Antitubercular Drugs

Classification

1st-line: isoniazid(H), rifampicin(R), pyrazinamide(Z), ethambutol(E), streptomycin(S, less used now). 2nd-line: fluoroquinolones(levofloxacin, moxifloxacin), injectables(amikacin, kanamycin, capreomycin), newer(bedaquiline, delamanid, linezolid).

Rationale for Multi-Drug Therapy (organizing principle)

TB exists in 3 sub-populations: rapidly-dividing extracellular, slowly-dividing intracellular(macrophage, acidic), dormant(caseous necrotic material). NO single drug covers all 3. Multi-drug needed for: (1) covering all sub-populations(different drugs target different populations) + (2) PREVENTING resistant mutant selection(spontaneous resistance to any ONE drug occurs at low frequency in large cavitary-lesion bacterial population → multi-drug makes simultaneous multi-drug-resistance in one organism statistically very unlikely) — clearest highest-stakes application of General Considerations’ resistance-prevention principle.

Regimen Structure

Intensive phase(2mo): 4 drugs(HRZE) — targets ACTIVELY multiplying population, rapid load reduction, non-infectious quickly. Continuation phase(4mo): typically H+R only — actively-dividing population reduced, goal=sterilize slow/persister populations+prevent relapse; fewer drugs OK since resistance-prevention logic matters less as bacterial burden(=absolute number of potential resistant mutants) has fallen.

Mechanism — Individual Agents

Isoniazid: PRODRUG, activated by mycobacterial KatG(catalase-peroxidase) → active metabolite inhibits InhA(mycolic acid synthesis — the waxy cell wall component = basis of acid-fastness). Bactericidal vs ACTIVELY DIVIDING only. KatG mutation = MOST COMMON isoniazid resistance mechanism(tied to activation step, not InhA target itself).

Rifampicin: inhibits DNA-dependent RNA polymerase → blocks mRNA synthesis. Bactericidal vs BOTH dividing+semi-dormant(broader than isoniazid → in both phases). Potent broad CYP450 INDUCTION = single most clinically significant property beyond antitubercular action — ↓OCP efficacy(counsel patients), ↓warfarin, many others.

Pyrazinamide: PRODRUG, activated by mycobacterial pyrazinamidase→pyrazinoic acid, accumulates in ACIDIC intracellular macrophage environment → disrupts membrane potential/transport. pH-dependent activation = WHY uniquely effective vs semi-dormant INTRACELLULAR population(weak vs neutral extracellular) — distinct niche from H/R. INTENSIVE PHASE ONLY(once extracellular population ↓, its advantage matters less relative to hepatotoxicity risk).

Ethambutol: inhibits arabinosyl transferase(arabinogalactan synthesis, another cell wall component). BACTERIOSTATIC(unlike H/R/Z). Included to PROTECT other drugs from resistance emergence(4th drug “covers” possible pre-existing isoniazid resistance) — not for potent independent bactericidal activity.

Adverse Effects — Drug-Specific

Isoniazid: peripheral neuropathy(interferes with pyridoxine/B6 metabolism, competes with pyridoxal phosphate+↑renal excretion) → PYRIDOXINE co-administered routinely(esp malnourished, pregnancy, diabetics, alcoholics=higher baseline risk). Hepatotoxicity(↑age, +alcohol). INHIBITS hepatic microsomal enzymes(OPPOSITE direction from rifampicin — contrast directly).

Rifampicin: hepatotoxicity(ADDITIVE with isoniazid’s own — important in standard 4-drug regimen). Harmless orange-red discolouration(urine, tears, sweat, contact lenses) — benign/cosmetic, PRE-COUNSEL to avoid unnecessary treatment discontinuation.

Pyrazinamide: MOST hepatotoxic of 1st-line agents at standard dosing. Hyperuricaemia(↓renal urate excretion, can precipitate gout) — usually ASYMPTOMATIC, doesn’t require stopping unless actual gouty attack(not automatic CI).

Ethambutol: optic/retrobulbar neuritis — dose-related, ↓visual acuity + distinctive RED-GREEN colour blindness, generally REVERSIBLE if caught early(baseline+periodic visual/colour testing needed). Caution/avoid in YOUNG CHILDREN(can’t reliably report early visual symptoms — “can’t self-report” logic).

Streptomycin: SAME aminoglycoside toxicity(nephro+ototoxicity) as full Aminoglycosides topic — identical mechanism, not separate TB-specific fact set.

Drug-Resistant TB

MDR-TB: resistant to ≥isoniazid+rifampicin(2 most potent 1st-line agents) → longer/more toxic 2nd-line regimen, worse outcomes — direct consequence of resistance-prevention logic FAILING(inadequate regimen/poor adherence/malabsorption allowing resistant mutant selection). XDR-TB: MDR-TB + resistance to a fluoroquinolone + ≥1 second-line injectable — progressively narrower/more dangerous → underscores WHY multi-drug, full-course, DOT approach exists to prevent this escalation.

Clinical Relevance

Every 1st-line drug’s specific role/timing traces directly to WHICH mycobacterial sub-population it targets and BY WHAT mechanism — isoniazid/rifampicin’s broad dividing-organism activity, pyrazinamide’s unique pH-dependent intracellular activity(intensive-phase-only), ethambutol’s resistance-PROTECTIVE(not independently curative) role — regimen structure = direct pharmacological reasoning, not arbitrary drug list/schedule to memorize.

Classification

First-line drugs (form the backbone of standard therapy): isoniazid (H), rifampicin (R), pyrazinamide (Z), ethambutol (E), streptomycin (S, now used less than the other four).

Second-line drugs (reserved for resistant/intolerant cases): fluoroquinolones (levofloxacin, moxifloxacin), injectable agents (amikacin, kanamycin, capreomycin), and newer agents (bedaquiline, delamanid, linezolid).

Rationale for Multi-Drug Therapy

This is the organizing clinical principle for the entire topic, directly extending the general combination-therapy rationale introduced under Antimicrobials — General Considerations: Mycobacterium tuberculosis exists within a lesion in multiple distinct sub-populations with different metabolic states — rapidly dividing extracellular organisms, slowly dividing organisms within macrophages (acidic intracellular environment), and dormant/semi-dormant organisms within caseous necrotic material — and no single drug is effective against all three populations simultaneously. Multi-drug therapy is required both to cover all sub-populations (different drugs are more effective against different populations, detailed below) and, critically, to prevent selection of drug-resistant mutants — spontaneous resistance mutations to any single drug occur at a low but real frequency in the very large bacterial population within a cavitary lesion, and using multiple drugs simultaneously makes it statistically very unlikely that a single organism would spontaneously carry resistance mutations to more than one drug at once, the same “prevent resistance emergence during therapy” principle from Antimicrobials — General Considerations, here in its clearest, highest-stakes clinical application.

Standard Regimen Structure

Intensive phase (2 months): four drugs (isoniazid, rifampicin, pyrazinamide, ethambutol) — the larger drug combination during this phase targets the actively multiplying bacterial population, achieving rapid bacterial load reduction and rendering the patient non-infectious relatively quickly. Continuation phase (4 months): typically isoniazid and rifampicin alone — by this point the actively-dividing population has been substantially reduced, and the remaining goal is sterilizing the slower-growing/persister populations and preventing relapse, achievable with fewer drugs since the resistance-prevention statistical logic above matters less once the bacterial burden (and therefore the absolute number of potential spontaneous resistant mutants) has been substantially reduced.

Mechanism of Action — Individual Agents

Isoniazid: a prodrug, activated by the mycobacterial catalase-peroxidase enzyme KatG, after which the active metabolite inhibits InhA, an enzyme in mycolic acid synthesis — mycolic acids being the distinctive, waxy long-chain fatty acids of the mycobacterial cell wall (the basis of acid-fastness itself) — blocking this synthesis is bactericidal specifically against actively dividing organisms (a static organism isn’t building new cell wall), analogous in principle to β-lactams’ preferential activity against dividing bacteria despite a completely different target. KatG mutation is the most common cause of isoniazid resistance — a specific, examined resistance mechanism directly tied to the prodrug-activation step rather than the ultimate InhA target itself.

Rifampicin: inhibits bacterial DNA-dependent RNA polymerase, blocking mRNA synthesis — bactericidal against both actively dividing and semi-dormant organisms (a broader-population activity than isoniazid, part of why it’s included in both treatment phases). Potent, broad-spectrum hepatic CYP450 induction is rifampicin’s single most clinically significant, most frequently examined property beyond its own antitubercular action — accelerating metabolism of oral contraceptives (a specific, high-yield contraceptive-failure risk requiring patient counselling), warfarin, and numerous other drugs, a genuinely important interaction given how many patients on antitubercular therapy are also on other chronic medications.

Pyrazinamide: a prodrug, activated by mycobacterial pyrazinamidase to pyrazinoic acid, which accumulates specifically in the acidic environment inside macrophages and disrupts mycobacterial membrane potential/transport — this pH-dependent activation is exactly why pyrazinamide is uniquely effective against the semi-dormant, intracellular macrophage population (its activity is comparatively weak against organisms in a neutral extracellular environment), a genuinely distinct spectrum-of-activity niche from isoniazid/rifampicin, and the specific reason it’s included only in the intensive phase (once the actively-dividing extracellular population has been reduced, its distinctive intracellular-targeting advantage matters proportionally less relative to its hepatotoxicity risk).

Ethambutol: inhibits arabinosyl transferase, an enzyme involved in arabinogalactan synthesis (another mycobacterial cell wall component, distinct from but functionally complementary to mycolic acid) — bacteriostatic (unlike the three drugs above), included in the intensive phase primarily to protect the other drugs from resistance emergence in settings of possible pre-existing isoniazid resistance (a fourth drug “covering” for the possibility that one of the other three is already ineffective in a given patient) rather than for potent independent bactericidal activity of its own.

Adverse Effects — High-Yield, Drug-Specific

Isoniazid: peripheral neuropathy, caused by isoniazid interfering with pyridoxine (vitamin B6) metabolism (structurally competing with pyridoxal phosphate, and increasing its renal excretion) — the specific, mechanism-linked reason pyridoxine supplementation is routinely co-administered with isoniazid, particularly in malnourished patients, pregnancy, diabetics, and alcoholics, who are at higher baseline neuropathy risk. Hepatotoxicity (idiosyncratic, risk increasing with age and with concurrent alcohol use). Also inhibits hepatic microsomal enzymes (the opposite direction from rifampicin), a specific point worth contrasting directly with rifampicin’s induction.

Rifampicin: hepatotoxicity (additive with isoniazid’s own hepatotoxicity when combined, a genuinely important consideration in the standard four-drug regimen) and harmless orange-red discolouration of body fluids (urine, tears, sweat, contact lenses) — a benign, purely cosmetic effect but important to pre-counsel patients about specifically so they don’t mistake it for a dangerous reaction and stop treatment unnecessarily.

Pyrazinamide: hepatotoxicity (the most hepatotoxic of the first-line agents at standard dosing, a specific comparative point) and hyperuricaemia (inhibits renal urate excretion, can precipitate gout) — this hyperuricaemia is usually asymptomatic and doesn’t require stopping the drug unless a genuine gouty attack occurs, a nuance worth distinguishing from an automatic contraindication.

Ethambutol: optic neuritis/retrobulbar neuritis — dose-related, presenting as reduced visual acuity and, distinctively, red-green colour blindness, generally reversible with prompt discontinuation but requiring baseline and periodic visual acuity/colour vision testing during therapy, and specific caution/avoidance in young children (unable to reliably report early visual symptoms, the same “can’t self-report early warning signs” logic that makes certain drugs specifically cautioned in populations who can’t communicate a developing adverse effect).

Streptomycin: the same aminoglycoside toxicity profile (nephrotoxicity, ototoxicity) already covered fully under Aminoglycosides — worth recognizing as the identical mechanism and adverse-effect profile rather than a separate fact set specific to tuberculosis treatment.

Drug-Resistant Tuberculosis

MDR-TB (multidrug-resistant): resistant to at least isoniazid and rifampicin, the two most potent first-line agents — requiring a longer, more toxic, second-line regimen with substantially poorer treatment outcomes, the direct clinical consequence of the resistance-prevention logic above failing (whether from inadequate initial regimen, poor adherence, or drug malabsorption allowing resistant mutants to be selected). XDR-TB (extensively drug-resistant): MDR-TB plus additional resistance to a fluoroquinolone and at least one second-line injectable agent — a progressively narrower and more dangerous resistance pattern, underscoring why the multi-drug, full-course, directly-observed-therapy approach to standard TB treatment exists specifically to prevent this escalation.

Clinical Relevance

Every first-line drug’s specific role and timing in the standard regimen traces directly back to which mycobacterial sub-population it targets and by what mechanism — isoniazid and rifampicin’s broad activity against dividing organisms, pyrazinamide’s unique pH-dependent intracellular activity justifying its intensive-phase-only inclusion, and ethambutol’s resistance-protective rather than independently curative role — making the regimen’s structure a direct application of pharmacological reasoning rather than an arbitrary drug list and dosing schedule to memorize.

• Three mycobacterial sub-populations (extracellular dividing, intracellular macrophage, dormant caseous) mapped to which first-line drug targets each.
• Intensive phase (4 drugs) → continuation phase (2 drugs) timeline with bacterial burden reduction and resistance-prevention logic.
• Isoniazid and pyrazinamide as prodrugs, showing their respective activation steps (KatG; mycobacterial pyrazinamidase in acidic macrophage environment).

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