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Drugs for Tuberculosis - Complete MBBS Pharmacology

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Overview: Why Multiple Drugs?

1. Actively dividing extracellular bacilli (in lung cavities) - killed by isoniazid, rifampin
2. Slowly dividing intracellular bacilli (inside macrophages) - killed by pyrazinamide
3. Dormant/persister bacilli (in acidic granuloma environment) - killed by pyrazinamide
4. Semi-dormant bacilli (caseous foci) - killed by rifampin

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Classification of Anti-TB Drugs

FIRST-LINE DRUGS (RIPE mnemonic)

SECOND-LINE DRUGS

• Injectable aminoglycosides: Amikacin, Capreomycin, Kanamycin
• Fluoroquinolones: Moxifloxacin, Levofloxacin
• Oral bacteriostatic agents: Ethionamide, Cycloserine, PAS (para-aminosalicylic acid)
• Novel agents: Bedaquiline, Linezolid, Delamanid, Pretomanid, Clofazimine

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FIRST-LINE DRUGS (Detailed)

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1. ISONIAZID (INH / H)

• INH is a prodrug - activated by mycobacterial KatG catalase-peroxidase
• The activated INH-NADH complex inhibits InhA (mycobacterial ketoenoyl-reductase / enoyl-ACP reductase)
• This blocks mycolic acid synthesis - mycolic acids are essential long-chain fatty acids in the mycobacterial cell wall
• KatG activation also releases free radicals (including nitric oxide) that have direct antimycobacterial activity
• Selective toxicity: Human cells lack mycolic acid synthesis, so INH has no toxicity to human cells via this mechanism

• Excellent oral absorption (peak serum: 3-5 mcg/mL in 30 min-2 h)
• Widely distributed including CSF (CSF levels = serum levels) - important for TB meningitis
• Metabolized in liver by N-acetyltransferase 2 (NAT2) - acetylation + hydrolysis
• Polymorphic acetylation (genetically determined):
  • Slow acetylators (most Indians, Europeans) - higher drug levels, more toxicity (neuropathy)
  • Fast acetylators (East Asians) - lower drug levels, may need higher doses
• Inhibits CYP450 - increases levels of warfarin, carbamazepine, phenytoin

• Adults: 5 mg/kg/day (max 300 mg/day)
• Children: 10-15 mg/kg/day
• Intermittent: 15 mg/kg twice weekly (max 900 mg)
• Always give with pyridoxine 25-50 mg/day to prevent neuropathy

• 5 mechanisms identified:
  • katG mutations (most common - impairs prodrug activation)
  • inhA mutations (target modification - also causes low-level resistance to ethionamide)
  • kasA, NADH dehydrogenase 2 mutations
  • Efflux pumps (efpA, mmpL7, Rv1258c) in 20-30%
• ~7-10% of US isolates resistant

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2. RIFAMPIN (Rifampicin / R / RIF)

• Semisynthetic derivative of rifamycin (from Amycolatopsis rifamycinica)
• Binds β-subunit of bacterial DNA-dependent RNA polymerase → inhibits RNA transcription
• Bactericidal - active against both intracellular and extracellular organisms
• Penetrates phagocytic cells, abscesses, and lung cavities effectively
• Human RNA polymerase is not inhibited (selectivity)

• Well absorbed orally (take on empty stomach - food reduces absorption)
• Excreted mainly via bile → enterohepatic recirculation → feces (deacetylated metabolite)
• Small amount excreted in urine
• No dose adjustment in renal impairment
• Imparts orange-red color to urine, sweat, tears, saliva (warn patient - harmless)

• 600 mg/day (or 10 mg/kg/day) orally
• For LTBI (latent TB): 600 mg/day x 4 months as monotherapy (preferred over INH for LTBI)

• Oral contraceptives (OCP failure - use barrier method)
• Warfarin (reduced anticoagulation)
• Antiretrovirals (protease inhibitors, NNRTIs, integrase inhibitors)
• Cyclosporine, tacrolimus (organ rejection risk)
• Methadone (precipitates withdrawal)
• Anticonvulsants (phenytoin levels fall)
• Oral hypoglycemics

• Point mutations in rpoB gene (β-subunit of RNA polymerase)
• Complete cross-resistance within all rifamycins (rifampin, rifabutin, rifapentine)
• Rifampin resistance = marker for MDR-TB (since INH+RIF combination is the backbone)

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3. PYRAZINAMIDE (PZA / Z)

• Nicotinamide analogue - prodrug
• Converted by mycobacterial pyrazinamidase (encoded by pncA gene) to active pyrazinoic acid (POA)
• POA disrupts mycobacterial cell membrane metabolism and transport; fatty acid synthase I is likely the primary target
• Active only in acidic environment (pH <6.0) - the acidic milieu inside macrophage lysosomes and within caseous granulomas
• Therefore kills the intracellular "persister" population - no other drug does this as effectively
• This is why adding PZA to the initial 2-month phase allows treatment to be shortened from 9 months to 6 months

• Well absorbed orally; peak serum: 20-60 mcg/mL at 1-2 h
• Widely distributed including CSF (important for TB meningitis)
• Metabolized in liver; metabolites cleared renally
• Dose reduction needed in renal impairment (CrCl <30 mL/min - give 3x weekly, not daily)

• 25 mg/kg/day (max 2 g/day) or 15-30 mg/kg/day

• Mutations in pncA gene (72-98% of resistant strains) → impaired pyrazinamidase → can't convert PZA to active POA

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4. ETHAMBUTOL (EMB / E)

• Bacteriostatic (only first-line drug that is bacteriostatic - the rest are bactericidal)
• Inhibits arabinosyltransferases (embB gene) involved in mycobacterial cell wall synthesis
• Specifically inhibits formation of arabinogalactan and lipoarabinomannan (components of the mycobacterial cell wall)
• MIC: 0.5-2 mcg/mL

• 75-80% absorbed orally; peak serum 2-4 mcg/mL at 2-4 h
• Well distributed but poorly penetrates CSF (needs 25 mg/kg for CSF levels)
• Mainly excreted unchanged in urine - dose reduction in renal impairment

• Intensive phase: 15-25 mg/kg/day
• The 4th drug in the RIPE regimen - primarily included to prevent resistance if INH or RIF resistance is present

• Missense mutations in embB gene (codon 306 in 50-70%)

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STANDARD TREATMENT REGIMENS

Drug-Susceptible Pulmonary TB (6-month standard regimen)

INTENSIVE PHASE (2 months): HRZE daily
    ↓
CONTINUATION PHASE (4 months): HR daily

• HRZE = Isoniazid + Rifampin + Pyrazinamide + Ethambutol
• Ethambutol can be dropped if susceptibility to INH + RIF is confirmed
• INH-RIF alone for 9 months cures 95-98% of susceptible TB

Newer 4-Month Regimen (2022 onward)

INTENSIVE PHASE (8 weeks): RPT + MOX + INH + PZA (daily)
    ↓
CONTINUATION PHASE (9 weeks): RPT + MOX + INH (daily)

• Rifapentine + Moxifloxacin + Isoniazid + Pyrazinamide
• Non-inferior to 6-month regimen for adults/adolescents ≥40 kg

Latent TB Infection (LTBI)

• Rifampin alone x 4 months - preferred, most effective
• INH alone x 6-9 months - alternative
• INH + Rifapentine weekly x 12 weeks (3HP regimen) - for contacts

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SECOND-LINE DRUGS (Detailed)

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FLUOROQUINOLONES (Moxifloxacin, Levofloxacin)

• Mechanism: Inhibit DNA gyrase (topoisomerase II) and topoisomerase IV → block DNA replication
• Moxifloxacin is the most potent anti-TB fluoroquinolone (now first-line in 4-month regimen)
• Used in MDR-TB and drug-intolerant patients
• ADR: QT prolongation (moxifloxacin), tendinopathy, CNS effects

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BEDAQUILINE

• First new TB drug in 40 years (FDA approved 2012)
• Mechanism: Inhibits mycobacterial ATP synthase (blocks energy production)
• Bactericidal against both replicating AND non-replicating bacilli
• Used in MDR-TB and XDR-TB regimens
• ADR: QT prolongation (most important - ECG monitoring mandatory), hepatotoxicity, nausea

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AMINOGLYCOSIDES (Amikacin, Kanamycin, Capreomycin)

• Mechanism: Bind 30S ribosomal subunit → inhibit protein synthesis (amikacin); capreomycin is a cyclic peptide with similar mechanism
• Injectable agents - used in MDR-TB
• ADR: Nephrotoxicity, ototoxicity (8th nerve damage - vestibular + cochlear)

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ETHIONAMIDE

• Mechanism: Structural analogue of INH; also a prodrug, also inhibits InhA (mycolic acid synthesis) - activated by EtaA monooxygenase (not KatG)
• Cross-resistance with INH (inhA mutations) but not katG mutations
• Dose: 500-750 mg/day in divided doses
• ADR: Severe GI intolerance (nausea, vomiting - dose-limiting), hepatotoxicity, hypothyroidism, metallic taste, peripheral neuropathy

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CYCLOSERINE

• Mechanism: Analogue of D-alanine; inhibits alanine racemase and D-Ala-D-Ala ligase → blocks peptidoglycan cell wall synthesis
• Dose: 500-1000 mg/day in divided doses
• ADR: CNS toxicity - seizures, psychosis (suicide risk), peripheral neuropathy, somnolence
• Monitor drug levels; supplement pyridoxine
• Contraindicated in epilepsy, severe renal insufficiency, active alcohol use, depression history

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PAS (Para-aminosalicylic acid)

• Mechanism: Structural analogue of PABA; inhibits folate synthesis in mycobacteria (similar to sulfonamides)
• Also may inhibit iron uptake by mycobacteria
• Dose: 8-12 g/day in divided doses
• ADR: Severe GI intolerance, hepatotoxicity, hypothyroidism (interferes with iodine incorporation), hypersensitivity, malabsorption syndrome

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LINEZOLID

• Mechanism: Oxazolidinone; inhibits 50S ribosome assembly (unique binding site - prevents initiation complex formation)
• Active against MDR-TB and XDR-TB; excellent intracellular penetration
• Part of BPaL regimen (Bedaquiline + Pretomanid + Linezolid) for XDR-TB
• Dose: 600 mg/day (1200 mg/day for first 6 months in some protocols)
• ADR: Bone marrow suppression (anemia, thrombocytopenia), irreversible peripheral and optic neuropathy (prolonged courses), serotonin syndrome (if combined with serotonergic agents)
• Monitor CBC; supplement pyridoxine

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RIFABUTIN

• Semisynthetic rifamycin; same mechanism as rifampin (inhibits RNA polymerase)
• Complete cross-resistance with rifampin
• Key advantage: Less potent CYP450 inducer than rifampin
• Used instead of rifampin in HIV-TB co-infection - especially when patient is on protease inhibitors or NNRTIs (rifabutin does not drop PI levels as drastically)
• Dose: 300 mg/day (reduce by half with PIs; increase to 600 mg/day with efavirenz)
• ADR: Hepatotoxicity, rash, leukopenia, thrombocytopenia, optic neuritis, uveitis (unique to rifabutin)

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DELAMANID & PRETOMANID (Nitroimidazoles)

• Mechanism: Prodrugs activated by mycobacterial flavin-dependent nitroreductases → inhibit mycolic acid biosynthesis + generate nitric oxide and reactive oxygen species
• Delamanid: Used in MDR-TB (children <6 years with rifampicin-resistant TB); 100 mg twice daily
• Pretomanid: Part of BPaL regimen for XDR-TB; 200 mg/day
• ADR: QT prolongation (delamanid especially), hepatotoxicity (pretomanid in combination)

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CLOFAZIMINE

• Riminophenazine dye; primarily used in leprosy but increasingly in MDR-TB
• Mechanism: Increases reactive oxygen species, membrane destabilization; also anti-inflammatory
• Half-life: ~70 days
• ADR: GI intolerance, reversible orange-brown discoloration of skin and secretions

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MDR-TB and XDR-TB Treatment

• MDR-TB: Resistant to at least INH + Rifampin
• XDR-TB (formerly Pre-XDR + XDR): MDR-TB + resistance to fluoroquinolones ± injectable agents

• BPaZLfx: Bedaquiline + Pretomanid + Pyrazinamide + Linezolid + Levofloxacin
• BPaL: Bedaquiline + Pretomanid + Linezolid (for XDR-TB - Nix-TB trial)
• Duration: 18-20 months

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High-Yield Memory Tricks (MBBS Exam)

• Cell wall synthesis blockers: INH (mycolic acid), Ethambutol (arabinogalactan), Cycloserine (peptidoglycan), Delamanid/Pretomanid (mycolic acid via nitroreductases)
• RNA polymerase inhibitor: Rifampin (and all rifamycins)
• Protein synthesis inhibitor: Aminoglycosides (30S), Linezolid (50S)
• ATP synthase inhibitor: Bedaquiline
• Folate synthesis inhibitor: PAS
• Membrane disruptors: Pyrazinamide (in acidic pH), Clofazimine

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Special Situations

• Use rifabutin instead of rifampin (less drug interaction with ARVs)
• Efavirenz-based ART: rifampin can be used (efavirenz dose may need increase)
• Integrase inhibitors (dolutegravir): use rifabutin (rifampin reduces dolutegravir levels significantly)

• HRZE is acceptable (first-line regimen)
• Streptomycin is contraindicated (ototoxicity to fetus)
• Pyrazinamide: controversial in USA, used by WHO
• Add pyridoxine throughout

• All drugs except ethambutol (poor CSF penetration) penetrate CSF well
• Use INH, RIF, PZA as backbone; add fluoroquinolone or ethionamide if needed
• Duration extended to 9-12 months

• All first-line drugs are hepatotoxic; monitor LFTs
• Stop if ALT >3x ULN with symptoms, or >5x ULN without symptoms
• Streptomycin + ethambutol can replace hepatotoxic drugs temporarily

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