Pharmacology Antimycobacterium

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  1. Isoniazid (INH) (general info)
    • 1st line treatment of TB
    • most active against sensitive strains
    • small molecule water soluble
    • similar in structure to pyridoxine
    • in vitro bactericidal for most
    • Active against extra as well as intracellular
    • MDR-MTB is resistant to it
  2. INH mech of action
    • interferes with mycolic acid synthesis
    • stops complex with AcpM and KasA from making mycolic acid

    Prodrug -->activated form --> complex--> mycolioc acid

    KatG changes prodrug to active
  3. INH resistance
    • over-expression of inhA gene
    • KatG (peroxidase): no converstion of pro drug to active
    • (no cross resistance to ethionamide)
    • KasA
    • 1 in 10^6 in single drug
    • 1 in 10^12 in 2 drugs
  4. INH pharmacokinetics
    • fast absorption
    • 1-2h peak plasma 3-5 mcg/ml
    • metabolized by acetylation : liver N-acetyl transferase
    • excretion through urine
    • t1/2: 3 hr in slow acetylators and 1 hr in rapid
  5. INH clinical uses
    • usuall dose 300mg once orally
    • 5 mg/kg/day
    • 15 mg/kg twice weekly if with another drug
  6. INH toxicity
    • fever and rash, SLE (systemic lupus erythematosus)
    • Isoniazid induced hepatitis
    • peripheral neuropathy: common in AIDS avoid stavudine (NRTI)
    • CNS toxicity (rare)
  7. Rifampin general info
    • 1st line drug
    • bactericidal against M. TB and M. Leprae
    • no cross resistance with other classes
    • cross resistance with rifamycin derivatives (rifabutin for AIDS)
  8. Rifampin mechanism
    binds with beta subunit of RNA polymerase, stops transcritption of DNA to RNA
  9. Rifampin resistance
    mutation in rpoB and reduces binding to beta subunit.
  10. Rifampin pharmacokinetics
    • diffuses into most tissue and macrophages
    • metabolized in liver, secreted in bile
    • 5-7 mcg/ml in plasma
    • binds with protein and CSF conc in proportional to meningeal inflammatinon
  11. Rifampin clinical uses
    • 10mg/kg (600mg) in conj with other drugs (INH, Ethambutol, pyrazinamide)
    • Combo effective against atypical mycobateria and M. Leprae
    • 4 month treatment for latent infection
    • prophylactic against H. Flu type B
  12. Rifampin toxicity
    • orange excretions
    • rashes
    • thrombocytopenia, nephritis
    • flu like symptoms
    • liver toxicity
    • INDUCTION of CYP450 pathway: increases secretion of drugs like methadone, PI, and NNRTI etc.
  13. Ethambutol general info
    • 1st line drug
    • synthetic water soluble and stable
    • inhibits mycobacteria
    • over expression of emb leads to resistance
  14. ethambutol mech of action
    • inhibits polymerization of arabinoglycan (cell wall component)
    • inhibits arbinosyl transferase encoded by emb
  15. Ethambutol pharmacokinetics
    • good oral absorption
    • wide distribution (important cuz myco will be in macrophages)
    • T1/2: 2-4 hr
    • Excretion 75% unchanged, prolonged in renal disease
  16. Ethambutol clinical uses
    15-25 mg/kg d in combo with inh or rifampin
  17. Ethambutol side effects
    • rash
    • fever
    • retrobulbar neuritis (visual activity)
    • contraindicati in children
  18. Pyrazinamide (general info, mech of action, resistance)
    • 1st line drug
    • poorly soluble in water
    • related to nicotinamide
    • inactive at neutral pH but works at 5.5 (functional in lysosome)
    • mech of action unknown
    • resistance: mutation in pncA (encodes pyrazinamidase)
    • inhibits mycob at 20 mcg/ml
    • pyrazinamide --> pyrazinoic acid
    • (enzyme myco pyrazinamidase)
  19. Pyrazinamide pharmacokinectics
    • 25 mg/kg d
    • 1-2 hr peak plasma 30-50 mcg
    • T1/2: 8-11 hr
    • metabolized in liver, cleared through urine
  20. Pyrazinamide side effects
    • Hepatoxociity
    • N/V fever, jaundice
    • hyperuricemia (acute gouty arthiritis)
  21. Streptomycin general info
    • 1st line drug
    • aminoglycoside
    • 1st for treat of TB
    • injectable drug
    • used in combo to avoid resistance
  22. streptomycin mech of action
    • binds to 16s rRNA ribosome
    • blocks protein synthesis
  23. Streptomycin clinical use
    • adult: 1g gives 40mcg/ml in 30-60 min
    • Child: 20-40 mg/kg not exceeding 1-1.5g
  24. Streptomycin side effects
    • N/v
    • rash fever
    • eosinophilia
    • ototoxic: vertigo and hearing loss
    • nephrotoxic: impaired renal function especially in elderly with high doses.
  25. Ethionamide (general info)
    • second line drug
    • INH class (inhibits mycolic acid synthesis)
    • poor water solublility
    • liver metabolism
    • Side effects: GI irritation, hepatotoxic, neurotoxic (pyridoxine can help with neuro)
  26. Capreomycin
    • 2nd line drug for mycob
    • used for strep resis mTB
    • protein syntheis inhibitor (ribosome)
    • contraindicated in pregnancy
    • Side effects: nephrotoxic, ototoxic, local pain and abscess
  27. cycloserine
    • 2nd line of drug
    • inhibits cell wall synthesis (peptidoglycan)
    • secreted through urine
    • Side effects: nephro and ototoxic, peripheral neuropathy and CNS toxicity (pyridoxine is recommended)
  28. Aminosalicylic acid
    • 2nd line of treatment
    • folate synthesis antagonist specific against mTB
    • Side effects: GI irritation, peptic ulceration, hepatosplenomegaly, hepatitis joint pain in 3-8 weeks
  29. Rifabutin
    • 2nd line therapy
    • Related to rifampin
    • active against mTB and mAvium
    • Less potent inducer of CYP450 than rifampin, so used in HIV patients more.
  30. Dapsone
    • Used for leprosy
    • can be given in combo with rifampin
    • Side effects: GI, fever, rash, somtimes erythema nodosum leprosum
  31. Clofazimine
    • used for leprosy
    • phenazine dye dapsone alternative
    • T1/2: 2 months
    • Side effects: skin discoloration and GI irritation
Card Set
Pharmacology Antimycobacterium
Pharmacology, Antimycobacterium
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