Intro to antifungal agents Flashcards
Name the 2 (/3) main types of fungi?
1) Filamentous fungi (moulds)
2) Yeats
3) Also have dimorphic fungi which exist in both forms
Name the 5 main antifungal targets?
1) DNA synthesis
2) Mitosis
3) Cell wall: beta -1-3-glucan
4) Cell membrane: ergosterol
5) Protein synthesis
Why is ergosterol a good target for anti fungal agents?
Humans don’t have ergosterol in cell membranes (we have cholesterol) so reduces toxicity to humans
Why is beta-1-3-glucan that makes fungal cell walls a good target for anti fungal agents?
Humans don’t have cell walls so no toxicity to humans
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 membrane, hence fungal viability
What are the 2 relevant steps in ergosterol biosynthesis (including enzymes)?
1)Squalene -> Lanosterol
Enzyme = squalene epoxidase
2) Lanosterol -> Ergosterol
Enzyme = lanosterol 14a demethylase
What are Beta-1-3 glucans?
Large polymers of UDP glucose
Make up 50-60% of dry weight of fungal cell wall
Forms a fibrous network on the inner surface of the cell wall
Synthesised by Beta-1-,30glucan synthase
What are the 4 main classes of antifungal agents?
1) Polyenes
2) Allylamines
3) Azoles
4) Echinocandins
What is the mode of action of polyenes?
Association with ergosterol in a physical way, formation of pore-like molecular aggregates
Cause loss of membrane integrity and leakage of K+
Causes cell death
Give 2 examples of polyenes?
1) Amphotericin B
2) Nystatin
What is the spectrum of activity of Amphotericin B?
Most fungi of medical importance
What are the 2 main adverse effects of amphotericin B?
1) allergic reactions
2) nephrotoxicity (pores are formed in ergosterol-free membranes)
Why are lipid associated Amphotericin B formulations more commonly used that simply amphotericin?
Minimize delivery of AmB to kidney cells
Delivery is targeted to fungal cell and/or reticulo-endothelial system (liver, spleen, lymph nodes)
This reduces nephrotoxicity
When is amphotericin B used clinically and how?
Not absorbed orally so administered parenterally
Used in serious or systemic infections (such as aspergilllosis, candidiasis, cryptococcosis)
Not used, if possible in people with existing nephrotoxicity
When is nystatin used clinically and how?
Not absorbed orally and is too toxic for systemic use
Used in superficial infections (such as oral/vaginal candidiasis)
What is the mode of actions of Allylamines?
Inhibit ergosterol synthesis (inhibit squalene epoxidase)
Give one example of an allylamine?
Terbinafine
What is the spectrum of activity of allylamines (terbinafine)?
Broad spectrum of activity in vitro but in practise only used in one type of infection
What is the main adverse effect of allylamines?
Liver toxicity - jaundice, hepatitis - rarely fatal
What is the clinical use of allylamines?
Dermatophyte infections (superficial fungal infections)
1) Topical use: athletes foot (tinea pedis), tinea corporis, tinea cruris
2) Systemic (oral) use: scalp ringworm (tinea capitis), onychomycosis
What are azoles?
Synthetic compounds containing a 5-membered azole ring
Imidazoles have 2 N atoms
Triazoles have 3 N atoms
What is the mode of action of azoles?
Inhibit ergosterol synthesis
inhibit lanosterol 14a-demethylase leading to a build up of 14a-sterols in membrane
What is the spectrum of activity of azoles?
Complex, varies between drugs
Essentially broad spectrum - treat both yeasts and filamentous fungi
With the exceptions of fluconazole and aspergillus spp.
What is the toxicity and systemic use of imidazole and triazoles?
Imidazoles:
Toxic and rarely used systemically (ketoconazole)
Triazoles:
Less toxic, systemic use more common
Name the main imidazole in use?
Clotrimazole
Name the 3 main triazoles in use?
1) Fluconazole
2) Itraconazole
3) Voriconazole
What are the adverse effects of azoles? 2
1) Hepatotoxicity
- Mild liver enzyme abnormalities
- Life-threatening hepatitis
2) Drug interactions
- Inhibition of cytochrome P450 enzymes (increases concentration of all drugs metabolised by CP450 enzymes)
What is the spectrum of fluconazole (yeasts/aspergillus spp./mucoraceous moulds)?
Effective against yeasts
Not effective against Aspergillus spp. or mucoraceous moulds
What is the spectrum of Itraconazole/ voriconazole (yeasts/aspergillus spp./mucoraceous moulds)?
Effective against yeasts and aspergillus spp.
Not effective against mucoraceous moulds
What is the spectrum of posaconazole/ isavuconazole (yeasts/aspergilus spp./mucoraceous moulds)?
Effective against yeasts, aspergillus spp. and mucoraceous moulds
What is the clinical use of imidazoles (a type of azole)?
Superficial infections (topical administration)
Cadidiasis (canestan)
Dermatophyte infections
What is the clinical use of triazoles?
Systemic infections (oral/parenteral administration)
Aspergillosis (used in treatment and occasionally prophylaxis)
Candidiasis (fluconazole)
What is the mode of action of Echinocandins?
Inhibition of beta-1,3-glucan (used to make fungal cell walls)
Leads to construction of severely abnormal cell wall
Give 3 examples of Echinocandins?
1) Anidulafungin
2) Caspofungin
3) Micafungin
What is the spectrum of activity of echinocandins?
Apergillus spp and candida spp
Misses certain moulds and cryptococcus spp.
What are the adverse effects of echinocandins?
Minimal: eg. skin rash, nausea, vomiting, headache, diarrhoea in common with any other drug
What is the clinical use of echinocandins?
Systemic infections
Parenteral formulations only
What is 5-fluorocytosine (5-FC)?
Synthetic analogue of cytosine (a pyrimidine nucleoside)
Developed as an anti-cancer drug, has no anti-cancer properties but incidentally was found to have anti-fungal properties
What is the mode of action of 5-fluorocytosine, how does it show selective toxicity?
Entry into cell requires fungal cytosine permease (not found in humans so cant get into our cells - 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
When is 5-fluorocytosine used clinically?
To treat cryptococcal meningitis (in combination with AmB)
What are the 2 reasons for therapeutic drug monitoring?
1) To minimize toxicity - level should remain below a threshold value
2) To maximize efficacy - level should exceed threshold value
Why does itraconazole require therapeutic drug monitoring?
To maximize efficacy - has few side effects but their is a minimum level below which it doesnt work
Why does 5-fluorocytosine require therapeutic drug monitoring?
To minimize toxicity
Why does voriconazole require therapeutic drug monitoring?
To minimize toxicity AND to maximize efficacy
