ANTIFUNGAL AGENTS презентация

ANTIFUNGAL AGENTS Dr. Igor Khalin

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

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

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

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

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

Mechanism of action

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

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

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

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

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

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

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

Caspofungin Belongs to Echinocandis Inhibits β(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

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

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

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

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