Flashcards in TB Deck (16):
Slow-growing, slender, rod-shaped aerobic with a unique lipid-rich cell wall. May remain dormant in the host for long periods.
Mycolic acid makes up approximately 60% of the cell wall and makes it relatively impermeable to many antibiotics.
Mycobacteria can reside inside non-activated macrophages - another permeability barrier
Isoniazid (INH): MOA
Inhibition of cell wall synthesis by inhibiting mycolic acid synthesis through the formation:
reactive oxygen radicals
Is Isoniazid (INH) bactericidal or -static?
Bacteriostatic for stationary phase (pt isnt actively infected, just has Tb in body)
Bactericidal for rapid dividing phase (divides slow, this is when INH works)Penetrates host cells (gets into our macrophages) and drug retained within host cell longer (bc doesn’t get destroyed once in macrophage. Stays active. Cant be metabolized away)
Metabolized by N-acetylation and hydrolysis
Isoniazid (INH): Adverse effects
Peripheral neuritis: pyridoxine deficiency.
Supplement with B6 (essential).
Inhibits phentoin (antiepileptic) metabolism and may produce convulsions in patients prone to seizures.
Hepatitis/hepatotoxicity: Most severe side effect –increases with rifampin (another TB drug- also affects RNA polymerase)) or daily ETOH.
Isoniazid (INH) black box warning
Severe and sometimes fatal hepatitis associated with isoniazid therapy may occur & may develop even after many months of treatment
Blocks transcription by interacting with the betasubunit of bacterial DNA-dependent RNA polymerase (quinolones also).
Does not interact with human form of polymerase.
Rifampin, Rifabutin, Rifapentin
Which bacteria does Rifampin work against?
Broader spectrum vs INH
Bactericidal against gram (+) and (-) organisms: used prophylactically in individuals exposed to meningitis.
Rifamycin. analog of rifampin, active against Mycobacterium avium complex, but less active for TB
newest option induces 3A4 (creates huge potential for drug interactions)
Oral administration. Distribute all body fluids and organs.
Induces hepatic mixed-function oxidases increasing its own metabolism as well as other drugs. (i.e. oral contraceptives)
Eliminated via feces and urine which may have an orange-red color (warn patients). Tears may permanently stain soft contact lenses orange-red.
Enters M. tuberculosis by passive diffusion, converted to pyrazinoic acid (POA) by nicotinamidase/pyrazinamidase (PZase).
Inhibits fatty acid synthase I which is important in mycolic acid biosynthesis (like INH, but different mechanism). May also disrupt membranes by acid formation.
Accumulates within acidic environment of macrophages monocytes and kills tubercle bacilli (helps prolong therapy)
Pyrazinamide: adverse effects
Liver injury (15%) with jaundice (2-3%), rarely fatal.
Get liver function test for pts on these drugs, do not use if problems
Inhibit cell wall synthesis, by inhibiting synthesis of polysaccharides and transfer of mycolic acids to the cell wall (so cell wall inhibitor