Antitubercular Drugs

A high-yield, perennially-tested chapter blending mechanisms, classic organ-specific toxicities, resistance-directed regimens, and India's national programme (NTEP/DOTS). The exam loves single-fact recall (which drug causes which toxicity) and the rationale behind drug combinations.

Classification

Antitubercular drugs are classified by efficacy, the WHO resistance-based grouping, and the older first-/second-line scheme. For NEET PG, master all three frames.

Line	Drugs	Note
First-line (essential)	Isoniazid (H), Rifampicin (R), Pyrazinamide (Z), Ethambutol (E)	Backbone of drug-sensitive TB ("HRZE")
First-line (supplemental)	Rifabutin, Rifapentine, Streptomycin	Rifabutin = less CYP induction (HIV)
Second-line (injectables)	Amikacin, Kanamycin, Capreomycin	Capreomycin = polypeptide, not aminoglycoside
Second-line (fluoroquinolones)	Levofloxacin, Moxifloxacin	High-yield in MDR-TB
Newer / repurposed	Bedaquiline, Delamanid, Pretomanid, Linezolid, Clofazimine, Cycloserine, Ethionamide, PAS	BPaL/BPaLM regimens

WHO (2019) MDR-TB grouping — frequently asked:

• Group A: Levofloxacin/Moxifloxacin, Bedaquiline, Linezolid (most effective; include all three when possible).
• Group B: Clofazimine, Cycloserine/Terizidone (add to complete regimen).
• Group C: Ethambutol, Delamanid, Pyrazinamide, Imipenem-cilastatin/Meropenem, Amikacin (or Streptomycin), Ethionamide/Prothionamide, PAS (used when A & B cannot complete the regimen).

High-yield: Group A = "BeLL" — Bedaquiline, Linezolid, Levo/Moxifloxacin. Aminoglycosides (kanamycin/capreomycin) were demoted out of the preferred core in the 2019 revision because of injectable toxicity.

Mechanism of action — the bactericidal logic

Different drugs hit physiologically distinct bacterial populations, which is the basis of combination therapy.

• Isoniazid → inhibits mycolic acid synthesis (cell wall). Prodrug activated by mycobacterial catalase-peroxidase (KatG); targets InhA/enoyl-ACP reductase. Most active against rapidly multiplying extracellular bacilli.
• Rifampicin → inhibits DNA-dependent RNA polymerase (β-subunit, rpoB gene). Bactericidal against all populations — actively dividing, intracellular, and slow/intermittently dividing ("persisters"). This sterilising action shortened therapy from 18 to 6 months.
• Pyrazinamide → prodrug activated by pyrazinamidase (pncA) to pyrazinoic acid; acts in acidic intracellular environment (caseous foci, macrophages). Key sterilising drug in the first 2 months.
• Ethambutol → inhibits arabinosyl transferase (embB) → blocks arabinogalactan synthesis. Bacteriostatic; added mainly to prevent resistance.
• Streptomycin → 30S ribosomal inhibition; acts only on extracellular bacilli (poor cell penetration), inactive in acidic pH.

High-yield: Best sterilising drugs = Rifampicin + Pyrazinamide. Best at preventing resistance = Isoniazid + Rifampicin. Pyrazinamide works only at acidic pH; streptomycin works only at alkaline/neutral extracellular pH.

Stepwise concept: Drug-sensitive TB → intensive phase (2 months HRZE kills the bulk + sterilises) → continuation phase (4 months HR clears persisters) → cure with low relapse.

Organ-specific toxicities (the single most tested table)

Drug	Hallmark toxicity	Pearl / antidote
Isoniazid	Peripheral neuropathy (pyridoxine deficiency), hepatitis, SLE-like syndrome	Prevent/treat with pyridoxine (vit B6); slow acetylators at higher risk
Rifampicin	Orange-red secretions (urine/sweat/tears), hepatitis (cholestatic), flu-like syndrome (intermittent dosing), potent CYP450 inducer	Stains contact lenses; warn the patient
Pyrazinamide	Hyperuricaemia/gout, hepatotoxicity (most hepatotoxic at high dose), arthralgia	Inhibits renal urate excretion
Ethambutol	Retrobulbar (optic) neuritis — ↓ visual acuity, red-green colour blindness	Dose-related, usually reversible; baseline + periodic visual checks
Streptomycin	Ototoxicity (vestibular > cochlear), nephrotoxicity	Avoid in pregnancy (8th nerve damage to fetus)

High-yield mnemonic: "RIPE" side effects — Rifampicin = red-orange fluids/enzyme inducer; Isoniazid = INH = "I Numb Hands & feet" (neuropathy); Pyrazinamide = "Pee acid" (hyperuricaemia); Ethambutol = Eye (optic neuritis).

Isoniazid neuropathy & pyridoxine

INH increases urinary excretion of pyridoxine and inhibits its conversion to the active coenzyme, causing a dose-dependent distal sensorimotor peripheral neuropathy. Pyridoxine 10 mg/day prevents it; slow acetylators, diabetics, alcoholics, pregnant women, malnourished, HIV, and CKD patients are high-risk and routinely co-prescribed B6.

High-yield: In INH overdose the triad = refractory seizures, metabolic (anion-gap) acidosis, coma — treat with high-dose IV pyridoxine (gram-for-gram with ingested INH). INH causes a pyridoxine-responsive sideroblastic anaemia too.

Rifampicin and CYP450 induction

Rifampicin is one of the strongest inducers of CYP3A4 and P-glycoprotein, accelerating metabolism of oral contraceptives (contraceptive failure — advise alternate/barrier method), warfarin, oral hypoglycaemics, protease inhibitors/NNRTIs, corticosteroids, phenytoin, and itself (autoinduction). In HIV co-infection where antiretroviral interaction is critical, rifabutin (weaker inducer) is substituted.

High-yield: Rifampicin flu-like syndrome, thrombocytopenia, haemolytic anaemia and acute renal failure are typically seen with intermittent or interrupted therapy (immune-mediated). Rifampicin also competes with bilirubin → transient unconjugated hyperbilirubinaemia.

Drug-resistant TB — definitions & regimens

Resistance terminology is exam gold:

• Mono-resistant = resistant to one first-line drug.
• MDR-TB = resistant to at least Isoniazid + Rifampicin.
• Pre-XDR-TB (2021 WHO) = MDR/RR-TB plus resistance to any fluoroquinolone.
• XDR-TB (revised 2021) = MDR/RR-TB + FQ resistance + resistance to at least one Group A drug (bedaquiline or linezolid).
• RR-TB = rifampicin resistance (detected by GeneXpert), managed as MDR.

Regimen	Composition	Use
Drug-sensitive	2 HRZE / 4 HR (daily, fixed-dose combinations)	New pulmonary/extrapulmonary TB
BPaLM	Bedaquiline + Pa (pretomanid) + Linezolid + Moxifloxacin × 6 months	MDR/RR-TB & pre-XDR (WHO 2022 preferred, all-oral)
Shorter all-oral	Bedaquiline-based 9–11 month	Eligible MDR-TB

High-yield: The first-line drug NOT given in renal failure without adjustment = ethambutol & streptomycin (renally cleared); pyrazinamide and rifampicin are hepatically handled. Pyrazinamide is omitted in gout/severe liver disease. In pregnancy, the standard HRE/HRZE is safe but streptomycin is contraindicated (fetal ototoxicity); pyridoxine is added to INH.

Newer drugs — quick facts

• Bedaquiline → inhibits mycobacterial ATP synthase; risk = QT prolongation, hepatotoxicity, long half-life (months).
• Delamanid / Pretomanid → nitroimidazoles inhibiting mycolic acid synthesis; also QT prolongation.
• Linezolid → oxazolidinone (50S); toxicity = myelosuppression, peripheral & optic neuropathy, lactic acidosis.
• Clofazimine → reddish-black skin discolouration; also used in leprosy.
• Cycloserine → CNS toxicity (psychosis, seizures) — give pyridoxine.
• Ethionamide → GI intolerance, hypothyroidism, hepatotoxicity.

DOTS & the national programme

DOTS (Directly Observed Treatment, Short-course) is the WHO-endorsed strategy operationalised in India under the NTEP (National TB Elimination Programme), the renamed RNTCP, targeting TB elimination by 2025.

The five components of DOTS:

1. Sustained political & administrative commitment.
2. Diagnosis by quality-assured sputum microscopy / molecular tests (GeneXpert/CBNAAT).
3. Uninterrupted supply of quality fixed-dose combination drugs.
4. Directly observed treatment with patient support.
5. Standardised recording & reporting and outcome evaluation.

High-yield: CBNAAT/GeneXpert MTB/RIF is the recommended initial diagnostic test — it detects M. tuberculosis DNA and rifampicin resistance within ~2 hours, and is the upfront test for HIV-associated, paediatric, and presumptive DR-TB. Liquid culture (MGIT) is the gold standard for confirmation and drug-susceptibility testing.

Chemoprophylaxis (TB Preventive Therapy)

Treatment of latent TB infection (LTBI) prevents progression to active disease. Diagnose latent TB with Tuberculin Skin Test (Mantoux) or IGRA (Interferon-Gamma Release Assay) — IGRA is unaffected by prior BCG.

Indications (high-yield):

• All household contacts of pulmonary TB, especially children <5 years.
• HIV-positive individuals (after ruling out active TB).
• Patients starting anti-TNF biologics, organ transplant, or prolonged steroids/immunosuppression.
• Silicosis, dialysis patients.

Regimen	Duration
Isoniazid (with pyridoxine)	6 months (6H)
Isoniazid + Rifapentine weekly	3 months (3HP)
Rifampicin + Isoniazid	3 months (3HR)
Rifampicin alone	4 months (4R)

High-yield: Mantoux ≥ 5 mm = positive in HIV, recent contacts, immunosuppressed, and organ-transplant candidates; ≥10 mm in moderate-risk; ≥15 mm in low-risk persons. Reaction read at 48–72 hours (delayed type-IV hypersensitivity).

BCG vaccination — immunology

Bacille Calmette-Guérin is a live attenuated strain of Mycobacterium bovis. Given intradermally over the deltoid, ideally at birth under India's Universal Immunization Programme.

• Confers protection chiefly against disseminated childhood TB — miliary TB and tubercular meningitis — rather than reliably preventing adult pulmonary TB.
• Induces cell-mediated (Th1) immunity; converts a previously negative Mantoux to positive (limits TST usefulness, hence IGRA preference).
• A normal scar/induration appears in ~6 weeks.
• Contraindicated in symptomatic HIV/immunodeficiency (risk of disseminated BCG-osis).
• Also used intravesically for superficial bladder carcinoma (an immunotherapy fact often tested).

High-yield: BCG protects best against TB meningitis and miliary TB in children; efficacy against adult pulmonary TB is variable (0–80%). It is a live vaccine.

Clinical features (orienting context)

Pulmonary TB classically presents with chronic cough >2 weeks, evening-rise low-grade fever, night sweats, weight loss/anorexia, and haemoptysis. Extrapulmonary forms — lymphadenitis (scrofula), Pott's spine, TB meningitis, pleural effusion, abdominal/genitourinary TB — round out the picture. The upper-lobe cavitary lesion on chest X-ray is the classic radiological hallmark.

Diagnosis — investigation of choice

Flow: Presumptive TB → Sputum CBNAAT/GeneXpert (initial, gives rifampicin resistance) → if rifampicin-resistant, send for culture + line probe assay / phenotypic DST → start appropriate regimen → monitor with follow-up smears at end of intensive phase, month 5 and end of treatment.

• Screening/initial: GeneXpert MTB/RIF (Ultra) — preferred over smear microscopy.
• Gold standard: Mycobacterial culture (MGIT/LJ medium) — also enables full DST.
• Smear (ZN/auramine stain) — cheap, but needs ~10,000 bacilli/mL.
• Histology: caseating granuloma with Langhans giant cells.

Monitoring therapy

• Baseline + periodic LFTs (INH, R, Z all hepatotoxic — stop if ALT >3× ULN with symptoms or >5× ULN).
• Visual acuity & colour vision before ethambutol.
• Serum uric acid if pyrazinamide-related symptoms.
• Audiometry/renal function with aminoglycosides; ECG (QTc) with bedaquiline/delamanid/moxifloxacin.

Complications & key drug interactions

• Drug-induced hepatitis — most feared; pyrazinamide most hepatotoxic per dose, but combined HRZ risk is additive.
• Rifampicin–OCP failure, warfarin under-anticoagulation, ARV interactions.
• Paradoxical reaction / IRIS in HIV co-infection on ART.
• INH–phenytoin interaction (INH inhibits phenytoin metabolism → toxicity, opposite of rifampicin).

Key differentials (which drug is the culprit?)

Presentation	Likely drug
Tingling/numbness of feet	Isoniazid
Orange tears/urine	Rifampicin
Painful big toe / raised uric acid	Pyrazinamide
Difficulty distinguishing red–green	Ethambutol
Vertigo / hearing loss	Streptomycin
Refractory seizures + metabolic acidosis (overdose)	Isoniazid
QT prolongation in MDR-TB	Bedaquiline / Moxifloxacin / Delamanid

Recently asked / exam angle

• "Drug acting in acidic pH within macrophages" → Pyrazinamide.
• "Best sterilising drug / acts on persisters" → Rifampicin.
• "Initial diagnostic test detecting rifampicin resistance" → CBNAAT/GeneXpert.
• "Antitubercular contraindicated in pregnancy" → Streptomycin.
• "INH overdose antidote" → Pyridoxine (high-dose IV).
• "Definition of MDR-TB / XDR-TB / pre-XDR" — match-the-following style.
• "WHO Group A drugs for MDR-TB" → bedaquiline, linezolid, fluoroquinolone.
• "Mechanism of bedaquiline" → ATP synthase inhibition.
• "BCG protects against" → miliary TB & TB meningitis in children.
• "Drug needing pyridoxine supplementation" → INH and cycloserine.
• Assertion–reason on rifampicin + OCP failure (CYP induction).

Rapid revision

1. HRZE = 2-month intensive phase; HR = 4-month continuation phase for drug-sensitive TB.
2. Isoniazid → mycolic acid (KatG-activated); causes peripheral neuropathy prevented by pyridoxine.
3. Rifampicin → RNA polymerase (rpoB); orange secretions, strong CYP450 inducer, best sterilising drug.
4. Pyrazinamide → acts at acidic pH; causes hyperuricaemia/gout; most hepatotoxic per dose.
5. Ethambutol → arabinosyl transferase; retrobulbar optic neuritis with red–green colour loss.
6. Streptomycin → 30S; ototoxicity, contraindicated in pregnancy.
7. MDR-TB = resistance to INH + Rifampicin; XDR adds FQ + a Group A drug resistance.
8. WHO Group A = bedaquiline, linezolid, levo/moxifloxacin ("BeLL").
9. Bedaquiline inhibits ATP synthase; watch QTc.
10. CBNAAT/GeneXpert = initial test (detects rifampicin resistance); MGIT culture = gold standard.
11. BCG (live, M. bovis) given intradermal at birth; protects against childhood miliary TB & TB meningitis; also intravesical for bladder cancer.
12. INH overdose = seizures + metabolic acidosis + coma → IV pyridoxine; rifabutin preferred over rifampicin in HIV on ART.