1. Antifungal agents Flashcards by Eleanor Barnard

What are fungi?

A group of spore-producing organisms feeding on organic matter.
-includes moulds, yeasts, mushrooms.

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How do fungi differ in size from bacteria and viruses?

Fungi are generally larger

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What are the 2 main pathogenic classifications of pathogenic fungi?

Yeasts
Filamentous fungi

NB. some are dimorphic (exist in both forms)

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How do filamentous fungi divide?

Spore-production

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How do yeasts divide?

Budding

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What is the difference in the structures of filamentous fungi and yeasts?

FILAMENTOUS FUNGI = hair-like structures

YEASTS = large, oval structures

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Give 3 examples of dimorphic fungi.

Histoplasma spp (»Endemic mycoses)
Candida albicans
Malasezzia spp.

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Give an example of a condition caused by filamentous fungi.

Athlete’s foot

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Give an example of a condition caused by yeasts.

Thrush (candida albicans)

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What is an important feature for antifungal targets?

Selective toxicity - don’t cause harm to humans.

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What is ‘Pneumocystis jirovecii’?

Yeast&raquo_space; pneumonia

especially in immunosupressed

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What types of cells do fungi contain? What problem does this cause for antifungal targets?

Eukaryotic

-more similar to human cells, so makes selective toxicity harder

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What are the main targets for antifungals, and why?

CELL WALL (humans don’t have one)
CELL MEMBRANE (different composition to humans)
DNA/PROTEIN SYNTHESIS

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What is a fungal cell wall composed of?

B-1,3-glucans

not peptidoglycan like bacteria

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What do fungal cell membranes contain instead of cholesterol?

Ergosterol

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What is the function of ergosterol in fungal cell membranes?

Forms clusters in phospholipid bilayer
»regulates membrane permeability
»required for normal growth & function of cell wall

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What is the process of ergosterol biosynthesis?

SQUALENE &raquo_space; LANOSTEROL &raquo_space; ERGOSTEROL

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What are the enzymes involved in ergosterol synthesis? (2)

Squalene epoxidase

Lanosterol 14a demethylase

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How do antifungal agents act on ergosterol synthesis?

Inhibit the enzymes involved

squalene epoxidase & lanosterol 14a demethylase

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What is B-1,3-glucans?

Large polymer of UDP-glucose&raquo_space; fibrous nerwork of fungal cell wall

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What is B-1,3-glucans synthesised by?

B-1,3-glucan synthase

antifungal target

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What are the 4 classes of antifungals?

Polyenes
Allylamines
Azoles
Echinocandins
(Other; 5-fluorocytosine, griseofulvin)

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What is the mode of action of polyenes?

Association with ergosterol
» forms pore-like aggregates
» loss of membrane integrity & K+ leakage
» cell death

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Give 2 examples of polyenes.

Amphotericin B

Nystatin

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What is nystatin used for?

Superficial infections (eg. thrush) - too toxic for systemic use - not orally absorbed

What is the spectrum of Amphotericin B?

Broad spectrum - most fungi

What are the adverse effects of Amphotericin B?

- Allergic reactions | - Nephrotoxicity (>>pores in human membranes)

What type of Amphotericin B is now used and why?

Lipid-associated AmB | eg. liposomal AmB - reduced nephrotoxicity

How is Amphotericin B clinically used?

Administered parenterally for serious/systemic infections (eg. pulmonary aspergillosis). -not absorbed orally

When should Amphotericin B be avoided?

With patients with existing nephrotoxicity

What is the mode of action of allylamines?

Inhibit ergosterol synthesis | -squalene epoxidase

Give an example of an allylamine.

Terbinafine

What is the spectrum of activity of Terbinafine (allylamine)?

Broad spectrum in vitro

What are possible adverse effects of Terbinafine?

Liver toxicity | >>jaundice, hepatitis

What are allylamines used to treat?

DERMATOPHYTE (superficial fungal) infections - topcial (eg. Athletes foot) - systemic (eg. scalp ringworm)

What are azoles?

Synthetic compounds containing a 5-membered azole ring.

What are the 2 types of azoles, and how do they differ?

IMIDAZOLES - 2 nitrogen atoms | TRIAZOLES - 3 nitrogen atoms

What is the mode of action of azoles?

Inhibit ergosterol synthesis (lanosterol 14a-demethylase) | >> build up of non-ergosterol 14a-sterols in membrane

What is the spectrum of activity in azoles?

Complex/variable. - mainly broad - exceptions; fluconazole >> Aspergillus spp.

Which azoles are less toxic, and commonly used systemically?

Triazoles | not imidazoles

Give an example of an imidazole.

Clotrimazole

Give 3 examples of triazoles.

Fluconazole Itraconazole Voriconazole

What are possible adverse effects of azoles?

HEPATOTOXICITY - mild liver enzyme abnormalities (fluconazole) - life-threatening hepatitis (ketoconazole - rare)

What drug interactions do azoles have?

Inhibition of cytochrome P-450 enzymes. | -increases concentration of drug metabolised by it

Rank the following in order of their antifungal spectrum: - Itraconazole/voriconazole - Fluconazole - Posaconazole/ isavuconazole

NARROW >> BROAD: - Fluconazole - Itraconazole/voriconazole - Posaconazole/ isavuconazole

What are imidazoles used for clinically?

Superficial infections (topical) - candidiasis - dermatophyte infections

What are triazoles used for clinically?

Systemic infections (oral/parenteral) - Aspergillosis - Candidiasis

What is the mode of action of echinocandins?

Inhibit B-1,3-glucan synthase | >>abnormal cell wall

Give 3 examples of echinocandins.

- Anidulafungin - Caspofungin - Micafungin

What is the spectrum of activity of echinocandins?

Aspergillus & Candida spp. | -Not Cryptococcus spp

What are possible adverse effects of ecinocandins?

Minimal | -eg. skin rash, nausea, headache

What are ecinocandins used for clinically?

Systemic infections | -parenteral only

What is 5-fluorocytosine (5-FC)?

Synthetic analogue of cytosine | -pyrimidine nucleoside

What was 5-fluorocytosine developed as, and what is it now used as?

Developed as an anti-cancer drug | -now used as an antifungal

What is the mode of action of 5-fluorocytosine?

Enters cell with fungal cytosine permease (selective toxicity) >> converted to 5-fluorouracil & 5-fluorodeoxyuridine monophosphate >> inhibits RNA/protein synthesis & DNA synthesis

What is the spectrum of activity of 5-fluorocytosine?

Yeasts only | -Candida & Cryptococcus spp.

What are the possible adverse effects of 5-fluorocytosine?

Bone marrow suppression | -selective toxicity is incomplete

What is 5-fluorocytosine used for clinically?

Cryptococcal meningitis | in combination with AmB

What is the mode of action of Griseofulvin?

Inhibits fungal mitosis.

What is the spectrum of activity of Griseofulvin?

Dermatophytes

What are the possible adverse effects of Griseofulvin?

Minimal

What is Griseofulvin used for clinically?

Dermatophyte infections in children - eg. kerion - NB. only agent licensed for scalp infection in children

What is therapeutic drug monitoring?

Measuring drug concentrations in blood.

What is the purpose of therapeutic drug monitoring?

- Minimise toxicity | - Maximise efficacy

Which antifungal drugs require therapeutic drug monitoring? (3)

- ITRACONAZOLE (make sure it doesn't decrease too much) - 5-FLUOROCYTOSINE (bone marrow toxicity if too high) - VORICONAZOLE (liver toxicity when too high)