31. Antifungal agents

Question 1

What are 5 possible targets/mechanisms of action of antifungal drugs?

Answer 1

1. Inhibition of ergosterol synthesis (..fines + ..azoles)
2. Pore-forming agents (nystatin, natamycin, amph B)
3. Mitosis spindle disruption (griseofulvin)
4. Cell wall synthesis inhibition (..fungins)
5. DNA inhibition (flucytosine)

Question 2

Antifungal agents. Drug list

Answer 2

Terbinafin, Naftifine
Clotrimazole, Miconazole, Ketoconazole, Enilconazle, Bifonazole
Itraconazole, Fluconazole, Voriconazole, Posaconazole
Griseofulvin
Nystatin, Natamycin
Amphotericin B
Caspofungin, Micafungin, Anidulafungin

Question 3

Steps of ergosterol formation

Answer 3

Squalene —> Lanosterol —> Ergosterol

First reaction’s enzyme is squalene epoxidase - target of allylamines: terbinafine and naftifine

Second reaction’s enzyme is 14-alpha-sterol demethylase - target of azoles. Also is CYP family enzyme! Interactions!

Question 4

Terbinafine

Answer 4

• dermatomycosis + yeasts
• topically or orally
• accumulation in the skin (good and long effect)
• moderate hepatotoxicity (itra < terbinafine < keto)
• Naftifine is kinda same but only topically

Question 5

How do decide between local vs systemic application of antifungal drugs?

Answer 5

1. If no effect after several weeks of local (topical) application —> oral
2. Lots of lesions —> oral
3. Long hair animals —> oral

Question 6

Ketoconazole

Answer 6

• local or systemic use
• systemic use only in dogs
• broad spectrum against dermatophytes and yeasts
• CYP450 inhibition, hepatotoxicity

Question 7

How to treat Aspergillus infection?

Answer 7

1. In case of local intranasal irrigations: clotrimazole, enilconazole
2. In case of systemic infection (lungs are affected as well): voriconazole

Question 8

Itraconazole

Answer 8

• can be used systemically in cats
• mild hepatotoxicity
• also ok in birds

Posacomazole is a derivative of Itraconazole, used as ear drops.

Question 9

Which drug is a first choice treatment for systemic treatment of Aspergillosis?

Answer 9

Voriconazole

Question 10

Fluconazole

Answer 10

• was widely used systemically —> resistance (Candida!)
• orally / IV
• gastric pH independent absorption

Question 11

Griseofulvin

Answer 11

• inhibits mitotic spindles formation
• only against dermatophytes
• per os/spot on
• skin accumulation

Question 12

Which antifungal drugs act through pores formation?

Answer 12

Locally: nystatin (ear/orally (GIT fungi)), natamycin (eye/skin)
Systemically: amphotericin B

• mainly against yeasts
• severe nephrotoxicity!, cytokin storm

Question 13

Amphotericin B

Answer 13

• pores forming agent
• used IV in life-threatening conditions, cryptococcus meningitis with flucytosine
• SE: neprotoxic!, cytokine storm

Question 14

What antifungal agents target cell wall of fungi?

Answer 14

Echinocandins: caspofungin, micafungin, anidulafungin

• only parenteral
• Candida + Aspergillus
• very safe

Question 15

Why is it important to know which azoles are imidazoles (2N) and which are triangles (3N) ?

Answer 15

Imidazoles are applied locally (except Ketoconazole in dogs)
Triazoles are applied systemically (except posaconazole: ear drops)

Question 16

What antifungal drugs have skin accumulation feature?

Answer 16

Terbinafine and griseofulvin

Question 17

Is griseofulvin active against Candida?

Answer 17

No, griseofulvin only active against dermatophytes. Per os / spot on

Question 18

What antifungal drugs are NOT very good against dermatophytes?

Answer 18

Pore-forming agents (polienes): nystatin, natamycin, amphotericin B
And echinocandins

Question 19

Classification of fungi

Answer 19

1. Yeasts: Molassezia, Candida, Cryptococcus
2. Molds: dermatophytes belong here: Trychopgyton, Microsporum, Epidermophyton
3. Dimorphic fungi: Histoplasma, Blastomyces

Question 20

What does Molassezia cause very often?

Answer 20

Otitis externa, dermatitis