TB PHARM Flashcards
MOA of isoniazid
interferes w/ mycolic acid synth. and thus disrupts cell wall synth.
- cidal for dividing bacilli
- static for slow growing
- penetrates host cells-effective for intracellular bacilli
Describe the resistance of isoniazid
inability to take up the drug
alteration in target enzyme
overprod. of target enzyme
resist. emerges rapidly (never used as a single agent)
describe route of isoniazid therapy
rapidly absorbed from GI tract w/ oral dose
also IM injection
how does isoniazid distribute in the body?
all tissues & fluids (crosses the placenta, breast milk)
how is isoniazid metabolized?
acetylated via N-acetyl transferase in liver
- slow and fast acetylators affects therapy
- chronic liver disease will decrease metabolism
describe the 2 major adverse effects of isoniazid therapy?
INH (INJURES NEURONS & HEPATOCYTES)
- peripheral neuropathy (competition b/w isoniazid & B6)
- hepatotoxicity (major problem due to toxic metabolite)
What are the important drug interactions to remember about isoniazid?
- antacids w/ Aluminum decrease absorption
- inhibits the P450 isozyme
MOA of rifampin
inhibits RNA synthesis by binding to beta subunit of RNA polymerase (bactericidal)
describe the resistance to rifampin
alteration in the beta subunit of the RNA polymerase so that it no longer binds the drug
whats important to remember about the distribution of rifampin?
it penetrates all tissues well, including the CSF (75-80% is protein bound)
what are some adverse effects of rifampin?
4 R’s (rna polymerase inhibitor, revs up CYP450, red body fluids, rapid resistance alone)
- turns body fluids orange-red
- GI & nervous system complaints
- fever, chills, aches
- Hepatotoxicity (jaundice occurs w/ chronic liver disease, alcoholics and elderly, more relevant in pts that are slow acetylators)
what do you have to remember about rifampin and drug interactions?
rifampin induces cytochrome P450
what is the main therapeutic use of rifampin?
first line against mycobacterium tuberculosis (works on both rapidly and slowly dividing cells)
what is the most active antileprosy drug right now?
rifampin
MOA of ethambutol
disrupts cell wall synthesis by inhibiting arabinosyl transferase (enzyme used to attach mycolic acids to D-arabinose residues of arabinogalactan in peptidoglycan wall)–>increased cell wall perm.)
-may also inhibit RNA synth.
when does ethambutol work on MTB?
ACTIVELY DIVIDING BACILLI
- has static effect (possibly cidal at high levels)
- slow development of resistance
- no cross resistance
describe the absorption of ethambutol
75% of oral dose
What are the must know adverse effects of ethambutol?
ETHAMBUTOL CAUSES EYE PROBLEMS
optic neuritis (decreased visual acuity, loss of color discrimin.)
allergic reactions
hyperuricemia
MOA of pyrazinamide
bacilli convert pyrazinamide to pyrazinoic acid
- decrease pH below threshold for growth
- resistant strains may lack the pyrazinamidase”
- cidal or static depending on conc. in infected site
- active against tubercle bacilli in acid environment of lysosome and mphages
where is pyrazinamide metabolized?
liver
how is pyrazinamide administered?
orally and is rapidly absorbed from GI tract
how is pyrazinamide distributed in body?
widely distributed
what are the adverse effects of pyrazinamide?
- dose related hepatotoxicity
- mild non-gout arthralgias
- hyperuricemia (due to inhibition of urate excretion)
what does MDR TB refer to?
resistant to isoniazid and rifampin
MOA of cycloserine
blocks cell wall synthesis
- structural analog of D-alanine
- can block L-alanine racemase & D-alanine synthetase–>weak cell wall and –>cell lysis
- based on concentration at the site, could be cidal or static
what is the indication for cycloserine?
broad spectrum, second line agent for active pulmonary and extrapulmonary TB
Describe the pharmacology of cycloserine
administered orally w/ good absorption
distributed widely and not protein bound
how is cycloserine excreted ?
excreted unchanged by kidneys
what are the adverse effects of cycloserine?
CNS issues
- headache, tremor, vertigo, confusion, …
- contraindicated in persons w/ hx of epilepsy (EtOH increases risk for seizures)
what are the first-line therapy drugs for MTB?
isoniazid+rifampin+pyrazinamide+ethambutol or streptomycin
which pts are not recommended to take isoniazid & rifampin?
- children <2 yrs
- HIV pts (taking retrovirals)
- pregnant women
- pts w/ LTBI w/ presumed resistance to INH or RIF
how is rifampin metabolized
deacetylated in liver
which anti-TB drug turns body fluid color to orange-red?
rifampin
where does pyrazinamide exert its most significant effect?
intracellular sites where MTB replicates slowly in mphages
