Lecture 3 - AntiTB Drugs Flashcards
What are some reasons why treating TB so difficult?
Cell wall is impermeable (d/t lipid rich - mycolic acid)
Abundance of efflux pump on cell membrane (responsible for responsible for intrinsic resistance)
Intracellular (macrophages —inaccessible)
Latent vs active infection
What drugs are approved for TB treatment?
Fluoroquinolone (levofloxacin)
Rifamycin
Streptomycin
Macrolides
Isoniazid and ethlonamide
Ethambutol
Pyrazinamide
What experimental drugs are being testing for TB treatment?
Bedaquiline (TMC-207)
What is the MOA of fluoroquinolone?
Inhibits DNA synthesis and supercoiling by targeting topoisomerase
What is the MOA of rifamycin?
Inhibits RNA synthesis by targeting RNA polymerase
What is the MOA of streptomycin?
Inhibits protein synthesis by targeting the 30S ribosomal subunit
What is the MOA of macrolides?
Target 23S ribosomal RNA, inhibiting peptidyl transferase
What is the MOA of isoniazid and ethionamide?
Inhibit mycolic acid synthesis
What is the MOA of ethambutol?
Inhibits cell wall synthesis
What is the MOA of pyrazinamide?
Inhibits cell membrane synthesis
What is the MOA of bedaquiline?
TMC-207
Inhibits ATP synthase
Streptomycin
Oldest TB agent CanNOT enter cells Bactericidal Resistance led to new agents May be used in severe cases (ie. disseminated disease, meningitis) Ototoxicity/nephrotoxicity Risk in pregnancy
Isoniazid (INH)
PO
Prodrug
Renal clearance
Good CNS/CSF penetrance
Most effective Rx in susceptible strains
Penetrates macrophages
-effective against intra/extracellular organism
Bactericidal
Inhibits mycolic acid synthesis; inhibits dihydrofolate reductase
Isoniazid is a prodrug that needs catalase-peroxidase to form activated drug
Adverse effects: Hepatic toxicity (most common) (Age dependent >35 yr) Peripheral neuropathy (d/t pyridoxne deficiency-vtB6) Not to be used in pregnancy
Drug-drug interaction:
Acetaminophen - CYP2E1 induction
Warfarin - CYP2C9 inhibition
Resistance:
KatG deletion/mutation
InhA overexpression
What is the MOA of isoniazid?
Bactericidal
Inhibits mycolic acid synthesis - inhibits dihydrofolate reductase
Prodrug that gets activated by catalase -peroxidase
What resistance is present with isoniazid?
KatG deletion/mutation
InhA overexpression
What is the SE of isoniazid?
Hepatic toxicity (most common) -age dependent >35yo
Peripheral neuropathy
-d/t pyridoxine deficiency (vit B6)
Overdose: seizure/coma
Drug drug interaction of isoniazid
Acetaminophen - CYP2E1 INDUCTION —> hepatotoxicity
Warfarin - CYP2C9 inhibition —> possibility of increased bleeding
Pyrazinamide
PO
Renal clearance
Excellent distribution (including CNS) Synthetic analog of nicotinamide
Inactive at neutral pH, “active” at acidic pH
Penetrates macrophages
Prodrug:
Converted to pyraxinoic acid by mycobacterial pyrazinamidase (pncA)
Inhibition of FAS1 (decrease mycolic acid synthesis)
Bactericidal (pncA mutations - mechanism of resistance)
SE:
Hyperuricemia (100% - exacerbates gout)
CI: pregnancy
What is the MOA of pyrazinamide?
Inactive at neutral pH, “Active” at acidic pH
Penetrates macrophages
Prodrug converted to pyrazinoic acid by mycobacterial pyrazinamidase (pncA)
Inhibition of FAS1 (decrease mycolic acid synthesis)
What is the mechanism of resistance for pyrazinamide?
pncA mutations
What are the SE of pyrazinamide?
Hyperuricemia
Exacerbates gout
Inhibits uric acid excretion
Hepatic toxicity
Risk can not be ruled out in pregnancy
Ethambutol
PO
Renal clearance
CSF penetration w/ meningeal inflammation
Inhibits mycobacterial arbinosyl transferase (embAB operon)
- enhances bacterial cell wall permeability
- bacteriostatic
Resistance:
-embB mutations
SE: Optic neuritis (red-green color blindness)
What is the MOA of ethambutol?
Inhibits mycobacterial arbinosyl transferase (embAB operon)
-enhances bacterial cell wall permeability
What is the mechanism of resistance for ethambutol?
EmbB mutations
What are the SE of Ethambutol?
Optic neuritis
Red-green color blindness
CI: pregnancy
Rifampin
PO
Hepatic clearance/primarily biliary excretion
Bactericidal in mycobacteria
Inhibits RNA synthesis: bind beta subunits of bacterial DNA dependent RNA polymerase (rpoB) - no effect on eukaryote RNA polymerase
Resistance:
RpoB mutations
SE:
N/V
Fever, rash
May turn urine, tears, and other body fluids reddish-orange
CI: pregnancy
Caution in pts with chronic liver disease/alcoholics
Drug-drug interaction:
Induces hepatic metabolism
Accelerates metabolism of the antiHIV cocktail (protease/rev T’criptase inhibitors)
Rifabutin is used in TB for pts taking protease inhibitors for HIV
What is the MOA of rifampin?
Bactericidal in mycobacteria
Inhibits RNA synthesis: binds beta subunit of bacterial DNA dependent RNA polymerase (rpoB) - no effect on eukaryote RNA polymerase
What is the mechanism of resistance of rifampin?
RpoB mutations
What are the SE of rifampin?
N/V
Fever, rash
May turn urine, tears, and other body fluids reddish-orange
CI:
Pregnancy
Caution in pts with chronic liver disease/alcoholics
What are the drug drug interactions with rifampin?
Induces hepatic metabolism
Accelerates metabolism of the anti HIV cocktail (protease/rev T’criptase inhibitors)
Which rifamycin can be used when a TB pt is on protease inhibitors of HIV?
Rifabutiin
What is the preferred TB treatment for active TB?
2 months INH Rifampin Pyrazinamide Ethambutol if INH resistance is suspected
4 months
INH plus RIF
What is the preferred TB treatment for latent TB?
INH (9 months) or RIF (4 months)
What is the most common cause of TB tx failure?
Poor compliance
Bedaquiline
PO
Tx: 24 weeks in combination w/ >/= 3 drugs
$30K
Inhibits mycobacterial ATP synthase
-enzyme essential for the generation of energy
Resistance:
AtpE (subunit c ATP synthase)
Metabolized by CYP3A4 (do NOT administer with CYP3A4 inducers like rifampin)
SE:
Monitor liver functions
BOXED warning —QT prolongation with sirturo
