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Flashcards in Antifungals Deck (34):
1

What are the two main types of pathogenic fungi?

Filamentous fungi

Yeasts

Some are dymorphic (exist in both forms)

2

What are the 5 main antifungal targets?

DNA synthesis

Mitosis

Cell membrane: ergosterol

Protein synthesis

Cell wall: Beta-1,3-glucan

Protein synthesis

3

What is ergosterol?

Found mainly in fungal cell membranes
Forms clusters within the phospholipid bilayer
Has a role in the regulation of membrane permeability
Required for normal growth and function of the fungal cell wall, hence fungal viability

4

How is ergosterol biosynthesised?

Squalene is converted into Lanosterol by squalene epoxidase.
>
Lanosterol is converted into Ergosterol by Lanosterol 14a demethylase.

5

What are β-1,3-glucans?

Large polymers of UDP-glucose
50 ‑ 60% of the dry weight of the fungal cell wall
Form a fibrous network on the inner surface of the cell wall
Synthesized by β-1,3-glucan synthase

6

What are the 4 main classes of antifungals?

Polyenes
Allylamines
Azoles
Echinocandins

7

What is a polyene's mode of action?

Association with ergosterol
Formation of pore-like molecular aggregates
- Aqueous vs. non-aqueous pores
Loss of membrane integrity and leakage of K+
Cell death

8

Give 2 examples of polyenes

Amphotericin B
Nystatin

9

Amphotericin B can treat most fungi of medical importance. What are its adverse effects?

Allergic reactions
Nephrotoxicity
- Pores are formed in ergosterol-free membranes

10

How does lipid associated AmB reduce nephrotoxicity?

Delivery targeted to fungal cells and/or reticulo-endothelial system
Liver, spleen, lymph nodes

11

What are the clinical indications for Amphotericin B?

Serious/systemic infections
e.g. aspergillosis, candidiasis, cryptococcosis

Not absorbed orally
Administered parenterally
Not used, if possible, in patients with existing nephrotoxicity

12

What are the clinical indications for Nyastatin?

Superficial infections
e.g. oral/vaginal candidiasis

Not absorbed orally
Too toxic for systemic use

13

What is the mode of action of allylamines?

Inhibit ergosterol synthesis
- specifically squalene epoxidase

14

Give an example of an allylamine

Terbinafine

15

Terbinafine - adverse effects?

Liver toxicity
Jaundice, hepatitis – rarely fatal

16

What are allylamines used for?

Dermatophyte infections (superficial fungal infections)
Topical use
Athletes foot (tinea pedis), tinea corporis, tinea cruris
Systemic (oral) use
Scalp ringworm (tinea capitis), onychomycosis

17

What are azoles?

Synthetic compounds containing a 5-membered azole ring
Imidazoles
- Two nitrogen atoms
Triazoles
- Three nitrogen atoms

18

What is the mode of action of azoles?

Inhibit ergosterol synthesis
- Lanosterol 14α-demethylase
- Build up of non-ergosterol 14α-sterols in cell membrane

19

Properties of imidazoles and triazoles?

Imidazoles
- Toxic
- Rarely used systemically
-Ketoconazole
Triazoles
- Less toxic
- Systemic use common

20

Examples of imidazoles?

Clotrimazole
Miconazole
Ketoconazole

21

Examples of Triazoles?

Fluconazole
Itraconazole
Voriconazole
Posaconazole
Isavuconazole

22

What are the possible drug interactions with azoles?

Inhibition of cytochrome P-450 enzymes
- Increases concentration of all drugs metabolised by Cy P-450 enzymes

23

What are the clinical uses of azoles?

Imidazoles
Superficial infections (topical administration)
Candidiasis - Clotrimazole
Dermatophyte infections

Triazoles
Systemic infections (oral/parenteral administration)
- Aspergillosis (used in treatment and occasionally as prophylaxis)
- Candidiasis (fluconazole)

24

What is the mode of action of Echinocandins?

Mode of action
Inhibition of β-1,3-glucan synthase
Construction of severely abnormal cell wall

25

Name some examples of Echinocandins

Anidulafungin
Caspofungin
Micafungin

26

What is the spectrum of activity of echinocandins?

Aspergillus and Candida spp.
Misses certain moulds and Cryptococcus spp.

27

What are the adverse effects of Echinocandins?

Minimal
e.g. skin rash, nausea, vomiting, headache, diarrhoea in common with any other drug

28

What is the clinical use of Echinocandin?

Systemic infections
Parenteral formulations only (IV)

29

What is 5-fluorocytosine (5-FC)?

Synthetic analogue of cytosine
- Pyrimidine nucleoside

Developed as an anti-cancer drug
- Has no anti-cancer activity, but was found incidentally to have antifungal activity

30

What is the mode of action of 5-fluorocytosine (5-FC)?

Entry into cell requires fungal cytosine permease
- Selective toxicity
Converted to 5-fluorouracil and 5-fluorodeoxyuridine monophosphate
- Inhibit RNA/protein synthesis and DNA synthesis

31

What is the spectrum of activity of 5-fluorocytosine?

Yeasts only
Candida and Cryptococcus spp.

32

What are the adverse effects of 5-fluorocytosine?

Bone marrow suppression
- Selective toxicity is incomplete
- 5-fluorouracil (5FU) is an anti-cancer drug

33

What is the clinical use of 5-fluorocytosine?

Cryptococcal meningitis (in combination with AmB)

34

Which 3 antifungal drugs require Therapeutic Drug Monitoring? (TDM)

Itraconazole
5-fluorocytosine
Voriconazole