Antifungal agents

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Antifungal Targets - The Fungal Fortress

Fungal cell structure & antifungal drug targets

  • Cell Membrane (Ergosterol)

    • Polyenes (Amphotericin B): Bind to ergosterol, forming membrane pores causing lethal ion leakage.
    • Azoles (-conazoles): Inhibit lanosterol 14-α-demethylase, blocking ergosterol production.
    • Allylamines (Terbinafine): Inhibit squalene epoxidase, an early step in ergosterol synthesis.
  • Cell Wall (β-Glucan)

    • Echinocandins (-fungins): Inhibit β-(1,3)-D-glucan synthase, disrupting cell wall integrity and causing osmotic stress.
  • Nucleic Acid Synthesis

    • Flucytosine (5-FC): Converted by fungal cytosine deaminase to 5-FU, which blocks DNA and RNA synthesis.

⭐ Amphotericin B is reserved for severe, life-threatening systemic mycoses. Key toxicities are nephrotoxicity and infusion reactions ("shake and bake"), managed with hydration and premedication.

Nucleic Acid Synthesis - Fungal DNA Disrupters

  • Flucytosine (5-FC)
    • Mechanism: A pyrimidine analog. Fungal cytosine deaminase converts 5-FC → 5-fluorouracil (5-FU). This inhibits thymidylate synthase, disrupting fungal DNA synthesis. It also incorporates into fungal RNA, disrupting protein synthesis.
    • Clinical Use: Narrow spectrum. Used in combination with Amphotericin B for severe systemic mycoses (e.g., cryptococcal meningitis).
    • Adverse Effects: Bone marrow suppression (anemia, leukopenia, thrombocytopenia) due to conversion to 5-FU by gut bacteria.

Synergy with Amphotericin B: Amphotericin B creates pores in the fungal cell membrane, which increases the entry of flucytosine, leading to a synergistic antifungal effect.

Antifungal drug mechanisms of action in fungal cells

Clinical Spectrum - Match the Drug to Bug

Drug ClassKey DrugsPrimary Fungal Targets
PolyenesAmphotericin BBroad Spectrum: Candida, Aspergillus, Cryptococcus, Mucorales, Dimorphs (e.g., Histo). Used for severe, systemic infections.
NystatinCandida only (topical/oral rinse for thrush). Not absorbed systemically.
AzolesFluconazoleCandida (except krusei), Cryptococcus. Excellent for CNS infections.
ItraconazoleDimorphic fungi (Blastomyces, Histoplasma, Coccidioides), Aspergillus.
VoriconazoleDrug of Choice for Invasive Aspergillosis. Also covers Candida.
IsavuconazoleInvasive Aspergillus and Mucorales.
EchinocandinsCaspofunginInvasive Candida (especially azole-resistant), Aspergillus. Poor CNS penetration.
AllylaminesTerbinafineDermatophytes (especially onychomycosis).
AntimetabolitesFlucytosineSynergy with Ampho B for cryptococcal meningitis.

High‑Yield Points - ⚡ Biggest Takeaways

  • Amphotericin B and Nystatin bind ergosterol, creating membrane pores. Key toxicities include nephrotoxicity and infusion reactions.
  • Azoles inhibit a fungal P450 enzyme to block ergosterol synthesis, leading to significant drug-drug interactions.
  • Echinocandins target β-glucan synthesis, disrupting the fungal cell wall. They are used for Candida and Aspergillus.
  • Flucytosine blocks DNA and RNA synthesis, causing bone marrow suppression.
  • Terbinafine inhibits squalene epoxidase, but watch for hepatotoxicity.

Practice Questions: Antifungal agents

Test your understanding with these related questions

You are taking care of a patient with renal failure secondary to anti-fungal therapy. The patient is a 66-year-old male being treated for cryptococcal meningitis. This drug has a variety of known side effects including acute febrile reactions to infusions, anemia, hypokalemia and hypomagnesemia. What is the mechanism of action of this drug?

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Flashcards: Antifungal agents

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_____ produces melanocyte damaging acids (Azelaic acid) via lipid degradation

TAP TO REVEAL ANSWER

_____ produces melanocyte damaging acids (Azelaic acid) via lipid degradation

Malassezia furfur (M. furfur) (Which fungus)

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