ANTIFUNGAL AGENTS

Dr. Igor Khalin

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

FUNGAL INFECTIONS

• Yeast infections– Candida species– Cryptococcus neoformats

• Moulds (filamentous fungi)– Aspergillus sp.– Dermatophytes– Trichophyton– Microsporum

Infection disease caused by fungi called mycoses

• Major Types of Mycoses– superficial – cutaneous – subcutaneous – systemic– opportunistic

• Symptoms vary from cosmetic to life threatening

Antifungal agents

• Drugs used to treat fungal infection

– Systemic: amphotericin B, fluconazole, ketoconazole, itraconazole, caspofungin

– Topical: terbinafine, clotrimazole, grizeofulvin, nistatin

Antifungal agentsPolyene antibiotics– Nystatin – Amphotericin B

• Imidazoles and triazoles* =AZOLES– Ketoconazole Fluconazole *– Clotrimazole Itraconazole*– Mebendazole

• Allylamines– Terbinafine

• Echinocandins– Caspofungin

Mechanism of action

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

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

Amphotericin B

• A-Aspergillus• B-Blastomyces• C-Coccoides• C-Candida• C-Can not cross BBB

INTRATHECALLY

FLUCONAZOLE

Amphotericin B

• Adverse effects– “Shake and bake” (fever, chills), headache,

tachycardia, hypotension, muscle pain, anemia– Renal toxicity (Mg/K suppl), neural toxicity

(seizures, parestesias)

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

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

Ketoconazole• Drug interactions

– Inhibits CYP450• Adverse effects

– Alters synthesis of gonadal and adrenal steroid hormones

– Allergy– Dyspepsia– Anorexia– Gynecomastia– Impotence– Menstrual irregularities

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

Terbinafine

• Oral form is essential for the treatment of onychomycoses

• Cream of solution useful for skin infection

Mechanism of action

• Terbinafine inhibits squalene epoxidase of the fungi, which leads to decreasing of ergosterol synthesis

Terbinafine

• Has fungicidal action, mostly active against Trychophyton

• Half life from 200 to 400 hours• Adverse effects

– Dyspepsia– Rash– Neutropenia– Hepatotoxicity– Visual disturbances

Griseofulvin• Is fungistatic and used for dermatophytosis• Causes disruption of the

mitotic spindle, inhibitingmitosis

• Induces hepatic CYP450 activity

• Unwanted effects– Dyspepsia– Fatigue– Allergy