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Antifungal Agents Fen-Fei Gao. Overview  Fungal infections classification:  Superficial infections: Ringworm (tinea) → skin and mucous membrane. Incidence.

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Presentation on theme: "Antifungal Agents Fen-Fei Gao. Overview  Fungal infections classification:  Superficial infections: Ringworm (tinea) → skin and mucous membrane. Incidence."— Presentation transcript:

1 Antifungal Agents Fen-Fei Gao

2 Overview  Fungal infections classification:  Superficial infections: Ringworm (tinea) → skin and mucous membrane. Incidence rate is high.  Systemic infections: Candida albicans → opportunist infections. Fatality rate is high.  Antifungal agents classification:  Antibiotics: Amphotericin B;  Azole: Ketoconazole;  Allylamine: Terbinafine;  Pyrimidine: Flucytosine.

3 Antibiotic Antifungal Drugs  Polyenes: Amphotericin B, Nystatin  Non-polyenes: Griseofulvin

4 Amphotericin B  Produced by Streptomyces nodosus. Amphoteric polyene macrolide.  Pharmacological Effect: broad- spectrum  Mechanism: binds to ergosterol in fungi (cholesterol in humans and bacteria) to form pores

5  Pharmacokinetics:  Poorly absorbed from the gastrointestinal tract.  More than 90% bound by serum proteins.  Metabolized in liver, excreted slowly in the urine.

6  Adverse Effects:  Infusion-Related Toxicity: fever, chills, muscle spasms, vomiting, headache, hypotension.  Slower Toxicity:  Renal toxicity  K + ↓, Mg 2+ ↓  Anemia: erythropoietin ( 促红细胞生成素 )↓  Abnormalities of liver function  Neurologic sequela  Announcements:  Administration in advance of NSAIDs and Antihistamine drug, Glucocorticoid  Periodic Monitoring

7 Amphotericin B Liposomal Amphotericin B  Lipid preparations reduce toxicity without sacrificing efficacy.  Lipid formulations distributes mostly in reticular endothelial tissue (liver, spleen, lung), but less in kidney.

8 Nysfungin  Like Amphotericin B and has same mechanism of action.  Too toxic for parenteral administration, and is only used topically ( 局部 ).  Not absorbed from skin, mucous membranes, or the gastrointestinal tract, so little significant toxicity.

9 Griseofulvin  Derived from a species of penicillium.  Fungistatic drug ( 抑菌剂 ).  Insoluble.  Administered in a microcrystalline form only using in the systemic treatment of dermatophytosis ( 脚癣 ).  Deposited in newly forming skin where it binds to keratin ( 角蛋白 ), protecting the skin from new infection.

10 Azoles  Synthetic compounds.  Classification: according to the number of nitrogen atoms in the five- membered azole ring  Imidazoles: Ketoconazole, Miconazole, Econazole, Clotrimazole, Bifonazole  Triazoles: Itraconazole, Fluconazol, Vorionazole → systemic treatment

11 Mechanism of Action  Reduction of ergosterol synthesis by inhibition of fungal cytochrome P450 enzymes.  Greater affinity for funfal than for human cytochrome P450 enzymes.  Imidazoles exhibit a lesser degree of specificity than the triazoles, accounting for their higher incidence of drug interactions and side effects.

12 Ketoconazole  The first oral azole introduced into clinical use.  Less selective for fungal P450  Inhibition of human P450 interferes with biosynthesis of adrenal and gonadal steroid hormones;  Alter the metabolism of other drugs.  Best absorbed at a low gastric pH.

13 Miconazole, Econazole, Miconazole, Econazole, Clotrimazole  Bioavailability is low by taking orally.  Used topically.

14 Bifonazole  Double inhibition, antifungal action is more powerful.

15 Itraconazole  Its absorption is increased by food and by low gastric pH.  Treatment of dermatophytoses ( 皮真菌 病 ) and onychomycosis ( 甲真菌病 ).  The only agent with significant activity against aspergillus ( 曲霉菌 ) species.

16 Fluconazol  Water solubility and good cerebrospinal fluid penetration.  The widest therapeutic index ( 治疗指数 ) of the azoles.  Treatment and secondary prophylaxis ( 预防 ) of cryptococcal meningitis (隐 球菌脑膜炎 ).

17 Vorionazole  Available in an intreavenous and an oral formulation.  Metabolism is predominantly hepatic, but the propensity for inhibition of mammalian P450 appears to be low.  Similar to itraconazole in tits spectrum of action, having good activity against candida species.  More effective than itraconazole.

18 Acrylamide  Include Naftifine and Terbinafine.  non-competitive and reversible inhibitor of Squalene epoxidase.  Terbinafine is synthetic, oral formulation.  Fungicidal (杀菌剂)  Treatment of dermatophytoses, especially onychomycosis, more effective than griseofulvin or itraconazole.

19 Pyramine  Flucytosine ( 5-FC ) is a water-soluble pyrimidine analog.  Its spectrum of action is much narrower than that of amphotericin B.  Poorly protein-bound and penetrates well into all body fluid aompartments, including the cerebrospinal fluid.

20  Mechanism  5-FC (taken up by fungal cells via the enzyme cytosine permease) → 5-FU → F- dUMP and FUTP → inhibit DNA and RNA synthesis, respectively.  Synergy ( 协同 ) with amphotericin B.  Spectrum of action: Cryptococcus neoformans, some candida species, and the dematiaceous molds that cause chromoblastomycosis.

21  Not used as a single agent because of its demonstrated synergy with other agents and to avoid the development of secondary resistance.  Adverse effects: result from metabolism to fluorouracil (5-FU)  Bone marrow toxicity with anemia, leukopenia, and thrombocytopenia

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