TB Pharmacology

Question 1

describe the rx regimen for drug susceptible Tb

Answer 1

4 drugs for 2 months, 2 drugs for 4 months (first line)

Question 2

isoniazid and delamanid moa

Answer 2

block synthesis of mycolic acid

Question 3

how is resistance conferred to isoniazid

Answer 3

mutations in KagG (converts prodrug to active) and InhA (target)

Question 4

isoniazid toxicities

Answer 4

hepatotoxicity, peripheral neuropathy

Question 5

NAT2 role in isoniazid metabolism

Answer 5

acetylates the drug, converting it away from the CYP pathway and toxic metabolites

fast acetylators have less toxic accumulation and hepatotoxicity

Question 6

CYP2E1 role in isoniazid metabolism

Answer 6

convert drug to toxic metabolites in the liver, drugs that induce the enzyme (EtOH) make the toxicity worse

Question 7

advantage of delamanid

Answer 7

no CYP drug interaction

Question 8

moa of ethambutol, resistance

Answer 8

inhibits arabinsosyl transferase and the synthesis of galactan in the cell wall

mutations in this enzyme confer resistance

Question 9

moa of cycloserine

Answer 9

inhibits enzymes that make peptidoglycan in mycobacteria

Question 10

ethambutol toxicity

Answer 10

optic neuritis, red green color blindness

Question 11

cycloserine toxicities

Answer 11

neuro sx

Question 12

moa of rifampin and rifabutin

Answer 12

target RNA polymerase

mutations confer resistance

Question 13

rifampin/rifabutin toxicities

Answer 13

nausea/vomiting, rash, fever, orange coloration of skin/urine

nephrotoxicity/interstitial nephritis

Question 14

drug interactions of rifampin/rifabutin

Answer 14

induces lots of CYP enzymes, reduces efficacy of bedaqulline and HIV drugs that are metabolized by these CYPs

part of the reason for the TB-HIV syndemic

Question 15

selectivity of pyrazinamide

Answer 15

prodrug enters mycobacterium and is converted by PZase to more negative form

pH trapping occurs, stuck in the physiological pH in the cell as opposed to the low pH granuloma space

Question 16

moa of pyrazinamde

Answer 16

unknown, thought to disrupt proton gradient

Question 17

toxicities of pyrazinamide

Answer 17

hepatotoxicity (drug induced hepatitis, not as bad at current lower doses

Question 18

TB drugs and pregnancy

Answer 18

use normal drugs

Question 19

moa of bedaquilline

Answer 19

ATP synthase inhib

Question 20

drug interaction of bedaquiline

Answer 20

reduced efficacy when given w/ rifampin

Question 21

which drugs work on active TB? latent? both?

Answer 21

active: cell wall inhibs (INH, ETH)
latent: pyrazinamide
both: RNA pol inhibs (rifampin, rifabutin)

Question 22

drugs w/ hepatotoxicity

Answer 22

isoniazid and pyrazinamide