TB PHARM

Question 1

MOA of isoniazid

Answer 1

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

Question 2

Describe the resistance of isoniazid

Answer 2

inability to take up the drug
alteration in target enzyme
overprod. of target enzyme
resist. emerges rapidly (never used as a single agent)

Question 3

describe route of isoniazid therapy

Answer 3

rapidly absorbed from GI tract w/ oral dose

also IM injection

Question 4

how does isoniazid distribute in the body?

Answer 4

all tissues & fluids (crosses the placenta, breast milk)

Question 5

how is isoniazid metabolized?

Answer 5

acetylated via N-acetyl transferase in liver

• slow and fast acetylators affects therapy
• chronic liver disease will decrease metabolism

Question 6

describe the 2 major adverse effects of isoniazid therapy?

Answer 6

INH (INJURES NEURONS & HEPATOCYTES)

1. peripheral neuropathy (competition b/w isoniazid & B6)
2. hepatotoxicity (major problem due to toxic metabolite)

Question 7

What are the important drug interactions to remember about isoniazid?

Answer 7

• antacids w/ Aluminum decrease absorption

- inhibits the P450 isozyme

Question 8

MOA of rifampin

Answer 8

inhibits RNA synthesis by binding to beta subunit of RNA polymerase (bactericidal)

Question 9

describe the resistance to rifampin

Answer 9

alteration in the beta subunit of the RNA polymerase so that it no longer binds the drug

Question 10

whats important to remember about the distribution of rifampin?

Answer 10

it penetrates all tissues well, including the CSF (75-80% is protein bound)

Question 11

what are some adverse effects of rifampin?

Answer 11

4 R’s (rna polymerase inhibitor, revs up CYP450, red body fluids, rapid resistance alone)

1. turns body fluids orange-red
2. GI & nervous system complaints
3. fever, chills, aches
4. Hepatotoxicity (jaundice occurs w/ chronic liver disease, alcoholics and elderly, more relevant in pts that are slow acetylators)

Question 12

what do you have to remember about rifampin and drug interactions?

Answer 12

rifampin induces cytochrome P450

Question 13

what is the main therapeutic use of rifampin?

Answer 13

first line against mycobacterium tuberculosis (works on both rapidly and slowly dividing cells)

Question 14

what is the most active antileprosy drug right now?

Answer 14

rifampin

Question 15

MOA of ethambutol

Answer 15

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.

Question 16

when does ethambutol work on MTB?

Answer 16

ACTIVELY DIVIDING BACILLI

• has static effect (possibly cidal at high levels)
• slow development of resistance
• no cross resistance

Question 17

describe the absorption of ethambutol

Answer 17

75% of oral dose

Question 18

What are the must know adverse effects of ethambutol?

Answer 18

ETHAMBUTOL CAUSES EYE PROBLEMS

optic neuritis (decreased visual acuity, loss of color discrimin.)
allergic reactions
hyperuricemia

Question 19

MOA of pyrazinamide

Answer 19

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

Question 20

where is pyrazinamide metabolized?

Answer 20

liver

Question 21

how is pyrazinamide administered?

Answer 21

orally and is rapidly absorbed from GI tract

Question 22

how is pyrazinamide distributed in body?

Answer 22

widely distributed

Question 23

what are the adverse effects of pyrazinamide?

Answer 23

• dose related hepatotoxicity
• mild non-gout arthralgias
• hyperuricemia (due to inhibition of urate excretion)

Question 24

what does MDR TB refer to?

Answer 24

resistant to isoniazid and rifampin

Question 25

MOA of cycloserine

Answer 25

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

Question 26

what is the indication for cycloserine?

Answer 26

broad spectrum, second line agent for active pulmonary and extrapulmonary TB

Question 27

Describe the pharmacology of cycloserine

Answer 27

administered orally w/ good absorption

distributed widely and not protein bound

Question 28

how is cycloserine excreted ?

Answer 28

excreted unchanged by kidneys

Question 29

what are the adverse effects of cycloserine?

Answer 29

CNS issues

• headache, tremor, vertigo, confusion, …
• contraindicated in persons w/ hx of epilepsy (EtOH increases risk for seizures)

Question 30

what are the first-line therapy drugs for MTB?

Answer 30

isoniazid+rifampin+pyrazinamide+ethambutol or streptomycin

Question 31

which pts are not recommended to take isoniazid & rifampin?

Answer 31

• children <2 yrs
• HIV pts (taking retrovirals)
• pregnant women
• pts w/ LTBI w/ presumed resistance to INH or RIF

Question 32

how is rifampin metabolized

Answer 32

deacetylated in liver

Question 33

which anti-TB drug turns body fluid color to orange-red?

Answer 33

rifampin

Question 34

where does pyrazinamide exert its most significant effect?

Answer 34

intracellular sites where MTB replicates slowly in mphages