Antifungal agents Superficial mycoses Cutaneous mycoses Subcutaneous mycoses Systemic or deep mycoses Affects hair and skin epidermis e.g. tinea versicolor, tinea nigra, T.corporis, Affects skin and nail. Caused by dermatophytes; e.g. tinea pedis, T.capitis. Affects subcutaneous tissues e.g.candidiasis (oral, genital or invasive) Affects organs e.g. lung, lymphatics and other organs. e.g. Aspergillosis Aspergillosis There are 4 types of human fungal diseases according to depth and extent of infection: A] Sulfur compounds: topically used 1) Inorganic sulfur compounds: e.g. colloidal sulfur, selenium sulfide (Se 2 S) used as antidandruff and sodium thiosulfate (Na 2 S 2 O 3 ) used for T.versicolor. 2) Organic sulfur compounds: Tolnaftate (Thiocarbamate derivative) Mechanism of action: It inhibits squalene epoxidase essential in ergosterol biosynthesis (sterol found in fungi membrane). Ergosterol biosynthesis: Uses: used against dermatophytes (skin mycosis) but not against deeper infections (not for nail or scalp) due to poor permeability. SAR: - Naphthalene ring could not be replaced by other rings. - N-methyl group is essential for activity. - Methyl group on the phenyl ring can be replaced by H, OH, OCH 3 or the tolyl group is replaced by - or -naphthyl group. Activity is lost if this methyl group is replaced by Cl, COOH, NO 2. Tolnaftate (cont.) Synthesis: B] Phenols: topically used Phenolic compounds e.g. phenol, cresol, resorcinol, salicylic acid are used for superficial mycoses for their antifungal and keratolytic properties. C] Antifungal antibiotics: 1)Polyene antibiotics: [Polyene membrane disrupters] They are produced by Streptomyces sp. They are broad spectrum. NystatinAmphotericin B SourceStreptomyces nourseiS. nodosus Uses Used topically not parentrally (due to systemic toxicity) for fungal infections of the mouth, skin, eye, vagina, GIT (orally; it has poor absorption) infections caused by Candida and Aspergillus sp. Used intravenously against all systemic mycoses including: Candida, Aspergillus, Cryptococcus, Zygomycetes. Side effects It has no side effects (Clean drug)Cause phlebitis at the site of injection, chills, renal toxicity. Structural features of polyene antibiotics: Lipophilic part consisting of 4-7 double bonds all in trans configuration, and Hydrophylic part consisting of hydroxylated alkyl chain. A carbohydrate (sugar) moiety. Parts 1 and 2 are linked in a lactone skeleton to which the sugar part is attached. Mechanism of action: Clusters of 5-10 molecules bind to the sterol in the fungal cell membrane through the lipophilic portions of the molecules, leaving a central tunnel lined with the hydrophilic portions allowing the leakage of the polar contents of the cell, resulting in cell death. 2) Griseofulvin: Source: It is produced by Penicillium griseofulvum. Mechanism of action: Inhibit cell mitosis by interacting with the microtubules involved in mitotic spindle apparatus. It is fungistatic SAR: - Cl can be replaced by F not Br or H. - OMe on the cyclohexene ring can be replaced by propyloxy or butyloxy but not larger groups, H, NH 2 nor C=O. -OMe groups on the phenyl ring and C=O group on the cyclohexene ring are not essential for activity. Uses: for treatment of skin and nail infections. It is administered orally in a micronized form with fatty meals to enhance absorption. After being absorbed, the drug reaches the cutaneous tissues where it exerts its action. Long term treatment is needed since it is fungistatic, so time is needed for the infected keratinized cell to move outward and to be replaced by normal cells. Contraindications: it induces liver microsomal enzymes leading to rapid metabolism of warfarin and oral contraceptives. TerbinafineNaftifine Used orally and topically for skin and nail infections Used topically for skin and nail infections D] Allylamines: Mechanism of action: Inhibit squalene epoxidase. E] Antifungal antimetabolites: 5-Fluorocytosine Uses: In combination with amphotericin B, it is used for Cryptococcus meningitis, C.albicans and others. **5-FC enters the fungal cell via a cytosine specific permease (an enzyme not found in humans). This accounts for the selectivity of the drug to fungi not humans. Mechanism of action: Fdump(fluorodeoxyuridne monophosphate F] Azoles: They are antifungal agents possessing a 5-membered ring containing 2 or 3 nitrogens (imidazole or triazole). Mechanism of action: They inhibit cytochrome P450- lanosterol 14-demethylase, an important enzyme in the biosynthesis of ergosterol. This results in disturbance in cell membrane integrity since ergosterol is a component of fungal cell membrane. Selectivity of azoles to fungal enzymes comes from the fact that human lanosterol -demethylase is inhibited by concentrations of the drug higher than the therapeutic dose. They are broad spectrum antifungal agents. Mechanism of action of ketoconazole Decrease in the ergosterol in the funagal membrane By ketoconazle reduces the fungicidal action of amphotericin It is not useful for fungal infections of UT as level of parent drug in urine is very low Imidazole derivatives Phenylethylimidazole derivativesTriazole derivatives Fluconazole Used topically.Miconazole: used as topical cream or oral gel. Also, used as vaginal suppository. Ketoconazole: used topically and also orally for systemic infections. Side effects: It inhibits C lyase, 11- hydroxylase and cholesterol side chain synthesis in human. Therefore, it suppresses testosterone and cortisol biosynthesis in humans. Fluconazole: -Used orally or IV. -Can penetrate inflamed meninges. -No effect on androgens. -Long t. G- Pyridones Ciclopirox olamine is a pyridone derivative for the treatment of cutaneous dermatophyte infections, cutaneous C. albicans infections, and tinea versicolor. It interferes with fungal growth by inhibiting macromolecule synthesis. H. Echinocandins Caspofungin is a semisynthetic lipopeptide. It inhibits the synthesis of beta-D-glucan, a cell wall component of lamentous fungi. Caspofungin is approved for the treatment of invasive aspergillosis in patients not responding to amphotericin B. Adverse effects are mediated through histamine release: facial ushing, rash, fever, and pruritus. Dose reductions are required in the presence of moderate hepatic insufficiency. Tolnaftate