Antifungal Agents intro

Question 1

What are the 2 types of pathogenic fungi?

Answer 1

• Filamentous fungi
• Yeasts
• Dimorphic can become both/either

Question 2

What is Ergosterol?

Answer 2

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

Question 3

How is Ergosterol synthesised?

Answer 3

• Squalene–> Lanosterol by squalene epoxidase

- Lanosterol–> Ergosterol by lanosterol 14a demethylase

Question 4

What are B-1,3-glucans?

Answer 4

• Large polymers of UDP-glucose
• Forms fibrous network on the inner surface of the cell wall
• Synthesised by B-1,3-glucan synthase

Question 5

What are the anti fungal classes of drugs?

Answer 5

• Polyenes
• Allylamines
• Azoles
• Echinocandins
• Others

Question 6

What is the mode of action for Polyenes and give examples

Answer 6

• Association with ergosterol
• Formation of pore-like molecules aggregates
• Loss of membrane integrity & leakage of K+=cell death
• Nystatin & Amphotericin B

Question 7

Describe Amphotericin B

Answer 7

• Spectrum of activity includes most fungi
• Aspergillus, Candida, Cryptococcus
• Adverse effects: allergic reactions, nephrotoxicity (pores formed in ergosterol membrane also formed in kidney cells)

Question 8

Why is lipid-associated Amphotericin B (AmB) used?

Answer 8

• minimises delivery to kidney cells

- Delivery targeted to fungal cells

Question 9

What are the clinical uses of Polyenes?

Answer 9

• Amphotericin B= not absorbed orally, administered parentally, serious/systemic infections, not used in patients with existing nephrotoxicity
• Nystatin= not absorbed orally, too toxic for systemic use, superficial infections (vaginal/oral candidiasis)

Question 10

What is the mode of action for Allylamines and give an example

Answer 10

• Inhibit ergosterol synthesis (squalene epoxidase)

- Terbinafine

Question 11

Describe Terbinafine and clinical uses

Answer 11

• Broad spectrum of activity
• Adverse effects: liver toxicity-jaundice, hepatitis, rarely fata
• Dermatophyte infections (superficial fungal infections)
• Topical use-Athletes foot
• Systemic use-oral-scalp ringworm

Question 12

What are Azoles?

Answer 12

• Synthetic compounds containing a 5-membered azole ring
• Imidazoles (2N atoms)
• Triazoles (3N atoms)

Question 13

What is the mode of action for Azoles and their spectrum of activity?

Answer 13

• Inhibit ergosterol synthesis by lanosterol 14a-demethylase
• Build up of non-ergosterol 14a sterol in cell membrane
• broad spectrum of activity against yeasts & filamentous fungi
• Execption: fluconazole/aspergillus

Question 14

Which Azole is toxic and which is commonly used systemically?

Answer 14

• Imidazoles=toxic

- Triazoles=systemic use common

Question 15

Give examples of Imidazoles & Triazoles

Answer 15

I=Clotrimazole

T=Fluconazole, Itraconazole, Voriconazole

Question 16

What are the adverse effects and drug interactions of Azoles?

Answer 16

• AE=Hepatotoxicity-mild liver enzyme abnormalities

- DI=inhibition of cytochrome P-450 enzymes, inc conc of all drugs metabolised by P-450

Question 17

What types of fungi are the following used for:
Fluconazole
-Itra/voriconazole
-Posa/isavuconazole

Answer 17

• F= yeasts
• I/V= yeasts & aspergillus
• P/I=yeasts, aspergillus & mucoraceous moulds

Question 18

What is the mode of action for Echinocandins? Give examples

Answer 18

• inhibition of B-1,3-glucan synthase leads to construction of severely abnormal cell wall
• Anidulafungin

Question 19

What is the adverse effects, clinical use and types of fungi targeted by Echinocandins?

Answer 19

SA= Aspergillus & candida, misses certain moulds and cryptococcus

• AD=minimal
• CU=systemic infections

Question 20

What is 5-Fluorocytosine?

Answer 20

• Synthetic analogue of cytosine

- Developed as an anti-cancer drug (has no anti-cancer activity but anti fungal activity)

Question 21

What is the mode of action for 5-fluorocytoine?

Answer 21

• Entry into cell requires fungal cytosine permease
• Converted to 5-fluorouracil & 5-fluorodeoxyuridine monophosphate
• Inhibits RNA/protein synthesis & DNA synthesis

Question 22

What is the clinical use, adverse effects and spectrum of activity for 5-fluorocytosine>

Answer 22

• SA=yeasts only
• AE= bone marrow suppression
• CU=crytpococcal meningitis (with AmB)

Question 23

What is the mode of action, spectrum of activity, clinical use for Griseofulvin?

Answer 23

• MA=inhibition of fungal mitosis
• SA=dermatophytes
• CU=dermatophyte infections children requiring systemic treatment

Question 24

Which anti fungal drugs require therapeutic drug monitoring?

Answer 24

• Itraconazole
• 5-fluorocytosine
• Voriconazole