Table of Contents
Anti-Tuberculosis Drugs
Tuberculosis (TB) remains one of the most significant infectious diseases worldwide, caused by Mycobacterium tuberculosis. Unlike many bacteria, M. tuberculosis possesses a lipid-rich, mycolic acid–containing cell wall, slow replication rate, and ability to survive within macrophages. These properties necessitate prolonged multidrug therapy.
The principles of TB treatment are based on:
- Combination therapy – prevents resistance
- Prolonged duration (6 months or more) – eradicates dormant bacilli
- Bactericidal + sterilizing drugs – eliminate both active and latent organisms
Why Combination Therapy Is Essential
TB bacilli exist in different metabolic states:
- Rapidly multiplying extracellular bacilli
- Intracellular bacilli inside macrophages
- Semi-dormant organisms in caseating granulomas
No single drug effectively kills all populations. Therefore, combination therapy (e.g., HRZE) is mandatory.
First-Line Anti-Tuberculosis Drugs
These drugs are the backbone of standard therapy.
1. Isoniazid (INH)
Mechanism of Action
- Prodrug activated by bacterial catalase-peroxidase (KatG enzyme)
- Inhibits synthesis of mycolic acids
- Bactericidal against rapidly dividing organisms
Pharmacological Characteristics
- Excellent oral absorption
- Penetrates CSF
- Metabolized by liver via acetylation (NAT2 enzyme)
Adverse Effects
- Peripheral neuropathy (due to pyridoxine deficiency)
- Hepatotoxicity
- Drug-induced lupus
- Seizures (rare)
Clinical Pearl
Always administer pyridoxine (Vitamin B6) with INH to prevent neuropathy.
2. Rifampin
Mechanism of Action
- Inhibits DNA-dependent RNA polymerase
- Suppresses RNA synthesis
- Bactericidal
Key Features
- Broad-spectrum activity
- Potent enzyme inducer (CYP450)
Adverse Effects
- Hepatitis
- Orange discoloration of body fluids
- Drug interactions (e.g., oral contraceptives, warfarin)
Clinical Importance
Also used for:
- Meningococcal prophylaxis
- Leprosy
- Atypical mycobacterial infections
3. Pyrazinamide
Mechanism of Action
- Converted to active form pyrazinoic acid
- Active in acidic environments (inside macrophages)
- Sterilizing action on semi-dormant bacilli
Adverse Effects
- Hepatotoxicity
- Hyperuricemia (may cause gout)
Unique Role
Shortens total duration of therapy from 9 months to 6 months.
4. Ethambutol
Mechanism of Action
Inhibits arabinosyl transferase
Impairs cell wall synthesis
Adverse Effects
- Optic neuritis
- Decreased visual acuity
- Red-green color blindness
Monitoring
Visual acuity testing is recommended during therapy.
Standard Regimen (Drug-Sensitive TB)
Intensive Phase (2 months):
- Isoniazid
- Rifampin
- Pyrazinamide
- Ethambutol
Continuation Phase (4 months):
- Isoniazid
- Rifampin
This is often referred to as the HRZE regimen.
Second-Line Anti-Tuberculosis Drugs
Used in drug-resistant TB (MDR-TB) or intolerance.
Aminoglycosides
- Streptomycin
- Amikacin
- Kanamycin
Mechanism: Inhibit protein synthesis (30S ribosome)
Adverse effects: Ototoxicity, nephrotoxicity
Fluoroquinolones
- Levofloxacin
- Moxifloxacin
Mechanism: Inhibit DNA gyrase
Important in MDR-TB regimens
Other Agents
- Ethionamide
- Cycloserine
- Para-aminosalicylic acid (PAS)
- Linezolid
- Bedaquiline (inhibits ATP synthase)
Drug-Resistant Tuberculosis
MDR-TB
Resistant to:
- Isoniazid
- Rifampin
Requires second-line combination therapy for 18–24 months.
XDR-TB
Extensively resistant TB; very difficult to treat.
Mechanism Summary Diagram
Adverse Effect Comparison Table (Conceptual Overview)
| Drug | Major Toxicity | Preventive Strategy |
|---|---|---|
| Isoniazid | Neuropathy | Pyridoxine |
| Rifampin | Hepatitis | LFT monitoring |
| Pyrazinamide | Hyperuricemia | Monitor uric acid |
| Ethambutol | Optic neuritis | Vision testing |
Clinical Correlation
- TB meningitis → Ensure drugs penetrate CNS
- HIV co-infection → Drug interaction monitoring
- Pregnancy → Avoid streptomycin
Key Exam Points (High-Yield)
- INH → Mycolic acid inhibition
- Rifampin → RNA polymerase inhibition
- Ethambutol → Optic neuritis
- Pyrazinamide → Shortens therapy duration
- Combination therapy prevents resistance
Conclusion
Anti-tuberculosis drugs represent a carefully structured pharmacological strategy targeting different bacterial populations within the host. The first-line regimen—isoniazid, rifampin, pyrazinamide, and ethambutol—forms the foundation of therapy, while second-line agents are reserved for resistant strains.
Understanding mechanisms, adverse effects, and therapeutic principles is essential for safe and effective TB management.