5 - Introduction to antifungal agents

Question 1

Types of fungi

Answer 1

Filamentous (e.g. on coffee)

Yeasts

Question 2

Antifungal targets

Answer 2

DNA synthesis
Mitosis
Cell wall B-1,3,-glucan
Cell membrane (ergosterol)
Protein synthesis

Question 3

Ergosterol info

Answer 3

Mainly in fungal cell membranes
Forms clusters within the phospholipid bilayer
Role in regulation of membrane permeability
Required for normal growth and function of the fungal cell wall, hence fungal viability

Question 4

Ergosterol biosynthesis

Answer 4

Squalene -> lanosterol (via squalene epoxidase) -> ergosterol (via lanosterol 14a demethylase)

Question 5

B-1,3-glucans info

Answer 5

Large polymers of UDP-glucose
50-60% dry weight of fungal cell wall
Fibrous network on the inner surface of the cell wall
Synthesised via B-1,3-glucan synthase

Question 6

Antifungal classes

Answer 6

Polyenes
Allylamines
Azoles
Echinocandins
Others

Question 7

Polyene mode of action

Answer 7

Association with ergosterol
Formation of pore-like molecular aggregates (aq. vs non-aq.)
Loss of membrane integrity and leakage of K+
Cell death

e.g. Amphotericin B, nystatin

Question 8

Amphotericin B info

Answer 8

Spectrum of activity - most fungi of medical importance, (most filamentous)
Adverse rxns: allergic reaction, nephrotoxicity - due to forming pores in non-ergosterol membranes

Question 9

Lipid-associated AmB info

Answer 9

AmB = amphoericin B
Way of targetting fungi and ignoring nephrotoxicity.
Liposomal AmB is the one used today.
Minimises delivery of AmB to kidney cells
Administered parenterally

Question 10

Nystatin clinical use

Answer 10

Not absorbed orally
Too toxic for systemic use
Superficial injection e.g. oral/vaginal candidasis

Question 11

Allylamines info

Answer 11

Terbinafine.
Athlete’s foot
Target: inhibit squalene epoxidase

Question 12

Terbinafine spectrum and adverse effects

Answer 12

Spectrum of activity = broad spectrum in vitro

Adverse effects inc. liver toxicity: jaundice, hepatitis

Question 13

Clinical use of terbinafine

Answer 13

Dermatophyte infections (superfical fungal infections) 
Topical use = athlete's foot, tinea corporis, tinea cruris
Systemic (oral) use = scalp ringworm (tinea capitis), onychomycosis

Question 14

Azoles

Answer 14

Synthetic compounds containing a 5-membered azole ring
Imidazoles = 2N atoms, toxic + rarely used
Triazoles = 3N atoms, less toxic, systemic use common

Question 15

Azoles mode of action

Answer 15

Inhibit ergosterol synthesis via lanosterol 14a-demethylase

Spectrum of activity = broad but complex
Yeast and filamentous except fluconazole/aspergillus

Question 16

Azoles adverse effects and drug interactions

Answer 16

Hepatotoxicity

Inhibits cytochrome P-450

Question 17

Azole clinical use

Answer 17

Imidazoles - superficial e.g. candidais, dermatophyte infections
Triazoles - systemic infections (oral/parental administration) aspergilliosis and candidiassis

Question 18

Echinocandins mode of action

Answer 18

Inhibit B-1,3-glucan synthase

Construction of severely abnormal cell wall

Question 19

Echinocandins specrum, adverse and clinical use

Answer 19

Aspergillus and candida
Misses certain moulds and cryptococcus
Adverse effects are minimal and standard
Clinical use = systemic infection

Question 20

5-fluorocytosine (5-FC) mode of action

Answer 20

Synthetic analogue of cytosine
Entry into cell requires fungal cytosine permease (selective toxicity) which inhibits RNA/protein synthesis and DNA synthesis

Question 21

5-fluorocytosine spectrum, adverse and clinical use

Answer 21

Yeasts only (candida and cryptococcus)
Adverse: bone marrow suppression
Clinical use: cryptococcal meningitis

Question 22

Griseofulvin mode of action, spectrum, adverse effects, clinical use

Answer 22

Inhibition of fungal mitosis

Spectrum: dermatophytes
Adverse: minimal
Clinical: dermatophye infections in children requiring systematic treatment