OrgMed

• Populations of bacilli that must be addressed in tuberculosis treatment

  • M. tuberculosis
  • M. leprae

  
• First line of tuberculosis treatment

  • Regimen of 3-4 drugs for every 6 months to 2 years
• Second line of tuberculosis treatment

  • Reserve for multidrug resistant or unresponsive infection

  
• First line anti-tubercular drugs (RIPE)

  • Isoniazid
  • Pyrazinamide
  • Ethambutol
  • Rifampicin

  
• Second line anti-tubercular drugs (PECK)


  • Cycloserin
  • Kanamycin
  • Ethionamide
  • PAS (p-amino salicylic acid)

  
• Combination therapy with two or more anti-tubercular drugs

  • Reduces the emergence of strains
  • Shortens the period of therapy (6-18 month)
• Isoniazid

  Isonicotinic acid hydrazide, Isonicotinyl hydrazide, INH

  
• Isoniazid


  • Highly specific
  • Most potent drug
  • Active only on growing tubercle bacilli, not resting forms
  • Inhibits formation of outer mycolic acid
  • Widely distributes and penetrates CSF
  • Metabolized in the liver
  • Absorption and bioavailability decreased if taken with food

  
• Isoniazid mode of action

  1. Inhibits formation of outer mycolic acid

  2. Inhibition of cell wall synthesis

  
• Mycolic acid


  Component of the cell wall, fatty molecule that makes bacteria less susceptible to antibiotics, can help bacteria hide from immune system
• Side effects of isoniazid

  • Hypertension
  • Hepatotoxicity (increased when taken with rifampicin)
  • Peripheral neuritis (prevented by co-administration of pyridoxine)

  
• Pyridoxine (vitamin B6)


  Prevents peripheral neuritis caused by isoniazid due to B6 deficiency

  
• Hydrogen in isoniazid structure is constant, substitution makes the drug inactive

  
• Isoniazid metabolism


  Metabolized in the liver
• Pyrazinamide


  Pyrazinecarboxamide, PZA
• Pyrazinamide


  • Potent sterilizing activity and treatment shortening potential
  • Active only at slightly acidic pH
  • Active form is pyrazinoic acid
  • Targets semi-dormant bacilli residing in acidic environment

  
• Pyrazinamide analogs with antimycobacterial activity


  • Pyrazinoic acid (most potent)

  
• Pyrazinamide mode of action

  1. Lowers pH of medium, inhibiting growth of organism

  2. Acts as antimetabolite, inhibiting DNA synthesis

  
• Pyrazinamide mode of action

  • Lowers pH, inhibiting fatty acid synthesis
  • More lethal to bacilli showing inflammatory response
  • Weak bactericidal

  
• Substitution on pyrazine ring or use of alternate heterocyclic aromatic rings reduces pyrazinamide activity
• Pyrazinamide half-life


  12-24 hours
• Pyrazinamide and its metabolites interfere with uric acid excretion, caution with hyperuricemia or gout patients

  
• Pyrazinamide side effects


  • Hepatotoxicity
  • Hyperuricemia
  • GI upset
• Ethambutol


  (+)-2,2-(ethylenediimino)-di-1-butanoldihydrochloride, EMB, Myambutol

  
• Ethambutol


  • Active only against dividing tubercle bacilli
  • (+) enantiomer 200-500 times more active than (-) enantiomer

  
• Ethambutol mode of action

  Inhibits incorporation of mycobacterial cell wall components (bacteriostatic)

  
• Ethambutol mode of action

  • Inhibits arabinosyl transferase involved in cell wall biosynthesis, increasing cell wall permeability

  
• Substitution on ethambutol structure reduces activity
• Rifampicin


  Rifadin, Rimactane, Rifampin
• Rifampicin


  • From Streptomyces mediterranei
  • Belongs to ansamycin class of antibiotics, broad spectrum
  • Both antibacterial and antitubercular
  • Metabolized in the liver
  • Gives orange-red color to stool, urine and tears

  
• Rifampicin mode of action

  Inhibits DNA-dependent RNA polymerase activity by forming a stable complex
• Rifampicin


  • Powerful inducer of hepatic CYP450 oxygenases, potentiating actions of drugs inactivated by these enzymes

  
• Rifampicin


  Other names: Rifadin, Rimactane, Rifampin
• Rifampicin


  From Streptomyces mediterranei
• Ansamycins


  A class of antibiotics that has both Gram positive & negative
• Rifampicin


  • Broad spectrum due to widely used range
  • Both Antibacterial & antitubercle
• Rifampicin


  • Metabolized in the liver
  • Gives orange-red color to stool, urine and tears
• Rifampicin MOA


  Inhibits DNA dependent RNA polymerase activity by forming a stable complex with the enzyme = suppress initiation of RNA synthesis cell death
• Drugs potentiated by Rifampicin

  • Oral anticoagulant
  • Barbiturates
  • Benzodiazepine
  • Oral hypoglycemic agents
  • Phenytoin
  • Theophylline

  
• Rifampicin


  • A powerful inducer of hepatic CYP450 oxygenases