4 Antifungals

Question 1

What are the subclassifications of fungi?

Answer 1

Filamentous (form mycelium from hyphae).
Yeasts.
Dimorphic.
(and pneumocystis jiroveci)

Question 2

What is the main component in the lipid membrane of fungi? What does it do?

Answer 2

Ergosterol. Forms clusters. Regulates membrane permeability.

Question 3

How is ergosterol synthesised?

Answer 3

Squalene -> squalene epoxidase -> lanosterol -> lanosterol 14 alpha demethylase -> ergosterol

Question 4

What forms the majority of a fungal cell wall and how is it made?

Answer 4

Beta-1,3-glucans. A polymer of UDP-glucose. Forms fibrous network. Synthesised by Beta-1,3-glucan synthase.

Question 5

What are the five classes of antifungals?

Answer 5

Polyenes. 
Allylamines.
Azoles.
Echinocandins.
Others.

Question 6

What is the mode of action of polyenes? 2 examples.

Answer 6

Associate with ergosterol. Form pores, membrane loses integrity and leaks K+.

Amphotericin B and Nystatin.

Question 7

What are the adverse effects of Am B?

Answer 7

Allergic reactions.

Severe (but reversible) nephrotoxicity.

Question 8

What are the formulations of ApB and why do they exist?

Answer 8

Liposomal AmB (L-AmB)
AmB lipid complex (ABLC)
AmB colloidal dispersion (ABCD)

Minimise delivery of AmB to kidney cells.

Question 9

How is AmB used clinically?

Answer 9

AmB - parenterally for systemic infections (aspergillosis, cryptococcosis, candidiasis).

Question 10

How is Nystatin clinically used?

Answer 10

Too toxic for systemic use.

Superficial infections - candidiasis.

Question 11

How do Allylamines function? 1 example.

Answer 11

Inhibit ergosterol synthesis via squalene epoxidase.

Terbinafine.

Question 12

Adverse effects of Allylamines?

Answer 12

Liver toxicity

Question 13

Clinical use of Allylamines?

Answer 13

Dermatophyte infections.
Oral: scalp ringworm, onychomycosis
Topical: athletes foot, tine corporis/cruris

Question 14

How are azoles structured?

Answer 14

Synthetic compounds containing 5-membered azole ring.

Imidazole’s: 2 N’s
Triazoles: 3N’s

Question 15

How do azoles work?

Answer 15

Inhibit ergosterol synthesis via Lanosterol 14alpha demethylase.

Question 16

1 imidazole example.

3 triazole examples.

Answer 16

Clotrimazole.

Fluconazole, Itraconazole, Voriconazole.

Question 17

Adverse effects of azole use.

Answer 17

Hepatotoxicity.
Life threatening hepatitis (1/10,000)
Inhibition of cytochrome P-450 enzymes.

Question 18

What are azoles clinically used for?

Answer 18

Imidazoles: superficial infections (candidiasis).
Triazoles: systemic infections (aspergillosis, candidiasis).

Question 19

Which azole only works against yeasts?

Answer 19

Fluconazole

Question 20

How do echinocandins work? 1 example.

Answer 20

Inhibit beta-1,3-glucan synthase. Severley abnormal cell wall constructed.

Anidulafungin.

Question 21

What are the adverse effects of echinocandins?

What do they work against?

Answer 21

Minimal.

Aspergillus and Candida.

Question 22

What is the structure of 5-fluorocytosine?

How is it selectively toxic?

Answer 22

Synthetic analogue of cytosine.

Requires fungal cytosine permease enzyme.

Question 23

How does 5-fluorocytosine work?

Answer 23

Converted to 5-florouracil and 5-fluorodeoxyuridine.

Inhibits RNA/protein synthesis.

Question 24

What are the adverse effects of 5-fluorocytosine?

Answer 24

Bone marrow suppression (developed as an anti-cancer drug).

Question 25

What is 5-fluorocytosine clinically used for?

Answer 25

Cryptococcal meningitis (with AmB).

Question 26

How does Griseofulvin work and what is it used for?

Answer 26

Inhibition of fungal mitosis.

Used for dermatophyte infections requiring systemic treatment.

Question 27

Which fungal drugs require therapeutic monitoring and why?

Answer 27

Itraconazole (needs to b above).
5-fluorocytosine (needs to be below).
Voriconazole (for both reasons).