Anti-Fungals (O'Brien) Flashcards
Polyenes
Amphotericin B and Nystatin
Echinocandins
Caspofungin
Azoles
Fluconazole, Itraconazole, Voriconazole
Other anti-fungals
Griseofulvin, Terbinafine, Flucytosine
Mechanism of action of polyenes?
form artificial pores in membrane
Amphotericin B mechanism
binds ergosterol; forms artificial membrane pores and leakage of IC ions and macromolecules out of the fungal cell
Are amphotericin B broad spectrum? Fungicidal?
Yes!
Amphotericin B ADME
IV; slow excretion and can accumulate in tissues
Amphotericin B deoxycholate toxicity after infusion? How is it reduced?
- Chills, fever, muscle spasms, headache, vomiting, hypotension
- reduced by slow infusion and premed w. antipyretics and antihistamines
Amphotericin B deoxycholate long-term toxicity?
Renal damage - reversible at first then irreversible
Amphotericin B Lipid Formulations advantages and disadvantages
- advantages: decreased renal toxicity and less severe immediate infusion reactions
- disadvantages: w/ third lipid formulation the immediate infusion rxns are more severe than w/ amphotericin b deoxycholate; hepatotoxicity is greater than amphotericin b deoxycholate; more expensive
Amphotericin B clinical use
- serious, life-threatening system mycotic infections because it is broadest spectrum of action
- preferred for pregnancy
- poor BBB penetration
Nystatin
- similar amphotericin B
- used for candidal infections
Azole Antifungals
- broad spectrum
- Mechanism: decrease the synthesis of ergosterol by inhibiting fungal a cytochrome P450 enzyme (14-alpha-sterol demethylase)
- ADME: all inhibit human P450s leading to drug interactions
Fluconazole
- best penetration of all azoles into CSF
- high bioavailability is high and therapeutic index is highest of the azoles
- clinical uses: drug of choice for cryptococcal meningitis; prophylaxis in high risk neutropenic patients
- potent inhibitor of CYP2C9
Intraconazole
- poor CNS penetration
- clinical uses: drug of choice for dimorphic fungi histoplasma, blastomyces, and sporothrix
- toxicities: can produce congestive heart disease - avoid in pts with ventricular dysfunction
- potent inhibitor of CYP3A4
Voriconazole
- BROADEST spectrum
- clinical uses: drug of choice for invasive aspergillosis (better outcomes and less toxicity than amphotericin B)
- toxicities: visual disturbances common (blurry and changes in color vision or brightness; reversible)
Caspofungin (mechanism and clinical use)
- like penicillin!
- mechanism: inhibits synthesis of Beta(1-3) glucan (cell wall synthesis inhibitor); disrupts the fungal cell wall
- Clinical use: limited to Aspergillus and Candida; used in invasive aspergillosis in pt not responsive to voriconazole
Caspofungin (administration and toxicity)
- IV
- hepatotoxicity (increased in combo with cyclosporine)
Griseofulvin (mechanism and clinical use)
- mechanism: mitotic inhibitor (fungistatic); interferes with MT assembly
- deposited in newly growing keratin of skin and nails (keratophilic)
- clinical use: dermatophytosis only; treatment long-term treatment because only acts on new nail
Griseofulvin (toxicity)
- P450 inducer
Terbinafine (properties and clinical use)
- keratophilic (like griseofulvin); direct fungicidal
- clinical use: treatment of dermatophytoses, especially onychomycosis (fingernail and toenail infections)
Terbinafine (mechanism of action)
- inhibits fungal enzyme (squalene epoxidase - converts squalene to lanostorol, which is converted to ergosterol)
- results in increased levels of squalene, which is toxic
- decreased ergosterol = alters membrane integrity leading to lysis
Flucytosine (mechanism, toxicity)
- mechanism: in fungal cells - flucytosine is taken up by cytosine permease; flucytosine is converted to 5-FU via cytosine deaminase; 5-FU metabolized to nucleotide that blocks DNA and RNA synthesis
- narrow spectrum; only used as combo
- hematotoxicity
