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Flashcards in TB Deck (16):
1

Mycobacterium

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

2

Isoniazid (INH): MOA

Inhibition of cell wall synthesis by inhibiting mycolic acid synthesis through the formation:
reactive oxygen radicals
isonicotinic acid

3

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

4

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.

5

Isoniazid (INH) black box warning

Severe and sometimes fatal hepatitis associated with isoniazid therapy may occur & may develop even after many months of treatment

6

Rifampin: MOA

Blocks transcription by interacting with the betasubunit of bacterial DNA-dependent RNA polymerase (quinolones also).
Does not interact with human form of polymerase.

7

Rifamycins (list)

Rifampin, Rifabutin, Rifapentin

8

Which bacteria does Rifampin work against?

Broader spectrum vs INH
Bactericidal against gram (+) and (-) organisms: used prophylactically in individuals exposed to meningitis.

9

Rifabutin

Rifamycin. analog of rifampin, active against Mycobacterium avium complex, but less active for TB

10

Rifapentin

newest option induces 3A4 (creates huge potential for drug interactions)

11

Rifamycins metabolism

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)

12

Rifamycins elimination

Eliminated via feces and urine which may have an orange-red color (warn patients). Tears may permanently stain soft contact lenses orange-red.

13

Pyrazinamide: MOA

Bactericidal.
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)

14

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

15

Ethambutol: mechanism

Bacteriostatic
Inhibit cell wall synthesis, by inhibiting synthesis of polysaccharides and transfer of mycolic acids to the cell wall (so cell wall inhibitor

16

Ethambutol: adverse effects

Optic neuritis is most important adverse effect.
Results in diminished visual acuity and loss of red/green discrimination. Periodic vision exam.
Decreases urate excretion = gout if predisposed.