Antifungal Drugs

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Main Drug Classes

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1. Polyenes

2. Azoles

3. Pyrimidines

4. Echinocandins

5. Drugs used to treat dermatophytosis

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Antifungal Drugs

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Fungi are eukaryotic
-> harder to attack w/o harming host

Main targets
-> plasma membrane (polyenes, azoles), contains ergosterol [target]

-> cell wall (nikkomycins, echinocandins)

-> protein synthesis, nuc. acid synth.

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Amphotericin B (Polyenes)

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Mechanism:
->Binds ergosterol in fungal membrane -> insert itself into membrane -> forms pores -> lyses fungal cell (fungacidal)

Also binds cholesterol -> toxic to host

Spectrum:

->Broad

Clinical use:
->patients with life-threatening systemic mycoses

->ineffective against dermatophytes

Nystatin and natamycin are topical polyenes with little toxicity due to negligible absorption

Adverse effects:
-> most toxic antimicrobial

-> main problem is dose-dependant nephrotoxicity

Lipid-complex formulations are far safer
-> Abelcet (much less toxic)

Distribution
-> extracellular, everywhere but cns

-> albecet concentrates in lungs & reticuloendothelial system -> significant therapeutic advantage

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Azoles

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Newer than polyenes

Generally broad spectrum, sage

For systemic use:
-> older imidazoles are less effective and more toxic than newer TRIAZOLES

For topical use:

-> imidazoles and triazoles are often interchangeable (good efficacy, low toxicity)

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Triazoles

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Mechanism of action:
-> inhibit fungal P450 involved in ergosterol formation
-> also inhibit mammalian hepatic P450 enzymes (inhibit metab of many common drugs)

Draw:
-> usually fungistatic

Resistance:
-> previously rare; now more common esp. with fluconazole and intraconazole

Distribution:
-> excellent except to CNS

Adverse effects:
-> uncommon bc interfere w/ hepatic enzymes of host less than imidazole

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Intraconazole

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Triazole

-> Administered orally
-> many non-life threatening infections

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Fluconazole

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-> distributes well to CNS

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Flucytosine

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Pyrimidine
-> inhibits protein synthesis

-> further metabolized to a compound that inhibits DNA synthesis

Enters CNS readily

-> main use is fungal meningitis in combination with other drugs

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Ringworms

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Dermatophytes
-> infect skin, hair, nails

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Terbanifine

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-> inhibit ergosterol synthesis in virtually all dermatophytes

-> toxic metabolites accumulate (fungicidal)

-> more effective than itraconazole

-> given ORALLY for serious infections