Anti Tb drugs

Question 1

What is the MOA of Rifampin?

Answer 1

Inhibits bacterial RNA polymerase by binding to β subunit and interrupting formation
of mRNA chain.
Bactericidal to both intra- and extracellular mycobacteria

Question 2

What are the mechanisms of resistance for Rifampin?

Answer 2

Alteration of the binding site on RNA polymerase

May or may not confer resistance across rifamycin class

Question 3

ADEs of Rifampin?

Answer 3

Discoloration of body fluids (tears, urine, saliva) – orange/red color
■ GI disturbances (nausea, vomiting, diarrhea)
■ CNS effects (headache)
■ Fevers, chills, myalgias – flu-like syndrome less common with daily dosing
■ Hepatotoxicity (additive effect with concurrent hepatotoxic agents)
– Jaundice can occur in elderly and those with pre-existing liver disease,
alcoholism

Question 4

Drug interactions of Rifampin?

Answer 4

CYP 3A4 INDUCER
– Reduces half-life of drugs metabolized by P450 enzymes
■ Including: prednisone, propranolol, sulfonamides, dapsone, protease inhibitors,
chemotherapy
■ Can reduce efficacy of anticoagulants, oral contraceptives, and anticonvulsants
– Alternative method of contraception should be used
– Onset of induction: up to 14 days
■ Probenecid increases serum levels of rifampin

Question 5

What is the MOA of Isoniazid?

Answer 5

Inhibits mycolic acid synthesis - important component of mycobacterium cell wall
■ Can penetrate host cells, making it effective for intracellular bacilli
■ Bactericidal for rapidly dividing bacilli – i.e. extracellular spaces
■ Bacteriostatic for “resting” bacilli – i.e. closed granulomas and macrophages

Question 6

How does resistance happen for Isoniazid?

Answer 6

Inability to take up the drug
– Alteration in target enzyme
– Overproduction of target enzyme
– Prevalence of resistance within a community guides treatment selection

Question 7

Isoniazid ADME?

Answer 7

Food may slow and reduce extent of dose absorption
Crosses placenta and distributes in breast milk
Chronic liver disease impacts drug metabolism
– Does not require dose-adjustments in renal impairment
■ Excretion – 75-90% of drug and inactive metabolites excreted in the urine

Question 8

ADEs of Isoniazid?

Answer 8

Peripheral neuropathy - Can be overcome with B6 supplementation (pyridoxine)
Hepatotoxicity – dose-dependent
– Can be a major toxic reaction (incidence 2%)

Hypersensitivity

Question 9

Interactions with Isoniazid?

Answer 9

Antacids with aluminum salts decrease absorption
– Should be given 1 hour before antacids
■ Corticosteroids decrease efficacy
– Prednisolone reduces isoniazid concentrations
– Isoniazid inhibits hepatic metabolism of cortisol

Question 10

What is the MOA of Pyrazinamide?

Answer 10

Bacilli convert drug to pyrazinoic acid,
which decreases pH below threshold
for growth
– Active against bacilli in acidic
environment of lysosomes and
macrophages
– May accelerate the effects of
isoniazid and rifampin in
combination regimens

Question 11

Mechanism of resistance of Pyrazinamide?

Answer 11

Some strains may lack the

“pyrazinamidase”

Question 12

ADME of Pyrazinamide?

Answer 12

Similar concentrations intra- and extracellularly
– Distributes into breast milk, unknown if crosses placenta
■ Metabolism
– Extensive hepatic metabolism
– Dose adjustment in renal impairment not typically required
■ Excretion
– Up to 70% of metabolites excreted in urine