This document discusses antifungal agents used to treat fungal infections. It describes the major types of fungi that cause disease and the different types of fungal infections. It then summarizes several classes of antifungal drugs including their mechanisms of action, spectrum of activity, and common adverse effects. These include polyenes like amphotericin B and nystatin, azoles like fluconazole and ketoconazole, echinocandins like caspofungin, and others like terbinafine, flucytosine, and griseofulvin.

1. ANTIFUNGAL AGENTS
Dr. Igor Khalin

2. Fungi
• Very large and diverse group of
microorganisms
• Broken down into yeast and molds
– Yeast is single cell organism, useful for baking
and alcohol beverages
– Molds are multicellular, characterized by long,
branching filaments called hyphae

3. FUNGAL INFECTIONS
• Yeast infections
– Candida species
– Cryptococcus neoformats
• Moulds (filamentous fungi)
– Aspergillus sp.
– Dermatophytes
– Trichophyton
– Microsporum

4. Infection disease caused by fungi
called mycoses
• Major Types of Mycoses
– superficial
– cutaneous
– subcutaneous
– systemic
– opportunistic
• Symptoms vary from cosmetic to life
threatening

5. Antifungal agents
• Drugs used to treat fungal infection
– Systemic: amphotericin B, fluconazole,
ketoconazole, itraconazole, caspofungin
– Topical: terbinafine, clotrimazole, grizeofulvin,
nistatin

6. Antifungal agents
Polyene antibiotics
– Nystatin
– Amphotericin B
• Imidazoles and triazoles* =AZOLES
– Ketoconazole Fluconazole *
– Clotrimazole Itraconazole*
– Mebendazole
• Allylamines
– Terbinafine
• Echinocandins
– Caspofungin

7. Mechanism of action

8. Amphotericin B
• Pharmacokinetics
– is an amphoteric polyene macrolide
– is insoluble in water
– is poorly absorbed from the GIT
– more than 90% bound by serum
proteins

9. Amphotericin B
• Mechanism of action
– Binds to sterols in the cell membrane lining
– Allow to K+ and Mg2+ to leak out, altering
fungal cell metabolism
– Result fungal cell death

10. Amphotericin B
• A-Aspergillus
• B-Blastomyces
• C-Coccoides
• C-Candida
• C-Can not cross BBB
INTRATHECALLY
FLUCONAZOLE

11. Amphotericin B
• Adverse effects
– “Shake and bake” (fever, chills), headache,
tachycardia, hypotension, muscle pain, anemia
– Renal toxicity (Mg/K suppl), neural toxicity
(seizures, parestesias)

13. Flucytosine (5-FC)
• Synthetic pyrimidine, used in
combination with amphotericin B
• Amphotericin B increases cell
permeability
• 5-FC forms false nucleotide
• Disrupts nucleic acid and protein
synthesis
• Bone marrow depression, dyspepsia,
hepatic dysfunction

14. Ketoconazole
• Mechanism of action
– Inhibits an enzyme, resulting
in cell wall leaking
– Blocks demethylation of
lanosterol to ergosterol
– Leads to altered cell
membrane (unstable)
– Result: fungal cell death
• Spectrum
– Both topical and oral
forms used for wide spectrum mycoses

15. Ketoconazole
• Drug interactions
– Inhibits CYP450
• Adverse effects
– Alters synthesis of
gonadal and adrenal
steroid hormones
– Allergy
– Dyspepsia
– Anorexia
– Gynecomastia
– Impotence
– Menstrual irregularities

16. Caspofungin
• Belongs to Echinocandis
• Inhibits β(1,3)-D-glucan synthesis
destroying cell wall, resulting in lysis and
cell death
• Effective mostly against Aspergillus and
Candida
• Second line drug
• Fever, rush, nausea and phlebitis are
common adverse reactions

17. Terbinafine
• Oral form is essential for the treatment of
onychomycoses
• Cream of solution useful for skin infection

18. Mechanism of action
• Terbinafine inhibits squalene epoxidase of
the fungi, which leads to decreasing of
ergosterol synthesis

19. Terbinafine
• Has fungicidal action, mostly active
against Trychophyton
• Half life from 200 to 400 hours
• Adverse effects
– Dyspepsia
– Rash
– Neutropenia
– Hepatotoxicity
– Visual disturbances

20. Griseofulvin
• Is fungistatic and used for dermatophytosis
• Causes disruption of the
mitotic spindle, inhibiting
mitosis
• Induces hepatic CYP450
activity
• Unwanted effects
– Dyspepsia
– Fatigue
– Allergy