Antifungal agents

four classes of antifungal agents that were discussed

azoles, polyenes, allylamines, echinocandins

-azoles MOA

Act on cell membrane by Inhibit Cytochrome P-450 demethylase in ergosterol biosynthesis.  

polyenes MOA

Act on cell membrane by forming pores/channels

allylamines MOA

Act on cell membrane by inhibiting lanosterol biosynthesis

echinocandins MOA

Act on cell wall by inhibiting glucan biosynthesis

T/F Azoles have potential for drug-drug interactions due to inhibition of CYP’s including CYP3A4.  

True

terbinifine MOA

Allylamines;

• Inhibit Squalene epoxidase,

• inhibits the formation of lanosterol

• inhibits ergosterol biosynthesis and leads to a buildup of squalene, which damages membranes.

The accumulation of squalene is the major cause of cell toxicity and not the lack of ergosterol.

Azoles vs Allylamines

Aoles act on cell membrane

by inhibiting ergosterol

biosynthesis

Allylamines act on cell

membrane by inhibiting

lanosterol biosynthesis

The naming between these two classes is such that azoles end in “azole” and allylamines end in “ifine”

How do polyenes like amphotericin B work against fungal cells?

Polyenes preferentially interact with ergosterol in fungal cell membranes, forming channels/pores that increase membrane permeability and lead to cell death.

Why do polyenes have a therapeutic window?

Polyenes have a higher preference for binding ergosterol (found in fungal cell membranes) over cholesterol (in human cell membranes), providing a therapeutic window

What is special about Amphotericin B’s structure that allows it to form pores?

Amphotericin B has both a hydrophilic face and a hydrophobic face, which helps it insert into the membrane and form pores.

What happens when polyenes form pores in fungal cell membranes?

The pores disrupt membrane integrity, causing ions and small molecules to leak out, leading to cell death.

How do echinocandins work against fungi?

Echinocandins inhibit beta-D-glucan synthase, which is essential for fungal cell wall integrity.

Why do echinocandins have fewer toxic effects in patients?

The beta-D-glucan synthase enzyme is unique to fungi, so echinocandins do not target human cells.

What happens to fungal cells when treated with echinocandins?

Inhibition of beta-D-glucan synthase disrupts the cell wall, leading to cell lysis and fungal death.

What is unique about anidulafungin among echinocandins?

Anidulafungin has unique pharmacokinetics, such as slow degradation and minimal reliance on liver metabolism.

no drug drug interactions essentially

T/F Flucytosine is not generally used due to widespread resistance.

True