Anti-TB Drugs

Question 1

Name the drug approved for multi-drug resistant TB and its basic mechanism of action

Answer 1

Bedaquiline; inhibits ATP synthase.

• metabolized by CYP3A4 so don’t give w/ CYP3A inducers like rifampin
• monitor liver fxn
• Boxed warning for increased risk of death
• Category B in pregnancy :)

Question 2

Name the second-line drugs for TB treatment

Answer 2

Streptomycin, amikacin, levofloxacin (fluoroquinolones), and cycloserine

Question 3

Challenges with TB treatment

Answer 3

An abundance of efflux pumps on the cell membrane are responsible for intrinsic resistance

Question 4

Streptomycin against TB

Answer 4

Bactericidal. First drug against TB. Inhibits protein synthesis by binding the 30S ribosomal subunit. However, it can’t enter cells so it is not effective against latent TB.

Question 5

Isoniazid against TB

Answer 5

This is the most effective tx in susceptible strains. It disrupts the integrity of the cell wall by inhibiting mycolic acid synthesis (also inhibits DHFR) and CAN kill in the latent stage.

Question 6

Mechanism of resistance against Isoniazid

Answer 6

KatG deletion - KatG is what activates isoniazid within the bacteria.
InhA overexpression - used in fatty acid synthesis, so overexpression sustains synthesis counteracting isoniazid

Question 7

Adverse effects of isoniazid

Answer 7

Hepatic toxicity with clinically apparent hepatitis (worse >35y.o.), peripheral neuropathy d/t pyridoxone deficiency (aka B6) b/c both compete for reabsorption via same sites, overdose = seizures/coma

• several drug interactions w/ P450 users (several different CYPs)
• Category C

Question 8

Pyrazinamide against TB and resistance mechanism

Answer 8

Can penetrate macrophages, attacking latent TB. Requires mycobacterial pyrazinamidase (pncA) to activate it. Mutations to the pncA that converts it from prodrug to active form cause resistance.

Question 9

Adverse effects of pyrazinamide

Answer 9

hepatic toxicity, hyperuricemia (**exacerbates gout), pregnancy

Question 10

Ethambutol against TB and resistance mechanism

Answer 10

Enhances cell wall permeability by inhibiting mycobacterial arabinosyl transferases (embAB operon). Mutations in embB that prevent it from inhibiting transferases cause resistance.

Question 11

Adverse effects of ethambutol

Answer 11

optic neuritis - red-green color blindness

Question 12

Rifampin against TB and resistance mechanism

Answer 12

Bactericidal. Penetrates macrophages and inhibits RNA synthesis by binding to beta subunit of RNA polymerase (rpoB). Mutation of rpoB causes resistance.

Question 13

Adverse effects of rifampin

Answer 13

May turn bodily fluids (tears, urine, etc) reddish-orange. Category C in pregnancy.
**Induces hepatic metabolism (P450 enzymes–lots of CYPs), making anti-HIV drugs and oral contraceptives less effective

Question 14

Most common cause of TB treatment failure

Answer 14

Poor compliance. Hence why they have directly observed therapy now.

Question 15

Name the first-line drugs for TB treatment

Answer 15

Isoniazid, pyrazinamide, ethambutal, and rifampin (all cell wall inhibitors)