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ANTIFUNGAL AGENTS

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ANTIFUNGAL AGENTS Dr. Igor Khalin


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Fungi Very large and diverse group of microorganisms Broken down into yeast and molds Yeast is single cell organism, useful for baking and alcohol beverages Molds are multicellular, characterized by long, branching filaments called hyphae


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FUNGAL INFECTIONS Yeast infections Candida species Cryptococcus neoformats Moulds (filamentous fungi) Aspergillus sp. Dermatophytes Trichophyton Microsporum


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Infection disease caused by fungi called mycoses Major Types of Mycoses superficial cutaneous subcutaneous systemic opportunistic Symptoms vary from cosmetic to life threatening


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Antifungal agents Drugs used to treat fungal infection Systemic: amphotericin B, fluconazole, ketoconazole, itraconazole, caspofungin Topical: terbinafine, clotrimazole, grizeofulvin, nistatin


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Antifungal agents Polyene antibiotics Nystatin Amphotericin B Imidazoles and triazoles* =AZOLES Ketoconazole Fluconazole * Clotrimazole Itraconazole* Mebendazole Allylamines Terbinafine Echinocandins Caspofungin


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Mechanism of action


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Amphotericin B Pharmacokinetics is an amphoteric polyene macrolide is insoluble in water is poorly absorbed from the GIT more than 90% bound by serum proteins


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Amphotericin B Mechanism of action Binds to sterols in the cell membrane lining Allow to K+ and Mg2+ to leak out, altering fungal cell metabolism Result fungal cell death


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Amphotericin B A-Aspergillus B-Blastomyces C-Coccoides C-Candida C-Can not cross BBB INTRATHECALLY FLUCONAZOLE


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Amphotericin B Adverse effects “Shake and bake” (fever, chills), headache, tachycardia, hypotension, muscle pain, anemia Renal toxicity (Mg/K suppl), neural toxicity (seizures, parestesias)


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Flucytosine (5-FC) Synthetic pyrimidine, used in combination with amphotericin B Amphotericin B increases cell permeability 5-FC forms false nucleotide Disrupts nucleic acid and protein synthesis Bone marrow depression, dyspepsia, hepatic dysfunction


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Ketoconazole Mechanism of action Inhibits an enzyme, resulting in cell wall leaking Blocks demethylation of lanosterol to ergosterol Leads to altered cell membrane (unstable) Result: fungal cell death Spectrum Both topical and oral forms used for wide spectrum mycoses


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Ketoconazole Drug interactions Inhibits CYP450 Adverse effects Alters synthesis of gonadal and adrenal steroid hormones Allergy Dyspepsia Anorexia Gynecomastia Impotence Menstrual irregularities


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Caspofungin Belongs to Echinocandis Inhibits ?(1,3)-D-glucan synthesis destroying cell wall, resulting in lysis and cell death Effective mostly against Aspergillus and Candida Second line drug Fever, rush, nausea and phlebitis are common adverse reactions


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Terbinafine Oral form is essential for the treatment of onychomycoses Cream of solution useful for skin infection


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Mechanism of action Terbinafine inhibits squalene epoxidase of the fungi, which leads to decreasing of ergosterol synthesis


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Terbinafine Has fungicidal action, mostly active against Trychophyton Half life from 200 to 400 hours Adverse effects Dyspepsia Rash Neutropenia Hepatotoxicity Visual disturbances


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Griseofulvin Is fungistatic and used for dermatophytosis Causes disruption of the mitotic spindle, inhibiting mitosis Induces hepatic CYP450 activity Unwanted effects Dyspepsia Fatigue Allergy


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