Antifungal Drugs

  1. amphotericin B
    • polyene antibiotics - bind ergosterol, compromise fungal cell membrane
    • broadest spectrum antifungal
    • drug of choice for rx most life-threatening systemic fungal infections
    • usually fungicidal
    • pore former
    • selective toxicity: mammalian cholesterol (lower affinity) vs ergosterol (higher affinity)
    • resistance: rare, but observed in Candida; when used with inhibitors of ergosterol synthesis (azole); ergosterol reduced affinity for amphotericin B
    • pharmacokinetics: oral (poor absorption), topical, parenterally (systemic infections) w/ deoxycholate (significant factor for toxicity)
    • extensively metabolized, many metabolites
    • adverse effects: oral / topical = irritation
    • - IV immediate rxns are fever, chills, spasms, vomiting, HA, hypotension, anaphylaxis, thrombophlebitis; can be offset by decreasing dose and slowing infusion rate
    • - IV slower toxicities are nephrotoxicity*** - potentially irreversible and anemia (reduced EPO)
    • drug interactions: digitalis (hypokalemia), azoles, nephrotoxic agents
  2. Nystatin
    • polyene antibiotics - bind ergosterol, compromise fungal cell membrane
    • topical use for rx of candidal infection of oral cavity/vaginal mucosa - too toxic to be used parenterally
    • not well absorbed from skin, mucous membranes, or GI tract
    • adverse: bitter/unpleasant taste
  3. Griseofulvin
    • associates with polymerized MTs, disrupts fungal mitosis
    • fungistatic
    • induces various CYP isoforms = alters pharmacologic effectiveness of drugs
    • fetal harm and negative effects on sperm
  4. Flucytosine
    • antimetabolite - cytosine derivative that inhibits DNA and RNA synthesis
    • reduces protein synthesis
    • fungistatic
    • targets candida and cryptococcus
    • poor therapeutic window when used alone (resistance common)
    • use: in combination with amphotericin B to yield synergistic effect
    • pharmacokinetics: good CNS penetration (meningitis)
  5. miconazole
    • azoles - inhibits ergosterol synthesis by blocking fungal CYP enzyme (lanosterol 14-α-demethylase)
    • imidazole
    • fungistatic
    • resistance: reduced drug (active efflux pump), reduced affinity for target enzyme, up-regulation of target enzyme
    • selective toxicity: affect fungal CYP to greater extent than mammalian; imidazole much less specific for fungal CYP vs triazoles
    • interactions: numerous drug interactions
    • use: effective against local (topically used) fungal infections
  6. clotrimazole
    • azoles - inhibits ergosterol synthesis by blocking fungal CYP enzyme (lanosterol 14-α-demethylase)
    • imidazole
    • fungistatic
    • resistance: reduced drug (active efflux pump), reduced affinity for target enzyme, up-regulation of target enzyme
    • selective toxicity: affect fungal CYP to greater extent than mammalian; imidazole much less specific for fungal CYP vs triazoles
    • interactions: numerous drug interactions
    • use: oral / topical administration for local distribution; drug of choice for oropharyngeal candidiasis in AIDs pts
  7. itraconazole
    • azoles - inhibits ergosterol synthesis by blocking fungal CYP enzyme (lanosterol 14-α-demethylase)
    • triazole
    • fungistatic
    • resistance: reduced drug (active efflux pump), reduced affinity for target enzyme, up-regulation of target enzyme
    • selective toxicity: affect fungal CYP to greater extent than mammalian; imidazole much less specific for fungal CYP vs triazoles
    • interactions: numerous drug interactions
    • use: can be given systemically; treat aspergillus and fluconazole-resistant candida sp. (esophageal candidiasis); largely supplanted by voriconazole
  8. fluconazole
    • azoles - inhibits ergosterol synthesis by blocking fungal CYP enzyme (lanosterol 14-α-demethylase)
    • triazole
    • fungistatic
    • resistance: reduced drug (active efflux pump), reduced affinity for target enzyme, up-regulation of target enzyme
    • selective toxicity: affect fungal CYP to greater extent than mammalian; imidazole much less specific for fungal CYP vs triazoles
    • interactions: numerous drug interactions
    • use: better CNS penetration than other azoles (rx cryptococcal meningitis), NOT active against aspergillus; 1st line agent for invasive infections by Candida (except C. krusei) and refractory mucocutaneous candidiasis
  9. voriconazole
    • azoles - inhibits ergosterol synthesis by blocking fungal CYP enzyme (lanosterol 14-α-demethylase)
    • triazole
    • fungistatic
    • resistance: reduced drug (active efflux pump), reduced affinity for target enzyme, up-regulation of target enzyme
    • selective toxicity: affect fungal CYP to greater extent than mammalian; imidazole much less specific for fungal CYP vs triazoles
    • interactions: numerous drug interactions
    • use: same spectrum as itraconazole but more potent in vitro against yeast and molds (largely supplanted itraconazole); new standard of care for aspergillosis (**CIDAL effect against aspergillus)
    • adverse effects: dose-related transient visual side effects (20-30%)
  10. posaconazole
    • azoles - inhibits ergosterol synthesis by blocking fungal CYP enzyme (lanosterol 14-α-demethylase)
    • triazole
    • fungistatic
    • resistance: reduced drug (active efflux pump), reduced affinity for target enzyme, up-regulation of target enzyme
    • selective toxicity: affect fungal CYP to greater extent than mammalian; imidazole much less specific for fungal CYP vs triazoles
    • interactions: numerous drug interactions
    • use: only azole with significant activity against zygomycoses (rhizopus, mucor, rhizomucor); prophylaxis of invasive fungal infections in hematologic malignancy and prolonged neutropenia
  11. efinaconazole
    • azoles - inhibits ergosterol synthesis by blocking fungal CYP enzyme (lanosterol 14-α-demethylase)
    • triazole
    • fungistatic
    • resistance: reduced drug (active efflux pump), reduced affinity for target enzyme, up-regulation of target enzyme
    • selective toxicity: affect fungal CYP to greater extent than mammalian; imidazole much less specific for fungal CYP vs triazoles
    • interactions: numerous drug interactions
    • use: monotherapy topical rx of onychomycosis (fungal toenail infection)
  12. terbinafine
    • allyamine - inhibits ergosterol synthesis by blocking activity of squalene epoxidase
    • fungicidal
    • activity: effective against dermatophytes (largely replaced griseofulvin)
    • pharmacokinetics: accumulates in skin, nails, and fatty tissues
    • use: mainstay for skin/nail infections, used to treat unusual or refractory mold infections
  13. caspofungin and micafungin
    • echinocandins - inhibits glucan synthesis leading to lysis (CIDAL)
    • use: invasive candidiasis resistant to other antifungals, invasive aspergillosis / mold infections
Author
jboi
ID
322903
Card Set
Antifungal Drugs
Description
MOHD4 lecture 31
Updated