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63 Cards in this Set
- Front
- Back
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Is Isoniazid bactericidal or bacteriostatic?
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Bactericidal
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Isoniazid is a pro-drug-why? What has to activate it?
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Must first be activated by mycobacterial catalase (KatG)
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What is the mechanism of Isoniazid?
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Inhibits SYNTHESIS of mycolic acids by covalently binding ketoacyl carrier protein
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What drug is given with Isoniazid to combat adverse effects of peripheral neuropathy?
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Pyrodoxine
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Where is Isoniazid metabolized?
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Liver, genetically determined
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How is Isoniazid excreted?
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Renally
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What are the adverse effects of Isoniazid?
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Isoniazid induced hepatitis, and peripheral neuropathy
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Does Isoniazid penetrate the macrophage/phagocytic cells?
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Yes
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How can resistance develop to Isoniazid?
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1)Overexpression of inhA: carrier protein reductase
2)mutation in KatG gene 3)overexpression of ahpC (protects cell from oxidative stress) 4)mutation in kasA |
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Is Rifampin bactercidal or bacteriostatic?
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Bactericidal
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What is the MOA of Rifampin?
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Binds to the Beta subunit of bacterial DNA-dependent RNA polymerase (therefore, INHIBITS RNA SYNTHESIS)
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How is Rifampin excreted?
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Via liver into bile
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What is the adverse effect of Rifampin?
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Orange secretions
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How does Rifampin effect cytochrome p450?
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Induces cytochrome p450
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How can resistance develop to Rifampin?
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Mutations in rpoB, which is the gene for the beta subunit
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Does Rifampin penetrate the macrophages/phagocytic cells?
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Yes
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Is Ethambutol bactericidal or bacteriostatic?
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Bacteriostatic, prevents cell division
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Why doesn't Ethambutol effect our human cells?
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Our cells don't have arabinosyl transferase, so they aren't affected
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What is the MOA of Ethambutol?
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Inhibits mycobacterial arabinosyl transferases, so can't polymerize arabinoglycan, which is an essential component of the cell wall
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What is the distribution of Ethambutol?
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Can take PO
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What is the excretion of Ethambutol?
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50% renal excretion, dose must be reduced in RF when the GFR is <10
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What is the adverse effect of Ethambutol?
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Retrobulbar neuritis (loss of visual acuity and color blindness)
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How can resistance develop to Ethambutol?
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Mutations leading to overexpression or changes in emb gene, resulting in overabundant/resistant arabinosyl transferases.
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Is Pyrazinamide bacteristatic or bactericidal?
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Bactericidal against actively dividing TB, otherwise bacteristatic
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How is Pyrazinamide specific for only targeting bacteria and not our own tissue?
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Active only at acidic pHs, which are found in the lysosome of the macrophage. Lacks activity at neutral pHs which protects most tissues
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Pyrazinamide is a prodrug, what activates it?
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Converted to pyrazinoic acid by mycobacterial pyrazinamidase
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What is the MOA of Pyrazinamide?
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The drug target is unknown, but it disrupts mycobacterial cell membrane metabolism and transport functions
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How is Pyrazinamide cleared from the body?
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Parent drug is cleared by liver, metabolites are cleared by the kidney, which means the drug dose needs to be reduced for RF patients with GFR <30
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What are the adverse effects of Pyrazinamide?
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1) Hepatoxicity
2) Nausea 3) Vomiting 4) Drug Fever 5) Hyperuricemia, which may cause gouty arthritis |
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How does resistance to Pyrazinamide develop?
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Impaired uptake or mutations in pncA leads to less production of active metabolite
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What mycobacterium is already resistant to Pyrazinamide?
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All of the M. Bovis
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Is Streptomycin (Aminoglycosides) bacteristatic or bactericidal?
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Bactericidal
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How is Streptomycin specific for targeting only bacteria?
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Only binds to bacterial 30s ribosomal subunit, not the human variety
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What is the MOA of Streptomycin?
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Irreversible inhibitor of protein synthesis when it binds to the 30S ribosomal subunit (leading to interference with initiation complex, misreading of mRNA, and breakup of polysomes)
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What does it mean for streptomycin to have a post-antibiotic effect
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The antibiotic does concentration dependent killing and has an effect on keeping bacterial counts low even after the antibiotic level has dropped below the minimum dose needed
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What is the route of administration for Streptomycin? Why?
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Give IM or IV because it has poor bioavailability
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How is Streptomycin excreted?
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Renal excretion, so reduce dose in RF <60 or for patients on dialysis
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What are the adverse effects of Streptomycin?
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Ototoxic and Nephrotoxic (causing vertigo and hearing loss)
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Would you use Streptomycin to treat intracellular bugs?
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No, it penetrates poorly into cells and is active against extracellular tubercle bacilli
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How does resistance to Streptomycin develop?
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1) Bacteria create an enzyme that acetylates or phosphorylates the drug to deactivate it
2) Altering the 12S binding site also causes resistance |
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What is another name for Pyridoxine?
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Vitamin B6
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Does Pyridoxine have a direct therapeutic effect on TB?
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No
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Why is Pyridoxine given?
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It's a supplement to Isoniazid treatment to prevent vitamin deficiency (prevents peripheral neuropathy and anemia)
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What is the route of administration of Pyridoxine?
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Available PO, IM, or IV
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Where is Pyridoxine metabolized?
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Metabolized to active pyridoxal phosphate in the liver
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How is Pyridoxine excreted?
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Renal excretion
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Is peripheral neuropathy from isoniazid more likely to develop in fast or slow acetylators?
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Slow acetylators (low CYP activity) since more isoniazid will accumulate in the blood, peripheral neuropathy develops in 10-20% of isoniazid patients
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Is Aminosalicylic Acid (PAS) bacteristatic or bactericidal?
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Bacteristatic
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What is the MOA of Aminosalicylic Acid (PAS)?
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Folate synthesis agonist
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What are the adverse effects of Aminosalicylic Acid (PAS)?
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1) GI symptoms
2) Peptic ulceration and hemorrhage 3) Hypersensitivity |
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Is Cycloserine bactericidal or bacteristatic?
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Bacteristatic
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What is the MOA of Cycloserine?
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Inhibitor of cell wall synthesis, it is a structural analog of D-alanine and thus prevents D-alanine incorporation into cell wall
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What are the adverse effects of Cycloserine?
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1) Peripheral neuropathy
2) CNS dysfunction (headache, tremors, psychosis, convulsions) |
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What drug should be given with Cycloserine? Why?
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Give Pyrodoxine (Vit B6) to ameliorate neurologic toxicity
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How is Rifampin different from Ritonoavir? How would the effects of Rifampin reduce concentrations of anti-reitroviral drugs in the blood?
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Rifampin induces CYP and Ritonoavir inhibits/slows CYP activity--the result of this is that rifampin will reduce concentrations of Anti-retrovirals and other drugs in the blood
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Which TB drugs require dose reductions for patients with renal failure? Which do not?
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Do:
1) Streptomycin 2) Ethambutol 3) Pyrazinamide Don't: 1) Isoniazid 2) Rifampin |
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Why are multiple drug combinations given in TB?
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To reduce resistance and target different sites
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Which of the TB drugs are effective against intracellular organisms such as Mycobacterium?
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1) Isoniazid
2) Rifampin 3) Pyrazinamide 4) Ethambutol |
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Why do you treat latent TB?
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Reduce chance that it will become active
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What are the risks of TNA-alpha inhibitors regarding TB?
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It may activate latent TB?
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WHat is the likelihood of drug interactions regarding treatment of TB?
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Rifampin: cytochrome P450 induce
Isoniazid) cytochrome P450 Inhibitor |
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Is there higher risk of hepatic injury in fast or slow acetylators of Isoniazid?
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Fast acetylators
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What population of people are fast acetylators of Isoniazid?
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Eskimos and Japanese
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