Antifungal Agents Fen-Fei Gao

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.

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

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

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

Adverse Effects: Infusion-Related Toxicity: fever, chills, muscle spasms, vomiting, headache, hypotension. Slower Toxicity: Renal toxicity K+↓, Mg2+↓ 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

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.

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.

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.

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

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.

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.

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

Bifonazole Double inhibition, antifungal action is more powerful.

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.

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 ）.

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.

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.

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.

Synergy (协同) with amphotericin B. 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.

Adverse effects: result from metabolism to fluorouracil (5-FU) 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