Lanosterol Ergosterol Sterol Demethylase- Cytochrome P450 dependent enzyme CH 3 Mechanism of Action of Imidazoles and Triazoles Imidazole or Triazole X
AZOLES Inhibition of the demethylase leads to accumulation of 14- -methylsterols. Disrupts the close packing of phospholipids, impairing the functions of certain membrane bound enzyme systems.
AZOLES Selective toxicity towards fungi. Imidazoles (ketoconazole) but not the triazoles (itraconazole) interact with the mammalian CYTOCHROME P450 system.
RESISTANCE Common with the newer triazoles. The primary mechanism is accumulation of mutations in erg11 the gene coding for the demethylase. Cross resistance to all azoles.
ANTIFUNGAL ACTIVITY Most species of fungi causing human infections are susceptible. Fungistatic or fungicidal. Several different kinds of fungi are sensitive to amphotericin. –pathogenic yeasts –pathogenic yeast-like fungi –dimorphic fungi –molds or filamentous fungi
DRUG FORMULATIONS Amphotericin B deoxycholate (DOC) administered IV as a colloidal dispersion. Lipid drug formulations for IV infusion are now available.
DEOXYCHOLATE- PHARMACOKINETICS Poorly absorbed from GI tract. Prepared in dextrose, given IV. Distributed to many tissues. It is sequestered in tissues and slowly released.
LIPID FORMULATIONS These preparations differ in the amount of amphotericin as well as physical form, serum clearance and acute toxicity.
LIPID FORMULATIONS Amphotericin B lipid complex (ABLC). Amphotericin B colloidal dispersion (Amphotericin B cholesteryl sulfate complex, ABCD). Liposomal amphotericin B (Ambisome).
LIPID FORMULATIONS Indicated for systemic infections in patients unresponsive to the deoxycholate or who are intolerant of it. Less nephrotoxicity (and less infusion related events) than the deoxycholate. 20-50X as expensive.
Product Size (mean diameter) Configuration AmBisome 45-80 nm Small spherical unilamellar liposomes Amphocil (Amp B colloidal dispersion), ABCD 115 nm, 4 nm thickness Disc shaped complexes, with Amp B attached. Colloidal dispersion of a stable complex of amp with cholesteryl sulfate. Abelcet (Amp B lipid complex), ABLC 1.6-11.1 m Ribbons of lipid with Amp B attached. Amphotericin Lipid Formulations
5-FC-ANTIFUNGAL ACTIVITY Narrow spectrum of activity (some Candida species and Cryptococcus neoformans). Most fungi causing systemic infections are resistant.
PHARMACOKINETICS Rapidly and well absorbed after oral administration. Widely distributed throughout the body including the CNS. Mainly excreted in the urine.
THERAPEUTIC USES Usually used in combination with Amphotericin B for cryptococcal and candidal infections.
DRUG INTERACTIONS Immunosuppressive drugs Nephrotoxic drugs
AZOLES Synthetic compounds. The imidazoles, miconazole and ketoconazole were introduced around 1978. During the 1990s use of ketoconazole diminished because of the release of the triazoles-fluconazole and itraconazole (2002- voriconazole).
KETOCONAZOLE- THERAPEUTIC USES Effective against several systemic fungal diseases when given orally (several limitations to its use). Dermatophyte infections.
ITRACONAZOLE (Sporanox) GI absorption is somewhat erratic and depends on acidic environment. Available as capsules and a new oral solution (about 30% better absorption). IV preparation now also available. Metabolized primarily by CYP3A4.
THERAPEUTIC USES Serious fungal diseases in patients intolerant or refractory to amphotericin. Oropharyngeal and esophogeal candidiasis. Dermatophytoses and onychomycosis.
DRUG INTERACTIONS Many can occur due to inhibition of CYP 3A4 (e.g. PIs,NNRTIs,anticancer drugs).
FLUCONAZOLE (Diflucan) More favorable pharmacokinetic and toxicity profiles than itraconazole. Relatively narrow spectrum of activity.
VORICONAZOLE (Vfend) Excellent oral bioavailability. Good activity vs. many fungi
ANTIFUNGAL ACTIVITY Inhibits the dermatophytes (ringworm fungi). Fungistatic or fungicidal.
PHARMACOKINETICS Variable oral absorption (Griseofulvin only works orally). Micronized preparations have the best absorption. Deposited in keratin precursor cells, new keratin becomes resistant.
THERAPEUTIC USES Treatment of choice for ringworm infections (hair, nails, skin, hands etc). Length of therapy depends on location of the infection.
ENDOCRINE EFFECTS Imidazoles but not triazoles produce impotence, oligospermia etc
INJECTION OR INFUSION RELATED EFFECTS Amphotericin B produces fever and chills Caspofungin (phlebitis)
Amphotericin B Serious systemic fungal diseases Flucytosine Crytpcoccosis in AIDS patients, candidiasis Itraconazole Serious systemic fungal diseases Griseofulvin Dermatophyte Infections Terbinafine Caspofungin Invasive Aspergillosis and candidiasis THERAPEUTIC USES OF THE ANTIFUNGAL AGENTS
Amphotericin B Bind to ergosterol, form pores in fungal membrane Fever and chills, Nephrotoxicity, Anemia and Neurotoxicity Flucytosine Inhibits fungal DNA and RNA synthesis GI, bone marrow depression Imidazoles and Triazoles Inhibit 14 demethylase (P450 enzyme) Ketoconazole-GI, endocrine Others-GI, liver Summary of the Mechanisms and toxicity of the Antifungals
Griseofulvin Inhibits fungal mitosis GI, headache Terbinafine Inhibits ergosterol synthesis GI, hepatotoxicity Caspofungin Inhibits fungal cell wall synthesis Phlebitis Summary of the Mechanisms and Toxicities of the Antifungals