This document discusses various classes of antifungal drugs, including their mechanisms of action and toxicities. The main classes covered are polyenes, flucytosine, azoles, echinocandins, griseofulvin, terbinafine, and tolnaftate. Polyenes like amphotericin B and nystatin bind to ergosterol in the fungal cell membrane to create pores. Flucytosine is converted to 5-fluorouracil which inhibits fungal DNA and RNA synthesis. Azoles like ketoconazole and itraconazole inhibit ergosterol synthesis. Echinocandins are the newest class and inhibit beta-
3. Polyenes
๏ Amphotericin B & Nystatin
๏ MoA: binds ergosterol on fungal cell membrane ๏
creates pores ๏ fungicidal/fungistatic
๏ Amphotericin B is insoluble in water so complexed
with bile salt or lipids; it is for general use (affects
many spp) in SYSTEMIC infections
๏ Nystatin has poor absorption from mucous
membranes; use for Candida spp ๏จ good for obese
and diabetic pts
4. Polyene Toxicity
๏ Amphotericin B
๏ TI is narrow
๏ Acute:
HA, arthralgia, nausea/vomiting, fever, hypotension, Th
rombophlebitis, delirium, seizures
๏ Chronic: Malaise, weight
loss, NEPHROTOXICITY, anemia
5. Flucytosine (5 โ FC)
๏ Distributes in all body tissues
๏ Almost entirely excreted by kidneys
๏ Converted to 5 โ FU (fluorouracil โ chemotherapeutic
agent)
๏ Fungal resistance develops fast during flucytosine
monotherapy ๏ use in combination with other
antifungals
6. Flucytosine MoA
๏ 5-FC is taken up into fungal cells ๏ converted to 5-FU
๏ 5-FU is phosphorylated to produce
5fluorouridine monophosphate (5 โ FUMP) โ this
metabolite can be used in 2 pathways
๏ First pathway: 5-FUMP is converted to 5-FdUMP ๏
acts as an irreversible inhibitor of Thymidylate
Synthetase (aids in making molecules for new DNA) โ
thus, inhibits fungal DNA synthesis
๏ Second pathway: 5-FUMP converted to 5-FUDP ๏
inhibits RNA synthesis
๏ Ultimate effect: Fungicidal/Fungistatic
11. Echinocandins
๏ Newest class of antifungals; large cyclic
๏ Caspofungin, Micafungin, Anidulafungin
๏ MoA: noncomp inhibitors of Beta-D-Glucan Synthase
(makes components of fungal cell wall) ๏ disrupts
integrity of fungal cell wall (not cell membrane!) ๏
Fungicidal
๏ Targets: Aspergillus & Candida
๏ Resistance develops via FSK1 mutations
๏ No major toxicities
12. Griseofulvin
๏
๏
๏
๏
๏
๏
Absorption ~ 50% ๏ improved by fatty foods
Ineffective topically
Induces liver enzymes
Distributes only in keratinized tissues
MoA: inhibits fungal mitosis ๏ Fungistatic
Use: Dermatophytes โ tx is continued until tissue is
replaced with normal healthy tissue
๏ Hair: 1 month; Skin/Finger nails: 6 โ 9 months; Toe
nails: 12 months
๏ Toxicity: induces CYP enzymes, Photosensitivity
๏ Itraconazole is more effective for toe nail infections
(Onychomycosis)
13. Terbinafine
๏ Distribution almost only in keratinized tissue and fat
๏ MoA: inhibits fungal enzyme Squalene Epoxidase
(inhibits ergosterol biosynthesis) ๏ accumulation
of squalene is toxic to fungi ๏ fungicidal
๏ Effective for onychomycosis
๏ Contraindicated in use with CYP inducers/inhibitors
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Editor's Notes
ThymidylateSynthetase converts Uridinemonophosphate (dUMP) toThymidinemonophosphate (dTMP) so it can be used to make new DNA molecules