EXAM 5 antifungals stahelin Flashcards
The main difference between cell membranes of fungal and human cells.
How are these differences exploited in antifungal drugs?
Fungal cell walls have ergosterol, humans cell walls have cholesterol
Antifungal drugs target ergosterol or its biosynthesis to selectively affect fungal cells w/o harming human cells
Drugs inhibit ergosterol biosynthesis
which steps (enzymes) are inhibited by the allylamines and the azole antifungals in ergosterol synthesis
Terbinafine:
inhibit Squaline epoxidase
azoles:
Inhibit CYP450 14-a demethylase
Which drugs are polyenes
amphothericin B
Nystatin
Polyenes MOA
binds ergosterol in membrane to reduce stability
Structure: lipophilic region on the bottom, mycosamine ring binds ergosterol
Allylamines: Terbinafine MOA
inhibits squalene epoxidase and disrupts ergosterol synthesis
Selective for fungal enzyme over mammalian
Azoles MOA
inhibit 14-alpha demethylase by binding iron in CYP450 and inhibits conversion of lanosterol to ergosterol
Selectivity: very selective for fungal infections
Echninofungins MOA
inhibits synthesis of beta 1-3 glucan cell wall component, beta 1-3 glucan synthase is target –> destabilize membrane, causing cell to die
not metabolized by CYPs
Selectivity: no enzyme in mammalian like beta-glucan
Antimetabolite: Flucytosine MOA
inhibit thymidylate synthase and interferes with protein synthesis
Specificity: can only be metabolized in fungal cells
Ibrexafungerp MOA
small molecule inhibitor of glucan synthase enzyme
Tavaborole MOA
inhibits leucyl transfer RNA synthetase (LeuRS), inhibits protein structure
Contains boron tavaBOROle
Explain the toxicity of amphotericin B. How does this relate to flucytosine therapy?
Toxicity is low enough to use, but still very toxic
Infusion related reactions – can premedicate
renal damage: occurs in all patients
reversible – reduced renal perfusion
irreversible – renal tubular injury
Flucytosine also has renal toxicity –> monitor levels
Describe the interaction of azole antifungal agents on cytochrome P450. How does this affect other drug therapies? Why can this be a problem?
Azoles inhibit CYP450 in humans, also metabolized by CYP450
Azole concentrations can be increased by other drugs
CYP inducers would decrease azole levels
Be able to recognize the azole functional group and explain its significance for the mechanism of action.
Imidazole and triazole functional group
Nitrogen from azole functional rings binds iron to prevent formation of intermediate
Ketoconazole CYP
3A4 inducer
Voriconazole CYP
2C19 substrate
Explain how the metabolism of flucytosine in fungal cells differs from that in animal cells
Fungal cells:
Flucytosine is converted to 5-FU by cytosine deaminase (animals lack this), so we are unable to metabolize this and there is minimal toxicity
Explain the reaction that is catalyzed by thymidylate synthase, and how flucytosine inhibits the reaction
Thymidylate synthase converts dUMP to dTMP
Flucytosine converted to 5-FU and FdUMP, which blocks thymidylate synthase and leads to the inability to form dTMP
dTMP is essential for making thymine triphosphate
results in inhibition of DNA synthesis and cell death
