Antifungal Drugs Flashcards

Antifungal Drugs Overview

• Antifungal therapies are divided into categories based on their administration route: oral/parenteral for systemic infections, oral for skin/mucous membranes, and topical for localized infections.

Major Antifungal Drug Classes

• Polyene Antibiotics: Bind to ergosterol; key example is amphotericin B.
• Azoles: Target the P450 enzyme involved in ergosterol synthesis; include two subclasses of drugs.
• Echinocandins: Inhibit fungal cell wall biosynthesis; also includes flucytosine, terbinafine, and griseofulvin.

Polyene Antibiotics

• Key Examples: Amphotericin B is the most critical, followed by nystatin and natamycin.

Amphotericin B Details

• Primary treatment for systemic mycoses, especially in immunocompromised patients; increasingly being replaced by newer drugs.
• Chemical structure: One side is highly polar with multiple hydroxyl groups; the other side is largely non-polar due to unsaturated double bonds.

Mechanism of Action of Amphotericin B

• Functions as a fungicide by causing cell leakage; resistant cells have lower ergosterol levels.
• Higher binding affinity to ergosterol than cholesterol, forming aqueous channels in fungal membranes that lead to cell death.

Pharmacokinetics of Amphotericin B

• Administered via IV; poorly absorbed in the gastrointestinal tract.
• High volume of distribution indicates extensive tissue binding; significant serum protein binding.
• Does not cross the blood-brain barrier easily, necessitating intrathecal administration for CNS infections.
• Slow elimination via metabolism with a half-life of 2-3 weeks.

Adverse Effects of Amphotericin B

• High therapeutic index implies potential toxicity; therapeutic index defined as TI = LD50/ED50.
• Common adverse effect: azotemia, an elevation of nitrogenous waste products in the blood.

Administration Methods

• Amphotericin B is primarily given through IV routes; intrathecal methods may be required for certain infections.

Therapeutic Use of Amphotericin B

• Considered the gold standard for invasive mycoses, effective against a wide range of fungi, including C. albicans and Aspergillus fumigatus.
• Administration ranges from 0.3 to 1.5 mg/kg/day for a total of 1-2 grams; switching to lipid form or triazoles may occur to mitigate kidney toxicity.
• Often used for initial "induction" therapy before transitioning to less toxic long-term treatments.

Nystatin and Natamycin

• Nystatin: Previously common treatment for skin and mucosal candidiasis; mostly replaced by fluconazole or echinocandins.
• Natamycin: Long-term food additive to prevent mold growth; used for specific ophthalmic fungal infections.