13 X Lanosterol Ergosterol Sterol Demethylase- Cytochrome P450 Imidazoleor TriazoleXLanosterolSterol Demethylase-Cytochrome P450dependent enzymeCH3ErgosterolMechanism of Action of Imidazoles and Triazoles
14 AZOLESInhibition of the demethylase leads to accumulation of 14--methylsterols.Disrupts the close packing of phospholipids, impairing the functions of certain membrane bound enzyme systems.
15 AZOLES Selective toxicity towards fungi . Imidazoles (ketoconazole) but not the triazoles (itraconazole) interact with the mammalian CYTOCHROME P450 system.
16 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.
32 ANTIFUNGAL ACTIVITYMost species of fungi causing human infections are susceptible.Fungistatic or fungicidal.Several different kinds of fungi are sensitive to amphotericin.pathogenic yeastspathogenic yeast-like fungidimorphic fungimolds or filamentous fungi
33 DRUG FORMULATIONSAmphotericin B deoxycholate (DOC) administered IV as a colloidal dispersion.Lipid drug formulations for IV infusion are now available.
34 DEOXYCHOLATE-PHARMACOKINETICS Poorly absorbed from GI tract.Prepared in dextrose, given IV.Distributed to many tissues. It is sequestered in tissues and slowly released.
36 THERAPEUTIC USESSystemic fungal diseases (DOC in the immunosuppressed).Selected patients with profound neutropenia and fever unresponsive to broad-spectrum antibacterial agents.
37 DRUG INTERACTIONSNephrotoxic Drugs (e.g. cyclosporine, aminoglycosides).Azole antifungals.
38 LIPID FORMULATIONSThese preparations differ in the amount of amphotericin as well as physical form, serum clearance and acute toxicity.
39 LIPID FORMULATIONS Amphotericin B lipid complex (ABLC). Amphotericin B colloidal dispersion (Amphotericin B cholesteryl sulfate complex, ABCD).Liposomal amphotericin B (Ambisome).
40 LIPID FORMULATIONSIndicated 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.
41 Amphotericin Lipid Formulations ProductSize (mean diameter)ConfigurationAmBisome45-80 nmSmall spherical unilamellar liposomesAmphocil (Amp B colloidal dispersion),ABCD115 nm, 4 nm thicknessDisc shaped complexes, with Amp B attached.Colloidal dispersion of a stable complex of amp with cholesteryl sulfate.Abelcet (Amp B lipid complex),ABLCmRibbons of lipid with Amp B attached.
42 5-FC-ANTIFUNGAL ACTIVITY Narrow spectrum of activity (some Candida species and Cryptococcus neoformans).Most fungi causing systemic infections are resistant.
43 PHARMACOKINETICS Rapidly and well absorbed after oral administration. Widely distributed throughout the body including the CNS.Mainly excreted in the urine.More than 90% excreted in the urine
44 THERAPEUTIC USESUsually used in combination with Amphotericin B for cryptococcal and candidal infections.Use as a single agent is usually precluded
47 DRUG INTERACTIONSImmunosuppressive drugsNephrotoxic drugs
48 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).
52 KETOCONAZOLE-THERAPEUTIC USES Effective against several systemic fungal diseases when given orally (several limitations to its use).Dermatophyte infections.
53 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.
54 THERAPEUTIC USESSerious fungal diseases in patients intolerant or refractory to amphotericin .Oropharyngeal and esophogeal candidiasis.Dermatophytoses and onychomycosis.
55 DRUG INTERACTIONSMany can occur due to inhibition of CYP 3A4 (e.g. PIs,NNRTIs,anticancer drugs).
56 FLUCONAZOLE (Diflucan) More favorable pharmacokinetic and toxicity profiles than itraconazole.Relatively narrow spectrum of activity.
57 VORICONAZOLE (Vfend) Excellent oral bioavailability. Good activity vs. many fungi
61 ANTIFUNGAL ACTIVITY Inhibits the dermatophytes (ringworm fungi). Fungistatic or fungicidal.
62 PHARMACOKINETICSVariable oral absorption (Griseofulvin only works orally).Micronized preparations have the best absorption.Deposited in keratin precursor cells, new keratin becomes resistant.
63 THERAPEUTIC USESTreatment of choice for ringworm infections (hair, nails, skin, hands etc).Length of therapy depends on location of the infection.Only effective orally. Use when topical therapy failed.
77 ENDOCRINE EFFECTSImidazoles but not triazoles produce impotence, oligospermia etc
78 INJECTION OR INFUSION RELATED EFFECTS Amphotericin B produces fever and chillsCaspofungin (phlebitis)
79 THERAPEUTIC USES OF THE ANTIFUNGAL AGENTS Amphotericin BSerious systemic fungal diseasesFlucytosineCrytpcoccosis in AIDS patients, candidiasisItraconazoleGriseofulvinDermatophyte InfectionsTerbinafineCaspofunginInvasive Aspergillosis and candidiasis
80 Summary of the Mechanisms and toxicity of the Antifungals Amphotericin BBind to ergosterol, form pores in fungal membraneFever and chills, Nephrotoxicity, Anemia and NeurotoxicityFlucytosineInhibits fungal DNA and RNA synthesisGI, bone marrow depressionImidazoles andTriazolesInhibit 14 demethylase (P450 enzyme)Ketoconazole-GI, endocrineOthers-GI, liver
81 Summary of the Mechanisms and Toxicities of the Antifungals GriseofulvinInhibits fungal mitosisGI, headacheTerbinafineInhibits ergosterol synthesisGI, hepatotoxicityCaspofunginInhibits fungal cell wall synthesisPhlebitis