Antifungal Agents intro Flashcards
What are the 2 types of pathogenic fungi?
- Filamentous fungi
- Yeasts
- Dimorphic can become both/either
What is Ergosterol?
- 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
How is Ergosterol synthesised?
- Squalene–> Lanosterol by squalene epoxidase
- Lanosterol–> Ergosterol by lanosterol 14a demethylase
What are B-1,3-glucans?
- Large polymers of UDP-glucose
- Forms fibrous network on the inner surface of the cell wall
- Synthesised by B-1,3-glucan synthase
What are the anti fungal classes of drugs?
- Polyenes
- Allylamines
- Azoles
- Echinocandins
- Others
What is the mode of action for Polyenes and give examples
- Association with ergosterol
- Formation of pore-like molecules aggregates
- Loss of membrane integrity & leakage of K+=cell death
- Nystatin & Amphotericin B
Describe Amphotericin B
- Spectrum of activity includes most fungi
- Aspergillus, Candida, Cryptococcus
- Adverse effects: allergic reactions, nephrotoxicity (pores formed in ergosterol membrane also formed in kidney cells)
Why is lipid-associated Amphotericin B (AmB) used?
- minimises delivery to kidney cells
- Delivery targeted to fungal cells
What are the clinical uses of Polyenes?
- 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)
What is the mode of action for Allylamines and give an example
- Inhibit ergosterol synthesis (squalene epoxidase)
- Terbinafine
Describe Terbinafine and clinical uses
- 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
What are Azoles?
- Synthetic compounds containing a 5-membered azole ring
- Imidazoles (2N atoms)
- Triazoles (3N atoms)
What is the mode of action for Azoles and their spectrum of activity?
- 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
Which Azole is toxic and which is commonly used systemically?
- Imidazoles=toxic
- Triazoles=systemic use common
Give examples of Imidazoles & Triazoles
I=Clotrimazole
T=Fluconazole, Itraconazole, Voriconazole
What are the adverse effects and drug interactions of Azoles?
- AE=Hepatotoxicity-mild liver enzyme abnormalities
- DI=inhibition of cytochrome P-450 enzymes, inc conc of all drugs metabolised by P-450
What types of fungi are the following used for:
Fluconazole
-Itra/voriconazole
-Posa/isavuconazole
- F= yeasts
- I/V= yeasts & aspergillus
- P/I=yeasts, aspergillus & mucoraceous moulds
What is the mode of action for Echinocandins? Give examples
- inhibition of B-1,3-glucan synthase leads to construction of severely abnormal cell wall
- Anidulafungin
What is the adverse effects, clinical use and types of fungi targeted by Echinocandins?
SA= Aspergillus & candida, misses certain moulds and cryptococcus
- AD=minimal
- CU=systemic infections
What is 5-Fluorocytosine?
- Synthetic analogue of cytosine
- Developed as an anti-cancer drug (has no anti-cancer activity but anti fungal activity)
What is the mode of action for 5-fluorocytoine?
- Entry into cell requires fungal cytosine permease
- Converted to 5-fluorouracil & 5-fluorodeoxyuridine monophosphate
- Inhibits RNA/protein synthesis & DNA synthesis
What is the clinical use, adverse effects and spectrum of activity for 5-fluorocytosine>
- SA=yeasts only
- AE= bone marrow suppression
- CU=crytpococcal meningitis (with AmB)
What is the mode of action, spectrum of activity, clinical use for Griseofulvin?
- MA=inhibition of fungal mitosis
- SA=dermatophytes
- CU=dermatophyte infections children requiring systemic treatment
Which anti fungal drugs require therapeutic drug monitoring?
- Itraconazole
- 5-fluorocytosine
- Voriconazole
