Tb drugs

Question 1

general adverse reactions of TB drugs

Answer 1

1. Cutaneous Reactions (pruritis)
2. GI Symptoms (pls take after light meal or before food)

Question 2

mech of action of rifampicin?

Answer 2

block DNA-dependent RNA polymerase, prevnting bacilus from synthesising mRNA and protein = cell death

Question 3

resistance to rifampicin is by?

Answer 3

mutations in gene which encodes the RNA polymerase beta chain

Question 4

apart from tb, what other conditions can rifampicin treat?

Answer 4

leprosy and mycobacterium leprae

Question 5

for rifampicin,
a) administration
b) absroption
c) metabolism
d) CNS levels
e) use during pregnancy
f) use during breastfeeding
g) use in kidney failure pt
h) use in liver failure pt

Answer 5

a) oral
b) good on empty stomach
c) hepatic
d) 10-20% of serum, increased in meningitis
e) can, but neonates born to mothers which used shd be given VitK (reduce postpartum hemorrhage bc rifampicin is associated with thrombocytopenia)
f) small conc can pass into breast milk but does not treat tb in infants. monitor infant for jaundice
g) ok
h) used if benefit > risk, but monitor liver function

Question 6

DDIs of rifampicin

Answer 6

induce cyp450 - warfarin, corticostreoids, oral contraceptives, HIV protease inhibitors affected

isoniazid + rifampicin = hepatotoxicity

Question 7

adverse effects of rifampicin?

Answer 7

cutaneous syndrome
flu-like syndrome
respiratory syndrome
thrombocytopenic purpura, hemolytic anemia, acute renal injury
hepatitis
orange discoloration of bodily fluids

Question 8

mech of action of isoniazid?

Answer 8

prodrug, activated by catalase-peroxidase enzyme of M. Tb. Produces oxygen-derived free radicals that inhibit formation of mycolic acids of the bacterial cell wall, cause DNA damage, and thus death of the bacillus

Question 9

Resistance to isoniazid is by?

Answer 9

1. mutations to catalase-peroxidase enzyme, and
2. mutations of the genes involved in mycolic acid synthesis

Question 10

for isoniazid,
a) administration (what to avoid too?)
b) absorption
c) metabolism
d) excretion

Answer 10

a) oral; no foods rich in tyramine and histamine - inhibit MAO and histaminase and cause serotonin syndrome - antacids increase gastric pH and delay absroption of isoniazid - pls separate intake by 2h
b) well on empty stomach
c) acetylation via N-acetyltransferase in liver
d) inactive metabolites

Question 11

what affects the metabolism of isoniazid?

Answer 11

genetic polymorphisms
- rapid acetylator phenotype vs slow acetylator phenotype
– half life is 1h in pt with rapid phenotype vs 2-5h in pt with slow phenotype

Question 12

how is isoniazid metabolized? which pathway is toxic?

Answer 12

2 main pathways. NAT2 pathway is not toxic, amidase pathway is toxic (hydrazine)

Question 13

can isoniazid penetrate CSF?

Answer 13

yes

Question 14

use of isoniazid in
a) pregnancy
b) breastfeeding
c) pt with liver failure
d) pt with kidney failure

Answer 14

a) Can, but take with pyridoxine
b) can, but monitor for jaundice + take with pyridoxine supplement
c) closely monitor
d) ok

Question 15

what is the significance of pyridoxine in isoniazid?

Answer 15

isoniazid tends to interfere with pyridoxine metabolism by inhibiting formation of active vit b6, hence causes peripheral neuropathy (pyridoxine critical for CNS function)

Question 16

DDI for isoniazid

Answer 16

CYP450 inhibitor - phenytoin, oral anticoagulants, carbamezapine increase

Question 17

adverse effects of isoniazid?

Answer 17

Peripheral neuropathy
Hepatitis
RARE: Toxic Psychosis, Convulsions, Hematologic reactions, Lupus like syndrome, hypersensitivity reactions

Question 18

importance of pyrazinamid

Answer 18

effective in eliminating persistent bacili that resposible for bacteriological relapse

Question 19

mechanism of action of pyrazinamide

Answer 19

prodrug, converted to pyrazinoic acid by microbial enzymes pyrazinamidase. lowers pH to inactivate critical pathways for bacterial survival

Question 20

how does resistance to pyrazinamid come about?

Answer 20

resistance from mutations in genes that encode for the pyrazinamidase

Question 21

for pyrazinamide,
a) administration
b) CSF
c) pregnancy use
d) breastfeeding use
e) liver failure use
f) kidney failure use
g) DDIs

Answer 21

a) oral
b) excellent
c) safe
d) can, monitor for jaundice
e) avoided, monitor closely if need, hepatotoxic drug
f) decrease dose, bc metabolites are eliminated in kidney,can accumulate
g) probnecid, rifampicin, isoniazid can increase toxic effects

Question 22

adverse effects of pyrazinamide?

Answer 22

1. GI
2. Photosensitivity
3. Hepatotoxicity
4. Hyperuricemia and arthralgia
5. Exanthema and pruritis

Question 23

mechanism of action of ethambutol

Answer 23

inhibits arabinosyltransferase enzyme encoded by embB gene, interfering with polymerisation of arabinose into arabinogalactan, the principal polysaccharide on the mycobacterial cell wall

affects integrity of cell wall, allows lipophilic antibiotics to enter (ie rifampicin and levofloxacin)

Question 24

how does resistance occur in ethambutol

Answer 24

mutations embB gene

Question 25

for ethambutol,
a) administration
b) metabolism and excretion
c) CSF

Answer 25

a) oral
b) 25% liver, 25% in feces unchanged, 50% in urine unchanged
c) not normally; only in meningitis

Question 26

adverse effects of ethambutol

Answer 26

1. Visual Toxicity (visual acuity, red-green colour blindness, blurring, central scotoma)
   - greater risk in pt with kidney failrue and in elderly individuals and prolonged treatment
2. Hyperuricemia/gout

Question 27

use of ethambutol in
a) pregnancy
b) breastfeeding
c) liver failure
d) kidney failure
e) DDIs

Answer 27

a) can
b) can
c) can
d) dose reduction. metabolites can accumulate in pt with renal failure
e) antacids can reduce maximum serum conc. separate by 2h