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Can you tell about the drugs used in tuberculosis
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I now have comprehensive information from Harrison's Principles of Internal Medicine (22nd Edition, 2025). Let me compile a thorough answer.
Drugs Used in Tuberculosis (TB)
TB is treated with a combination of drugs to prevent resistance and ensure eradication of both actively dividing and slowly growing "persister" mycobacteria. Drugs are classified as first-line and second-line agents.
First-Line Antituberculosis Drugs
The standard regimen is HRZE: Hisoniazid + Rifampin + Zyrazinamide + Ethambutol.
1. Isoniazid (INH, H)
| Feature | Detail |
|---|---|
| Mechanism | Prodrug activated by mycobacterial KatG catalase-peroxidase; the resulting acyl-NADH complex inhibits InhA (enoyl-ACP reductase), blocking mycolic acid synthesis. Also releases free radicals including nitric oxide. |
| Activity | Bactericidal against actively dividing organisms; bacteriostatic against slow-growers |
| Dose (adult) | 5 mg/kg/day (max 300 mg/day); children 10-15 mg/kg |
| Adverse effects | Peripheral neuropathy (prevented by pyridoxine 25-50 mg/day), hepatotoxicity, drug-induced lupus, CNS effects |
| Drug interactions | Inhibits CYP450 - interacts with warfarin, phenytoin, carbamazepine, benzodiazepines, acetaminophen |
| Metabolism | Hepatic acetylation by NAT2 - fast vs. slow acetylators |
| Key fact | ~7% of clinical isolates are isoniazid-resistant |
2. Rifampin (Rifampicin, R)
| Feature | Detail |
|---|---|
| Mechanism | Inhibits DNA-dependent RNA polymerase (encoded by rpoB gene), blocking RNA synthesis |
| Activity | Bactericidal; active against intracellular and extracellular organisms, including "persisters" |
| Dose | 10 mg/kg/day (max 600 mg/day) |
| Adverse effects | Hepatotoxicity (uncommon alone), rash, GI symptoms, orange/red discoloration of body fluids (urine, tears, sweat), pancytopenia; rarely hypersensitivity with intermittent therapy |
| Drug interactions | Potent CYP450 inducer - reduces levels of many drugs including antiretrovirals, oral contraceptives, warfarin |
| Key fact | Rifampin (with isoniazid) is the mainstay of all TB regimens |
Related rifamycins:
- Rifabutin - preferred when drug interactions with rifampin are problematic (e.g., HIV patients on antiretrovirals)
- Rifapentine - long-acting; used in weekly dosing regimens for LTBI (latent TB infection)
3. Pyrazinamide (PZA, Z)
| Feature | Detail |
|---|---|
| Mechanism | Prodrug converted by mycobacterial pyrazinamidase to pyrazinoic acid (POA); active only in acidic pH (<6.0) such as inside phagocytes/granulomas; targets fatty acid synthetase I |
| Activity | Bactericidal against slowly replicating organisms in acidic environments |
| Dose | 15-30 mg/kg/day (max 2 g/day); given for the first 2 months only |
| Benefit | Allowing pyrazinamide in the first 2 months shortens total treatment from 9 months to 6 months |
| Adverse effects | Hepatotoxicity (less common at current doses), hyperuricemia (may precipitate gout), GI upset |
| Resistance | Mutations in pncA gene (72-98% of resistant strains) |
| Note | Dose adjustment required in renal impairment; not recommended with rifampin for LTBI due to hepatotoxicity risk |
4. Ethambutol (EMB, E)
| Feature | Detail |
|---|---|
| Mechanism | Inhibits arabinosyl transferase enzymes involved in arabinogalactan cell wall synthesis |
| Activity | Bacteriostatic |
| Dose | 15-20 mg/kg/day |
| Adverse effects | Optic neuritis (dose-dependent) - causes decreased visual acuity and red-green color blindness; generally reversible if stopped early |
| Monitoring | Baseline and monthly visual acuity + color vision testing |
| Role | Used in the initial phase to protect against isoniazid resistance; can be stopped once susceptibility is confirmed |
5. Streptomycin (S)
| Feature | Detail |
|---|---|
| Mechanism | Aminoglycoside; inhibits 30S ribosomal subunit, blocking protein synthesis |
| Activity | Bactericidal |
| Route | Intramuscular (IM) only |
| Adverse effects | Ototoxicity (auditory + vestibular), nephrotoxicity, neurotoxicity |
| Status | Formerly a first-line drug; now classified as a second-line agent by WHO |
Standard TB Treatment Regimens
| Phase | Duration | Drugs |
|---|---|---|
| Intensive phase | 2 months | Isoniazid + Rifampin + Pyrazinamide + Ethambutol (HRZE) |
| Continuation phase | 4 months | Isoniazid + Rifampin (HR) |
| Total | 6 months | For drug-susceptible pulmonary TB |
- For TB meningitis or bone/joint TB: continuation phase extended to 7-10 months (total 9-12 months).
- For LTBI (Latent TB Infection): Isoniazid daily x 6-9 months, OR 3-month weekly isoniazid + rifapentine (3HP regimen).
Second-Line Antituberculosis Drugs
Used for drug-resistant TB (DR-TB), when first-line drugs are contraindicated, or in MDR/XDR-TB.
| Drug | Class | Mechanism | Key Adverse Effects |
|---|---|---|---|
| Fluoroquinolones (Levofloxacin, Moxifloxacin) | Group A | Inhibit DNA gyrase (topoisomerase II) | QT prolongation, tendinopathy |
| Bedaquiline (Bdq) | Diarylquinoline | Inhibits mycobacterial ATP synthase | QT prolongation, hepatotoxicity |
| Linezolid (Lzd) | Oxazolidinone | Inhibits 50S ribosomal subunit (23S rRNA) | Myelosuppression, peripheral neuropathy, lactic acidosis |
| Clofazimine (Cfz) | Riminophenazine | Generates reactive oxygen species, membrane disruption | Skin/conjunctival discoloration, GI upset |
| Pretomanid (Pa) | Nitroimidazooxazine | Inhibits cell wall synthesis + generates nitric oxide | Peripheral neuropathy, hepatotoxicity |
| Amikacin | Aminoglycoside | 30S ribosome inhibition | Ototoxicity, nephrotoxicity |
| Ethionamide (Eto) | Isonicotinic acid derivative | Inhibits InhA (same as INH but different binding) | Severe GI side effects, hypothyroidism, hepatitis, neuropathy |
| Para-aminosalicylic acid (PAS) | - | Inhibits folate synthesis + iron uptake | GI intolerance (nausea, vomiting, diarrhea); hemolysis in G6PD deficiency |
| Cycloserine | - | Inhibits peptidoglycan synthesis (blocks D-alanine racemase) | CNS toxicity (seizures, psychosis, depression) - pyridoxine supplement required |
| Capreomycin | Polypeptide | 70S ribosome inhibition | Ototoxicity, nephrotoxicity |
Drug-Resistant TB Regimens
- MDR-TB (resistant to INH + Rifampin): BPaLM regimen - Bedaquiline + Pretomanid + Linezolid + Moxifloxacin for 6 months (now the WHO-preferred regimen)
- XDR-TB (MDR + resistant to fluoroquinolones): Requires individualized regimen with group A, B, and C drugs for 18-20 months
- MDR-TB definition: Resistant to at least isoniazid and rifampin
- XDR-TB definition: MDR + resistant to any fluoroquinolone + at least one injectable second-line agent
Key Mnemonics
- RIPE or HRZE = the standard first-line intensive phase drugs
- "Please Rinse Every Hour" = Pyrazinamide, Rifampin, Ethambutol, isoniazid (H)
- Hepatotoxic first-line drugs: INH > Rifampin > Pyrazinamide
- Drug causing optic toxicity: Ethambutol
- Drug requiring visual monitoring: Ethambutol
- Pyridoxine supplementation needed with: Isoniazid (neuropathy), Ethionamide (neuropathy), Cycloserine (CNS toxicity)
Sources: Harrison's Principles of Internal Medicine, 22nd Edition (2025), Chapter on Mycobacterial Diseases; Murray & Nadel's Textbook of Respiratory Medicine.
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