Anti-Fungals (O'Brien)

Question 1

Polyenes

Answer 1

Amphotericin B and Nystatin

Question 2

Echinocandins

Answer 2

Caspofungin

Question 3

Azoles

Answer 3

Fluconazole, Itraconazole, Voriconazole

Question 4

Other anti-fungals

Answer 4

Griseofulvin, Terbinafine, Flucytosine

Question 5

Mechanism of action of polyenes?

Answer 5

form artificial pores in membrane

Question 6

Amphotericin B mechanism

Answer 6

binds ergosterol; forms artificial membrane pores and leakage of IC ions and macromolecules out of the fungal cell

Question 7

Are amphotericin B broad spectrum? Fungicidal?

Answer 7

Yes!

Question 8

Amphotericin B ADME

Answer 8

IV; slow excretion and can accumulate in tissues

Question 9

Amphotericin B deoxycholate toxicity after infusion? How is it reduced?

Answer 9

• Chills, fever, muscle spasms, headache, vomiting, hypotension
• reduced by slow infusion and premed w. antipyretics and antihistamines

Question 10

Amphotericin B deoxycholate long-term toxicity?

Answer 10

Renal damage - reversible at first then irreversible

Question 11

Amphotericin B Lipid Formulations advantages and disadvantages

Answer 11

• 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

Question 12

Amphotericin B clinical use

Answer 12

• serious, life-threatening system mycotic infections because it is broadest spectrum of action
• preferred for pregnancy
• poor BBB penetration

Question 13

Nystatin

Answer 13

• similar amphotericin B

- used for candidal infections

Question 14

Azole Antifungals

Answer 14

• 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

Question 15

Fluconazole

Answer 15

• 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

Question 16

Intraconazole

Answer 16

• 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

Question 17

Voriconazole

Answer 17

• 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)

Question 18

Caspofungin (mechanism and clinical use)

Answer 18

• 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

Question 19

Caspofungin (administration and toxicity)

Answer 19

• IV

- hepatotoxicity (increased in combo with cyclosporine)

Question 20

Griseofulvin (mechanism and clinical use)

Answer 20

• 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

Question 21

Griseofulvin (toxicity)

Answer 21

• P450 inducer

Question 22

Terbinafine (properties and clinical use)

Answer 22

• keratophilic (like griseofulvin); direct fungicidal

- clinical use: treatment of dermatophytoses, especially onychomycosis (fingernail and toenail infections)

Question 23

Terbinafine (mechanism of action)

Answer 23

• 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

Question 24

Flucytosine (mechanism, toxicity)

Answer 24

• 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