What 4 drugs are the standard first-line agents for tx of TB?
Which 3 first-line agents for TB can cause liver damage as an AE?
What is the MOA of isoniazid?
Inhibits mycolid acid synthesis
What are 3 ways of developing resistance to isoniazid?
- Overexpression of inhA or kasA
- Mutation/deleltion of katG
Which second-line TB drug has same pharmacokinetics as isoniazid, but can be used in its place when resistance to isoniazid develops?
What is the strategy for treating PPD reactors w/ active TB rules out (aka latent TB)?
- Isoniazid for 9 months
- Rifampin for 4 months or combo of 1x/week isoniazid + rifapetine for 3 months
What is the MOA of Rifampin?
Binds β subunit of bacterial DNA-dependent RNA polymerase --> inhibits RNA synthesis
Which first-line TB agent readily penetrates most tissues and phagoytic cells, allowing for bactericidal action in abscesses and lung cavities?
Resistance to rifampin may devlop by mutation in what gene?
After oral administration where is majority of rifampin excreted and enters into where?
Mainly via liver --> bile and undergoes enterohepatic circulation
What are 2 major AE's associated with Isoniazid?
- Peripheral neuropathy can be ↓ w/ pyridoxine (B6)
What are the major AE's associated with Rifampin?
- Orange/red color to urine, sweat, and tears
- Rashes, thrombocytopenia and nephritis
- Hepatitis and cholestatic jaundice
What is the MOA of Ethambutol?
Inhibits mycobacterial arabinosyl transferases, needed for polymerization of arabinoglycan essential for cell wall
Overexpression/mutuation of which gene may cause resistance to Ethambutol?
Higher does of ethambutol may be used to tx tuberculosis infections where?
Tuberculosis meningitis; crosses the BBB at high doses
Most common AE associated with Ethambutol and should not be given to whom?
- Retrobulbar neuritis --> ↓ visual acuity and red-green color blindness
- Don't give to children too young to permit assessment of visual acuity and color discrimination!
What is the MOA of Pyrazinamide and where does it exert its effects?
- Converted to pyrazinoid acid (active form) inside lysosome by mycobacterial pyrazinamidase
- Disrupts mycobacterial cell wall membrane metabolism and transport functions
What are 2 ways in which resistance to Pyrazinamide may occur?
- Impaired uptake of pyrazinamide into lysosome
- Mutations in pncA which encodes enzyme necessary for conversion to active form PZA
Which 1st line agent for TB is the "sterilizing agent" and what does adding this agent to the regimen do?
- Shortens regimen from 9 months --> 6 months!!!
Major AE's of Pyrazinamide?
- Hyperuricemia may precipitate gout
Which first-line TB agent diffuses readily into ALL tissues and body fluid, including the CNS?
How does the 6 month regimen of first-line agents for active TB work (i.e., which drugs given and when)?
- 2 months INTENSIVE phase w/ RIPE
- Then 4 months of isoniazid and rifampin
*Remember 4 for 2; then 2 for 4
Which class does Streptomycin belong to and its MOA?
When would it be used for TB?
- Aminoglycoside --> protein synthesis inhibitor
- Used when IV or IM route is desired and in cases where there is resistance
Ethionamide has the same MOA, resistance, and AE's as what other TB agent?
What is the MOA of Capreomycin?
Protein synthesis inhibitor
Which 2nd-line TB agents can be used for streptomycin-resistant strains?
Which is specifically used if an IV or IM route is desired?
- Capreomycin --> can be given IV or IM
- Kanamycin and Amikacin --> only amikacin used in US!
What is the MOA of Cycloserine?
Structural analog of D-alanine inhibits alanine racemase and D-alanyl-D-alanine ligase --> cell wall synthesis inhibitor
Cycloserine is given via which route and is cleared by which organ?
Oral dose and is cleared renally
What are the most serious AE's associated w/ Cycloserine?
- CNS dysfunction
- Peripheral neuropathy --> can be ↓ w/ pyridoxine (B6)
What is the MOA of Aminosalicylic Acid as 2nd-line against TB?
Structural analog of PABA = folate synthesis inhibitor