Antifungals Flashcards
What are the five classes of antifungals?
1) Polyenes
2) Flucytosine
3) Azoles
4) Echinocandins
5) Allylamine
What are the two Polyenes?
Amphotericin B and Nystatin
What are the two drug categories for Azoles?
Imidazoles and Triazoles
What drugs are Imidazoles?
1) Ketonconazole
2) Miconazole
3) Clotrimazole
What drugs are Triazoles?
1) Itraconazole
2) Fluconazole
3) Voriconazole
4) Posaconazole
5) Isavuconazole
What differentiates Triazoles from Imidazoles?
Triazoles have two nitrogens in their azole ring while imidazoles only have one nitrogen in their azole ring
What drug is an allylamine?
Terbinafine
What is the activity of the Polyenes?
Broad, fungicidal, and they are active in yeast infections
What is the activity of Flucytosine?
Narrow and fungistatic
What is the activity of the Azoles?
Broad and fungistatic
What is the activity of the Echinocandins?
Broad, fungicidal, and active against fungal and yeast infections
What is the activity of the drug Griseofulvin?
Narrow and fungistatic
What is the activity of the Allylamines?
Fungicidal against dermatophytes and fungistatic against yeast infections
How do Amphotericin B and Nystatin work against infections?
They bind to ergosterol in the fungal cell membrane forming pores, known as death rings, which disrupts cell membrane permeability and kills the cell
Why is resistance to the Polyenes rare?
Ergosterol is essential to certain functions in the fungal cell; therefore, if the cell modifies ergosterol, it could hurt its ability to function and launch infections
If a fungal infection were to try and become resistant to the polyenes, how would it do so?
It decreases the concentration of ergosterol or changes its structure to decrease affinity (target modification)
What is the most prominent toxicity associated with Amphotericin B?
Dose-dependent nephrotoxicity
What are the routes of administration for Nystatin?
Oral and topically because it is too toxic for parenteral use
Why is Amphotericin B less toxic than Nystatin?
Because Amphotericin B has a higher affinity for ergosterol rather than cholesterol and it is more selective
Mechanism of action for 5-FC (Flucytosine)
5-FC is converted to 5-FU by cytosine deaminase. 5-FU is then converted to F-dUMP and F-UTP. F-dUMP inhibits DNA synthesis and F-UTP inhibits RNA synthesis.
Mechanism of resistance to 5-FC
Altered metabolism of 5-FC which happens faster in monotherapy
Toxicity to 5-FC
Occurs when 5-FC is converted to toxic 5-FU by intestinal microflora. Can cause Thrombocytopenia, Leukopenia, Anemia, and Bone marrow toxicity
In regards to Polyenes, which one is stronger with less toxicity and why?
Amphotericin B because it has more double bonds than Nystatin
What happens when Polyenes interact with UV light?
Their double bonds become locked in the cis position and they are inactivated
What is 5-FC combined with to create a synergistic reaction?
Azoles and Amphotericin B because they compromise the cell membrane and increase intracellular concentrations of 5-FC
Mechanism of action for Azoles
They inhibit the biosynthesis of ergosterol by inhibiting the p450 14alpha-demethylase enzyme
Mechanism of resistance to Azoles
Altered p450 14alpha-demethylase enzyme and active efflux
Toxicity associated with Azoles
GI upset, liver enzyme abnormalities, rarely but sometimes hepatitis, and they all inhibit cytochrome p450 (especially CYP3A4)
Which types of Azoles are more effective and less toxic?
Triazoles because they are more selective
Which imidazole is a more potent inhibitor of human cyt. p450 meaning it is less selective and causes more adverse effects?
Ketoconazole
What has the widest therapeutic index of all the Azoles?
Fluconazole
What three drugs are Echinocandins?
Caspofungin, Micafungin, and Anidulafungin
Mechanism of action for Echinocandins
They inhibit the biosynthesis of the fungal cell wall by inhibiting Beta(1, 3)-glucan synthase
Mechanism of action for Griseofulvin
Not clearly understood but it binds to and protects newly formed keratin from fungal infection
Toxicity of Griseofulvin
Inducer of cytochrome p450
What is the route of administration for Griseofulvin?
Oral to treat systemic infections caused by dermatophytes
Mechanism of action for Terbinafine
Inhibits the biosynthesis of ergosterol by inhibiting the squalene epoxidase enzyme. This also leads to an accumulation of sterol squalene which is toxic to fungal cells
Toxicity for Terbinafine
Gi upset and headache. Inhibitor of cytochrome p450 2D6 enzyme
