Antifungals Flashcards
What are the two main types of pathogenic fungi?
Filamentous fungi
Yeasts
Some are dymorphic (exist in both forms)
What are the 5 main antifungal targets?
DNA synthesis
Mitosis
Cell membrane: ergosterol
Protein synthesis
Cell wall: Beta-1,3-glucan
Protein synthesis
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
How is ergosterol biosynthesised?
Squalene is converted into Lanosterol by squalene epoxidase.
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Lanosterol is converted into Ergosterol by Lanosterol 14a demethylase.
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
What are the 4 main classes of antifungals?
Polyenes
Allylamines
Azoles
Echinocandins
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
Give 2 examples of polyenes
Amphotericin B
Nystatin
Amphotericin B can treat most fungi of medical importance. What are its adverse effects?
Allergic reactions
Nephrotoxicity
- Pores are formed in ergosterol-free membranes
How does lipid associated AmB reduce nephrotoxicity?
Delivery targeted to fungal cells and/or reticulo-endothelial system
Liver, spleen, lymph nodes
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
What are the clinical indications for Nyastatin?
Superficial infections
e.g. oral/vaginal candidiasis
Not absorbed orally
Too toxic for systemic use
What is the mode of action of allylamines?
Inhibit ergosterol synthesis
- specifically squalene epoxidase
Give an example of an allylamine
Terbinafine
Terbinafine - adverse effects?
Liver toxicity
Jaundice, hepatitis – rarely fatal
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
What are azoles?
Synthetic compounds containing a 5-membered azole ring Imidazoles - Two nitrogen atoms Triazoles - Three nitrogen atoms
What is the mode of action of azoles?
Inhibit ergosterol synthesis
- Lanosterol 14α-demethylase
- Build up of non-ergosterol 14α-sterols in cell membrane
Properties of imidazoles and triazoles?
Imidazoles
- Toxic
- Rarely used systemically
-Ketoconazole
Triazoles
- Less toxic
- Systemic use commonExamples of imidazoles?
Clotrimazole
Miconazole
Ketoconazole
Examples of Triazoles?
Fluconazole Itraconazole Voriconazole Posaconazole Isavuconazole
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
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)
What is the mode of action of Echinocandins?
Mode of action
Inhibition of β-1,3-glucan synthase
Construction of severely abnormal cell wall
Name some examples of Echinocandins
Anidulafungin
Caspofungin
Micafungin
What is the spectrum of activity of echinocandins?
Aspergillus and Candida spp.
Misses certain moulds and Cryptococcus spp.
What are the adverse effects of Echinocandins?
Minimal
e.g. skin rash, nausea, vomiting, headache, diarrhoea in common with any other drug
What is the clinical use of Echinocandin?
Systemic infections
Parenteral formulations only (IV)
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
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
What is the spectrum of activity of 5-fluorocytosine?
Yeasts only
Candida and Cryptococcus spp.
What are the adverse effects of 5-fluorocytosine?
Bone marrow suppression
- Selective toxicity is incomplete
- 5-fluorouracil (5FU) is an anti-cancer drug
What is the clinical use of 5-fluorocytosine?
Cryptococcal meningitis (in combination with AmB)
Which 3 antifungal drugs require Therapeutic Drug Monitoring? (TDM)
Itraconazole
5-fluorocytosine
Voriconazole
