Anti-TB Drugs 1st line

Question 1

Isoniazid

Answer 1

• Bactericidal
• **cell wall inhibitor **
  
  • **​inhibits mycolic acid synthesis **(once activated by KatG and bound to NAD/NADP, acts as FAS inhibitor, inhibits InA)
• ​PO
• **renal clearance **
• **good CNS/CSF penetrance **
• penetrates macrophages (active against intra/extracellular orgs
• **most effective RX in susceptible strains **
• NAT2 deactivates INH by acetylation
  
  • ​slow vs fast acetylators (in slow, the drug 1/2life is longer)
• adverse effects =
  
  • **hepatic toxicity **(due to toxic metabolite) (decreased in fast acetylators)
    
    • **age dependent **
    • **clinically apparent hepatitis **
    • may be potentiated by rifampin
    • increased hepatotoxicity with acetaminophen
  • **peripheral neuropathy **
    
    • **​due to pyroxidine deficiency (vitB6) **(INH competes with vitB6 for renal reabsorption)
• resistance = KatG deletion/mutation; InA overexpression ​
• 9 mo tx for latent infection
• 4 mo plus RIF for active infection

Question 2

Pyrazinamide

Answer 2

• Bactericidal
• PO
• **Renal clearance **
• **excellent distribution, including CNS **
• penetrates macrophages
• inactive at neutral pH and “active” at acidic pH
• MOA = prodrug converted to POA at acidic pH by pncA, incorporated into extracell, antagonizes NADH; inhibits FAS1 interfering w/ mycolic acid synthesis
• adverse effects =
  
  • hepatic toxicity
  • **hyperuricemia = exacerbates gout **
  • **NOT approved during pregnancy **
• resistance = pcnA mutations

Question 3

Ethambutal

Answer 3

• **Bactericidal **
• PO
• **Renal clearance **
• CSF penetration w/ meningeal inflammation** **
• MOA = cell wall synthesis inhibitor= **inhibits embAB operon (polymerization of cell wall); enhances cell wall perm **
• adverse effects =
  
  • **optic neuritis **(1%) - loss of visual acuity, red green color blindness
• resistance = embB mutations

Question 4

Rifampin

(Rifamycins)

Answer 4

• **Bactericidal **in mycobacteria
• **PO **
• **effective against G+ and G- cocci, some enteric bacteria, mycobacteria, chlamydia **
• hepatic clearance and excretion
• little CNS penetration (high protein binding)
• penetrates macrophages
• MOA = inhibits RNA synthesis (binds beta subunit of bacterial RNA pol)
• adverse effects =
  
  • **may turn urine, tears, and other body fluids reddish-orange **
  • **category C in pregnancy **
• ​induces hepatic metabolism (drug interactions)
  
  • ​accelerates metabolism of anti-HIV cocktail (protease/rev T’criptase inhibitors)
  • decreases half life for OCs
• resistance = mutations of rpoB