Tuberculosis Treatment: Isoniazid Overview

Tuberculosis Treatment

• First Line Drugs (FLDs): Oral drugs used for initial treatment
  • Isoniazid (INH/H)
  • Rifampicin (R)
  • Pyrazinamide (Z)
  • Ethambutol (E)

Isoniazid (INH)

• Mechanism of Action: Inhibits cell wall synthesis by interfering with mycolic acid synthesis
  • Structurally related to vitamin B6
  • Activated by KatG in M. Tuberculosis
  • Effective on both intracellular and extracellular bacilli
• Resistance Mechanism: Mutations in catalase peroxidase and the promoter gene inhA
• Pharmacokinetics: Penetrates body fluids, accumulates in caseated lesions
  • Acetylated in the liver, resulting in faster elimination of the acetyl form
• Uses: Combined with other drugs for treatment; used alone for prophylaxis
• Adverse Effects:
  • Allergic reactions
  • Hepatotoxicity (increased risk with age, alcohol, drug use)
  • Peripheral neuropathy (with high doses), minimized with pyridoxine
  • Inhibits metabolism of other drugs (e.g., diphenylhydantoin)
• Drug Interactions: Alcohol and certain medications (e.g., phenytoin, carbamazepine) can affect INH absorption and metabolism

Rifampicin, Rifapentine, Rifabutin

• Mechanism of Action: Inhibits DNA-dependent RNA polymerase
• Bactericidal: Effective against various bacteria (including M. tuberculosis, M. leprae, and others)
• Resistance: Can develop quickly with monotherapy due to mutations in the rpoB gene
• Pharmacokinetics: Well absorbed orally; highly protein-bound; excreted primarily via liver and bile
  • Induces hepatic microsomes and therefore affects the metabolism of other drugs
• Adverse effects: Hepatitis (dose-dependent and reversible)
  • Nausea, vomiting, dizziness, fatigue, fever, jaundice
  • Urine discoloration
• Drug Interactions: Induces metabolism of other drugs like oral contraceptives, anticoagulants, protease inhibitors

Ethambutol (Myambutol)

• Mechanism of Action: Inhibits arabinosyl transferases involved in cell wall biosynthesis
• Mechanism of Resistance: Mutations in embB gene
• Adverse Effects:
  • Reversible retrobulbar neuritis (visual impairment)
  • Red-green colour vision loss
  • Mild gastrointestinal (GI) disturbances
  • Potential for gout precipitation (due to decreased urate secretion)

Pyrazinamide

• Mechanism of Action:
  • Derivative of nicotinamide
  • Converted to pyrazinoic acid by bacterial pyrazinamidase
  • Bactericidal, active in acidic environments of macrophage phagosomes (pH 5)
• Resistance Mechanism: Mutations in the pcnA gene (which encodes pyrazinamidase)
• Adverse Effects: Hepatotoxicity, vomiting, anorexia
• Special Considerations: Not recommended for use during pregnancy
• Action on TB: Acts on extracellular tubercle bacilli
• Other Considerations: Hepatotoxicity is a major concern; inhibits urate excretion and can precipitate gout attacks

Second-Line Drugs (SLDs)

• Fluoroquinolones: Levofloxacin, Moxifloxacin, Gatifloxacin
• Other SLDs: Ethionamide, Prothionamide, Cycloserine, Terizidone, Para-aminosalicylic Acid (PAS), Thiacetazone

MIC and Mechanism of Action Table

• Data on Minimum Inhibitory Concentration (MIC), genes involved in resistance, roles in resistance, and mechanism of action for various antituberculosis drugs.

Tuberculosis Treatment Categories

• Detailed descriptions of different treatment categories for latent and active tuberculosis infections, including specific drug combinations and durations.