Antifungals

Question 1

types of mycoses

Answer 1

• -superficial (dermatophytosis) like ringworm
• -mucocutaneous like thrush & denture stomatitis
• -systemic like C albicans or Aspergillus

Question 2

What is Candidiasis?

Answer 2

most common type of mucocutaneous oral fungal infection; a yeast

Question 3

What are the two categories of antifungal agents?

Answer 3

• -oral & parenteral drugs for systemic therapy of systemic infections
• -topical drugs & oral drugs for therapy of mucocutaneous infections

Question 4

mechanism of action of amphotericin B

Answer 4

binds to ergosterol; forms amph-B-associated membrane pores; alters membrane permeability, causes leakage of intracellular Na/K/H, leads to cell death

Question 5

Why is amphotericin B selectively toxic?

Answer 5

mammalian cell membranes have cholesterol, fungal cell membranes have ergosterol
*binds cholesterol to a far lesser extent than ergosterol

Question 6

How does resistance to amphotericin B occur?

Answer 6

• -develops when binding of the drug to ergosterol is impaired
• -when ergosterol conc in the membrane is decreased upon tx w/ inhibitors or ergosterol synthesis such as azoles
• -alternative sterols are substituted in the fungal membrane to alter the drug target

Question 7

**What is amphotericin B often reconstituted in and why?

Answer 7

deoxycholate (bile salt detergent) sol’n b/c it’s not soluble in aqueous media
*newer liposome formulations are less toxic to the kidneys

Question 8

What is the interaction of amphotericin B and azoles?

Answer 8

Inhibitors of ergosterol synthesis may induce the development of amphotericin B-resistant fungi.

Question 9

What is the interaction of amphotericin B and nephrotoxic agents?

Answer 9

Aminoglycosides, cyclosporine enhance the renal toxicity of amphotericin B.

Question 10

Why is nystatin used topically?

Answer 10

*too toxic to be used parenterally; not well absorbed from the skin, mucous membranes, or GI tract

Question 11

*mechanism of action of flucytosine

Answer 11

taken up by susceptible fungal cells; converted by enzyme cytosine deaminase of fungal cells into 5-fluorouracil (5-FU); *5-FU–>5-FdUMP which competitively inhibits thymidylate synthase to block fungal DNA synthesis; *5-FUTP is incorporated by fungal cells into defective RNA

Question 12

*Why does flucytosine have selective toxicity for fungi?

Answer 12

human cells lack the cytosine deaminase so there is little uptake by human cells

Question 13

*Explain how fungi are resistant to flucytosine?

Answer 13

mutations in cytosine permease or cytosine deaminase

Question 14

What is the structural difference b/n imidazoles and triazoles?

Answer 14

imidazoles: azole ring w/ 2 nitrogen atoms
triazoles: azole ring w/ 3 nitrogen atoms

Question 15

*mechanism of action of azoles

Answer 15

nontoxic fungistatic; oral and IV admin; *inhibit ergosterol synthesis by blocking fungal CYP enzyme activity (lanosterol 14-alpha-demethylase); *impair fungal cell membrane synthesis

Question 16

How do azoles show selective toxicity?

Answer 16

affect fungal CYPs to a greater extent than mammalian CYPs; **imidazoles are much less specific for fungal CYPs than are triazoles

Question 17

Which azole is used prophylactically in immunocompromised patients?

Answer 17

fluconazole

Question 18

What is glucan?

Answer 18

a complement of peptidoglycan in bacteria for fungi; gives rigidity to the yeast membrane

Question 19

mechanism of action of caspofungin

Answer 19

inhibits glucan synthesis; osmotic shock/lysis so yeast explode