4. Antifungal agents Flashcards
location of infections
cutaneous
subcutaneous
systemic infections
Drugs for subcutaneous and systemic infections
Amphotericin B
Flucytosine (5-FC)
Triazoles
Echinocandins
Drugs for cutaneous
Terbinafine
Griseofulvin
Nystatin
Imidazoles
Imidazoles for fungal infections
ketoconazole
Clotrimazole
Amphotericin B
fungicide or static depending on concentration and organism
MOA: binds to ergosterol and alters the membrane permeability
Pharmacokinetics:
Good distribution, does not enter CNS
Plasma half-life: 15 days
Lipid formulation has better effect and smaller toxicity
Administration: parenterally (IV microcolloid infusion or liposome packed) | intrathecally for candida meningitis | larger amounts can be given in lipid formulation
Spectrum: broad
Candida spp. Cr. Neoformans, aspergillus, dimorphs
Some protozoans (Leishmania and Trypanosoma)
Low TI
Adverse effects: Infusion related toxicity – fever, chills, anemia, thrombophlebitis | Kidney damage, hypotension
Flucytosine (5-FC)
Fungistatic
MOA: transformed to 5-FU, incorporated into the RNA, inhibits the protein synthesis, synergism with amphotericin B
Pharmacokinetics: good absorption good distribution also in CSF Administration: oral and parenteral Excretion: Kidney (glomerular filtration)
Spectrum: candida sp., Cryptococcus, aspergillus
Clinical use:
Urinary tract candidiasis In combination with amphotericin B or maybe itraconazole
pulmonary aspergillosis, Cryptococcus meningitis
Adverse effects: GI (severe enterocolitis may occur), liver impairment, bone marrow toxicity
Triazoles
Itraconazole
Fluconazole
Voriconazole
Posaconazole
Itraconazole
Fluconazole
Voriconazole
Posaconazole
MOA: Inhibition of ergosterol synthesis (cytochrome P450 enzyme)
Disrupts membrane structure and function of growing fungi
Spectrum: all fungi except aspergillus
!!! Voriconazole also against aspergillus and highly effective against Candida spp.
Inhibition of CYP3A4
Adverse effects: GI, liver impairment, antiandrogen effect
Itraconazole
administration: oral
accumulation in nail
treats blastomycosis, paracoccidioidomycosis, Histoplasmosis
Adverse effects: liver impairment, antiandrogen effect
Hypokalemia, hepatotoxicity
Fluconazole
hydrophilic
administration: oral, parenteral
distributes in CSF
elimination via kidney
DOC for cryptococcus neoformans after induction therapy
Posaconazole
broadest spectrum of the Triazoles
Voriconazole
also against aspergillus and highly effective against Candida spp.
Administration: oral, parenteral
Echinocandins
caspofungin
micafungin
anidulafungin
caspofungin
micafungin
anidulafungin
Echinocandins
MAO: interfere with the synthesis of the cell wall by inhibiting the synthesis of β(1,3)-D-glucan, leading to lysis and cell death (Inhibitors of polysaccharide synthesis)
Indications: Aspergillus, Candida sepsis, if poly resistant (minimal activity against other fungi)
Administration: IV
Adverse effects: well tolerated rash, fever, phlebitis at the infusion site.
Caspofungin
first line in invasive candidiasis 2nd line for invasive aspergillosis
Terbinafine
Mechanism: inhibition of squalene epoxidase inhibitor
DOC: dermatophyte onychomycosis (nail infection) | 3 months therapy
Oral form: tinea capitis
Topical form: tinea pedis, tinea corporis, tinea cruris | 1 week therapy
Kinetics: accumulation in nail, skin, breast milk and adipose tissue
excreted via urine
Adverse effects: GI symptoms (diarrhea, dyspepsia, nausea), headache, rash, rarely hepatitis, pregnancy is contraindication
Griseofulvin
MOA: disruption of mitotic spindle (inhibition of fungal mitosis)
Fungistatic
Onychomycosis treatment of 6-12 month (duration according to replacement of skin tissue)
Treats also dermatophytosis of the scalp
Many side effects: liver damage, bone marrow damage, GI, photosensitivity, psychic problems, enzyme inducer, teratogenic
Nystatin
Poleyn antifungal
Pharmacokinetics: no absorption from GI, local effect
Adverse effects: GI symptoms
“Swish and swallow”
Clinical use: mouth and cutaneous candida infection, Cryptococcus, histoplasma, blastomyces
ketoconazole
Clotrimazole
MOA: Inhibition of ergosterol synthesis (cytochrome P450 enzyme)
Disrupts membrane structure and function of growing fungi
Wide range of activity
Spectrum: epidermophyton, Microsporum, trichophyton, candida, malassezia
Used for: tinea pedis, tinea corporis, tinea cruris | Oropharyngeal and vuvovaginal candidiasis
