Antifungals Flashcards
Flucytosine
MOA: prodrug converted by fungus to 5-FdUMP which inhibits thymidylate synthetase which blocks synthesis of dTMP, and 5-FUTP inhibits protein synthesis
Spectrum: narrow (fungistatic)
Use: synergistic when used w/ Amphotericin B to tx serious Candida and Cryptococcus infections
SE: BM suppression d/t metabolism to 5-fluorouracil
Caspofungin
MOA: inhibit synthesis of β(1,3)-D-glucans in fungal CW
Effect: disruption in cell wall = cell death
PK: only IV
Use: tx Candida and Aspergillus
Amphotericin Infusion-related SEs
Fever, chills, muscle spasm, HA, hypotension
- slow rate or decrease dose, or pre-treat w/ antihistamine/glucocorticoids
Azoles
MOA: inhibit 14-α-sterol demethylase (fungal CYP450 enzyme) prevents ergosterol synthesis
Effect: disrupts membrane function and increases permeability
*specificity results from affinity for fungal rather than human CYP450 enzymes (triazoles more specific than imidazoles)
Fluconazole
PK: sorta inhibits CYP3A4, strong inhibitor of CYP2C9 (increase levels of Phenytoin, Zidovudine and Warfarin)
DOC: esophageal, vulvovaginal or urinary Candidiasis, Candidemia, Coccidiomycosis, Cryptococcal meningitis
Voriconazole
DOC: invasive aspergillosis
SE: transient visual disrurbances, inhibition of CYP2C19, CYP2C9, CYP3A4
Topical Azoles
Clotrimazole and Miconazole
Itraconazole
PK: metabolized CYP3A4, inhibits CYP3A4 (so potential for arrhythmias when given concurrently w/ Cisapride or Quinidine), poor bioavailability and CSF penetration, absorption reduced by antacids, H2RBs and PPIs
Use: preferred for Blastomyces, SPorothrix and Hisotplasma infections, effective against Aspergillus (but has been replaced by voriconazole), tx dermatophytoses and onychomycosis
Griseofulvin
MOA: disrupts mitosis spindle and inhibits mitosis
Use: tx severe dermatophytosis of skin/hair/nails (replaced by newer antifungals like Itraconazole and Terbinafine)
SE: induces CYP450 enzymes (increases concentration of Warfarin)
Azoles names
Imidazoles: Ketoconazole / Miconazole / Clotrimazole
Triazoles: Itraconazole / Fluconazole / Voriconazole / Posaconazole
PCP Tx options
Clindamycin + Primaquine
Dapsone + Trimethoprim
Atovaquone
Pentamidine
Nystatin
(Structurally similar to amphotericin B)
Use: candidiasis
PK: cutaneous, vaginal and PO administration
Posaconazole
Use: tx Zygomycetes (ie Mucormycoses)
SE: inhibits CYP3A4
Terbinafine
MOA: inhibits squareness epoxidase preventing synthesis of ergosterol, and accumulation of toxic levels of squalene
Use: onychomycosis
SE: GI sx’s, rash, HA, taste disturbances, elevated LFTs, inhibits CYP2D6
Amphotericin B
MOA: binds ergosterol forming pores in cell membrane = cell death
Spectrum: broad AF (yeasts, mycoses, molds)
PK: IV only, low CSF penetration so intrathecal tx for meningeal dz
Use: life-threatening fungal infections, initial drug to rapidly reduce fungal burden then continue pt on Azole, topical use for Candidiasis, tx deep infections during pregnancy
Amphotericin Slower Toxicity SEs
Renal toxicity, azotemia, decreased GFR, renal tubular acidosis w/ Mg2+ and K+ wasting
- co-administer NaCl infusion to attenuate renal damage
LFT abnormalities, decreased EPO
Amphotericin Lipid Formulations
Packaged in lipid carriers to reduce exposure to nephron = reduce nephrotoxicity
Co-Trimoxazole
DOC: tx PCP and prevention of PCP in immunocompromised pt’s
Terbinafine
Use: tx Tinea curis and Tinea corporis (topical cream)
Ketoconazole
PK: inhibits CYP3A4 (potentials toxicity of Warfarin and Cyclosporine), best absorbed at low pH
Uses: superficial mycoses
SE: decrease plasma testosterone levels = decreased libido, gynecomastia, menstrual irregularities in women
(High doses may inhibit adrenal steroid synthesis and decrease plasma cortisol)
CI: coadministration w/ antacids, PPIs, H2RBs
