Anti-Fungal Drugs

Drug ClassesPolyenes: Amphotericin B & NystatinFlucytosineAzolesEchinocandinsGriseofulvinTerbinafineTolnaftate

PolyenesAmphotericin B & NystatinMoA: 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 good for obese and diabetic pts

Polyene ToxicityAmphotericin B

TI is narrowAcute: HA, arthralgia, nausea/vomiting, fever,

hypotension, Thrombophlebitis, delirium, seizures

Chronic: Malaise, weight loss, NEPHROTOXICITY, anemia

Flucytosine (5 – FC)Distributes in all body tissuesAlmost entirely excreted by kidneysConverted to 5 – FU (fluorouracil –

chemotherapeutic agent)Fungal resistance develops fast during

flucytosine monotherapy use in combination with other antifungals

Flucytosine MoA5-FC is taken up into fungal cells converted

to 5-FU 5-FU is phosphorylated to produce 5-fluorouridine monophosphate (5 – FUMP) – 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) – thus, inhibits fungal DNA synthesis

Second pathway: 5-FUMP converted to 5-FUDP inhibits RNA synthesis

Ultimate effect: Fungicidal/Fungistatic

Flucytosine ToxicityAdverse effects due to 5 – FU

Reversible MYELOSUPPRESSION (13%)LIVER DYSFUNCTION (10%)

AzolesKetoconazole, ItraconazoleStructure contains 5 membered azole ringMoA: Inhibition of fungal ergosterol synthesis inhibits Lanosterol 14 – α – Demethylase fungicidal/fungistatic

Cross resistance is commonKetoconazole can inhibit human sterol

synthesis & Cyp P450 enzymesSeborrheic Dermatitis – ketoconazole

shampoo

Azole ToxicityGynecomastia (ketoconazole)Liver toxicityHypokalemia, hypertension

Itraconazole

EchinocandinsNewest class of antifungals; large cyclicCaspofungin, Micafungin, AnidulafunginMoA: 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 & CandidaResistance develops via FSK1 mutationsNo major toxicities

GriseofulvinAbsorption ~ 50% improved by fatty foodsIneffective topicallyInduces liver enzymesDistributes only in keratinized tissuesMoA: inhibits fungal mitosis FungistaticUse: Dermatophytes – tx is continued until tissue

is replaced with normal healthy tissueHair: 1 month; Skin/Finger nails: 6 – 9 months;

Toe nails: 12 monthsToxicity: induces CYP enzymes,

PhotosensitivityItraconazole is more effective for toe nail

infections (Onychomycosis)

TerbinafineDistribution almost only in keratinized tissue

and fatMoA: inhibits fungal enzyme Squalene

Epoxidase (inhibits ergosterol biosynthesis) accumulation of squalene is toxic to fungi fungicidal

Effective for onychomycosisContraindicated in use with CYP

inducers/inhibitors

Summary

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