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Class Polyenes

Drugs Amphotericin B - amphoteric polyene (many double bonds) macrolide (contains a large lactone ring)

Antifungal Agents - Ferguson Mechanism of Action Spectrum of Activity Amphotercin B binds to ergosterol and alters the permeability of the cell by forming Amphotericin Bassociated pores in the cell membrane Fungistatic at low concentrations, fungicidal at high concentrations Candida albicans Cryptococcus neoformans Aspergillus Cocciiodes immitus Histoplasma capsulatum Bastomyces

Limitations of Use & Side Effects ADRs include - Fever & Chills - Nausea & vomiting - Headache - Anorexia - Malaise, muscle & joint pains - Hypotension Toxicity occurs with chronic therapy nephrotoxicity

Nystatin Candicidin Natamycin

Esterol binding compounds Primary activity results in damage to the fungal cell membrane, altering membrane permeability binding to sterols Reduces ergosterol synthesis by inhibiting cytochrome P450dependent 14 alphademethlyation of lanosterol, a necessary step in the synthesis of ergosterol Binds to heme of fungal CYP450

Azoles

Imidazole Triazoles Fluconazole Voriconazole Ketoconazole Itraconazole

ADRs Include - Nausea - Vomiting - Headache - Rash, pruritus - Increased liver enzymes - Hepatotoxicity

Flucytosine (5Fluorocytosine)

Inhibits other oxidative CYP450s involved in sterol biosynthesis 5FC is actively taken up by yeast cells & is deaminated to 5fluorouracil (5FU) inhibits thymidylate synthetase, interfering with DNA synthesis

Used with amphotericin B for cryptococcal meningitis - Crytococcus neoformans - Candida species - Chromoblastomycosis

Never used alone ADRs include - nausea & vomiting - abdominal pain - diarrhea - GI hemorrhage - Ulcers ADRs include - hepatic toxicity - liver impairment - pregnancy, lactation - myelosuppression - renal insufficiency ADRs include - Hypersensitivity - Headache - Dizziness - Mental confusion - Nausea & vomiting - Urticaria ADRs include - Diarrhea - Skin rash - GI upset - Headache

Echinocandins

Anidulafungin Caspofungin Micafungin

Inhibit synthesis of Beta (1-3) glucan in fungal cell wall cell death

Used only for salvage therapy in pts with invasive aspergillosis & have failed to respons to Amphotericin B Active against candida species Used only in systemic treatment of dermatophytosis

Griseofulvin

Binds to fungal RNA and interferes with microtubule formation Fungistatic

Terbinafine

Interferes with ergosterol synthesis by inhibiting fungal enzymes (squalene epoxidase)