Flashcards in 14.0 Antifungals Deck (15):
What is the MOA of Amphotericin B?
-Binds to ergosterol, forming pores in cell membrane.
-Pores allow leakage of intracellular ions and macromolecules.
Describe the pharmacokinetics of Amphotericin B?
•Amphotericin B is highly insoluble: formulated as deoxycholate colloidal suspension.
•Poorly absorbed from the GI tract.
•Must be given IV.
•Penetration into the CSF is extremely low.
•Intrathecal therapy may be necessary for meningeal disease.
What is important to know regarding the uses of Amphotericin B?
•Often used as initial induction regimen to rapidly reduce fungal burden.
Is Amphotericin B safe for pregnancy?
Describe the AE related with slower toxicity?
•Amphotericin B also binds to cholesterol and forms pores in mammalian cell membranes, leading to renal toxicity.
•Renal impairment occurs in nearly all patients.
•Azotemia occurs in most patients.
•GFR may be decreased.
•Renal toxicity commonly presents with renal tubular acidosis with severe magnesium and potassium wasting.
•Renal damage can be attenuated with sodium loading: it is common practice to administer saline infusion with amphotericin B.
•Hypochromic normocytic anemia, due to reduced erythropoietin production.
•Intrathecal administration can cause seizures and serious neurological damage.
What are the 3 FDA approved lipid formulations of Amphotericin B?
•Liposomal amphotericin B (L-AMB)
•Amphotericin B lipid complex (ABLC)
•Amphotericin B colloidal dispersion (ABCD)
•Nephrotoxicity is less common and less severe with the lipid formulations.
Flucytosine is what type of drug?
•Synthetic pyrimidine antimetabolite.
What enzyme takes up Flucytosine into fungal cells?
Regarding MOA of Flucytosine, what is it converted to once it is taken up? What does this do?
Converted intracellularly first to 5-fluorouracil (5-FU) and then to 5-fluorodeoxyuridine monophosphate (5-FdUMP) which inhibits thymidylate synthetase, thus blocking synthesis of dTMP.
Combination of Flucytosine with what produces a synergistic effect?
•Combination of flucytosine and amphotericin B is synergistic.
What does 5-FUTP do?
•Fluorouridine triphosphate (5-FUTP) is also formed, which inhibits protein synthesis.
What is Flucytosine used for?
•Indicated only for serious infections caused by susceptible strains of Candida and/or Cryptococcus.
•Should be used in combination with amphotericin B for the treatment of systemic candidiasis and cryptococcosis in order to avoid resistance.
What are the AE of Flucytosine?
•Result from metabolism (possibly by intestinal flora) to 5-fluorouracil.
•Bone marrow toxicity is the most common.
What is the MOA of Azoles?
•The fungal cytochrome P450 enzyme 14-α-sterol demethylase catalyzes the conversion of lanosterol to ergosterol.
•Azoles inhibit the enzyme, thus reducing ergosterol synthesis.
•This disrupts membrane function and increases permeability.