Lecture 2: Pharm of TB Flashcards
What 4 drugs are the standard first-line agents for tx of TB?
- Rifampin
- Isoniazid
- Pyrazinamide
- Ethambutol
*RIPE*
Which 3 first-line agents for TB can cause liver damage as an AE?
- Isoniazid
- Rifampin
- Pyrazinamide
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?
Ethionamide
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?
Rifampin
Resistance to rifampin may devlop by mutation in what gene?
rpoB
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?
- Hepatotoxicity
- 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?
emb CAB
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?
- Pyrazinamide
- Shortens regimen from 9 months –> 6 months!!!
Major AE’s of Pyrazinamide?
- Hepatotoxicity
- Hyperuricemia may precipitate gout
Which first-line TB agent diffuses readily into ALL tissues and body fluid, including the CNS?
Isoniazid
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?
Isoniazid
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
What is unique about how Aminosalicyclic Acid is packaged for use and is given how?
Packet of delayed-release granules that are given by sprinkling over food such as applesauce or yogurt
What are the common and serious AE’s associated with Aminosalicyclic Acid?
- GI sx’s = common; may be ↓ by giving with food
- Peptic ulceration + hemorrhage
- Hypersensitivity rxn occurring 3-8 wks after beginning tx
What is the MOA of the fluoroquinolones and which 2 are used most?
- DNA gyrase inhibitors (topoisomerase II and IV)
- Moxifloxacin = Most active against TB; and Levofloxacin
What are the 5 major AE’s of the fluoroquinolones?
- GI effects = most common
- Achilles tendon RUPTURE
- QT prolongation (Moxifloxacin)
- C. difficile colitis
- CNS effects
What is MOA of linezolid and when is it used for TB?
- Protein synthesis inhibitor; bind 50s subunit and prevent fMET tRNA
- Used in rare case when resistance to both 1st and 2nd line agents
What are 2 major AE’s associated with Linezolid?
- Bone marrow suppression
- IRREVERSIBLE peripheral and optic neuropathy
What is the MOA of Rifabutin and Rifapentine?
Bind β-subunit of bacterial DNA-dependent RNA polymerase and inhibits RNA synthesis (same as Rifampin)
What are the uses of Rifabutin and Rifapentine for TB?
- Rifabutine used in place of rifampin for tx of TB in pt’s w/ HIV on HAART, due to being less potent inducer of CYP450
- Rifapentine: sometimes used in combo w/ isoniazid for latent TB
What is the MOA of Bedaquiline?
Inhibits ATP synthase in mycobacteria
What is unique about the half-life and pharmacokinetics of Bedaquiline?
HIGHLY protein bound and it’s half-life is 5.5 months!!!
What is the indication for use of Bedaquiline for TB?
Used when resistance to both, isoniazid and rifampin
What are the 3 most common AE’s associated w/ Bedaquiline; what is the black-box warning associated with this drug?
- Nausea + arthralgia + HA = common
- BBW = QTc prolongation w/ assoc. mortality
If resistance to TB develops what are the recommendations for adding new drugs (i.e., amount)?
NEVER add single agent, ALWAYS add 2 to prevent further resistance
