standard Short-Course Regimen)

• TB meningitis / TB bone: Continue for 12 months (2HRZE/10HR)
• 9 months if PZA cannot be used (2HRE/7HR)

MDR-TB (Resistant to INH + RIF)

• Group A: Levofloxacin/Moxifloxacin + Bedaquiline + Linezolid
• Duration: 18-24 months (shorter newer regimens being validated)

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Key Points Summary for Exam

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Important Exam Mnemonics

• Hepatitis
• Epilepsy (seizures)
• Lupus-like syndrome
• Inhibits CYP (drug interactions)
• Peripheral neuropathy (give B6!)
• Agranulocytosis
• Drug-induced SLE

• RNA polymerase inhibitor
• Induces CYP450 (lowers OCP, antiretrovirals, warfarin levels)
• Pigments urine/secretions orange-red
• Sterilizing activity

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Resistance Classification

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