Antifungal Drugs Targets of

Action

Drugs targeting the Sterol content of Fungal cell

membrane

Glucan Synthesis

Inhibitor

DNA/RNA synthesis

Inhibitor

Mitotic Spindle

Formation Inhibitor

Drug

Classes

Polyene Antifungal Azole Antifungals Allylamines Echinocandins Antimetabolites Miscellaneous

Agents

Drugs

Amphotericin B

Nystatin

Ketoconazole

Fluconazole

Clotrimazole

Terbinafine Caspofungin Flucytosine Griseofulvin

Antifungal Therapy

Systemic Fungal Infection Topical Fungal Infection Azole

Fluconazole

Azole

Itraconazole

Polyene Antifungal

Amphotericin B

Polyene Antifungal

Nystatin

Allyamines

Terbinafine

Allyamines

Terbinafine

Echinocandins

Caspofungin

Miscellaneous Agents

Undecylenic Acid

Drugs targeting the Sterol content of Fungal cell membrane

Polyene Antifungals

Drugs Pharmacokinetics Mechanism of Actions Indications Adverse Effects

Amphotericin B

Absorption

Poorly absorb orally

Lipid preparation is administered IV

o Nystatin never given IV, it’s too

Nephrotoxic

Distribution

90% bound to plasma protein

Distributed widely inside the body

compartment, but negligible

amount passes the BBB

Metabolism

Hepatic metabolism

o Drugs interaction

Excretion

Urine

Binds to Fungal Ergosterol in the Cell

Membrane

o Leads to depolarization of cell

membrane

o Formation of pores making it

permeable for

Monovalent and Divalent

Cation

Protein

o Consequently leading to cellular

death

It induces Oxidative stress on the

Fungus

Yeast

Candida spp

Cryptococcus

Endemic Mycoses

Histoplasma spp

Blastomyces spp

Coccidiodes spp

Pathogenic Mold

Aspergillus spp

Induce inflammatory response

by stimulating Monocytes to

release cytokine

o Fever

o Chills

o Rigor

o Nausea

o Vomiting

o Myalgias

o Arthralgia

Higher concentration

(Amphotericin B) will lose

selectivity towards human’s

Cholesterol

o Nephrotoxicity Nystatin

Yeast

Candida spp

Cryptococcus spp

Pathogenic Mold

Aspergillus spp

Azole Antifungals Systemic Mycoses

Ketoconazole

o Toxic

o Less

effective

Itraconazole

Fluconazole

Superficial/Cutane

ous Mycoses

Clotrimazole

Absorption

Good absorption upon oral

admin

Distribution

Well distributed across body

compartment

Metabolism

Hepatic metabolism

CYP450 Inhibitor

Excretion

Urine

Inhibits fungal 14a – Demethylase

(Fungal CYP450 dependent enzyme)

o Inhibits the synthesis of Ergosterol

Depletes Ergosterol

concentration in the cell

membrane

Increase cell membrane

permeability

o Accumulation of toxic intermediate

sterol

Inhibit fungal growth

Yeast

Candida spp

Cryptococcus

Endemic Mycoses

Histoplasma spp

Blastomyces spp

Coccidiodes spp

GIT upset

Hepatitis (very rare)

Relatively safe drug

Drug Drug Interactions

Inhibits human Demethylase in

high concentration

o Gyneacomastia

CYP450 inhibitor

o Increase level of

Phenytoin

Cyclosporine

Allylamines

Terbinafine

Absorption

Absorb quite well from GIT

Distribution

Keratophilic

o Deposited in the skin

o Prevent future infection

Metabolism

Hepatic metabolism

Excretion

Urine

Inhibit Ergosterol synthesis by

inhibiting Squalene Epoxidase

Accumulation of Squalene

Epoxide in the Fungus which is

toxic

Fungicidal

Mucocutaneous

Infection

Candida spp

Aspergillus spp

GIT upset

Headache

Bad taste upon oral

admin

Relatively safe drug

Glucan Synthesis Inhibitor

Echinocandins

Drugs Pharmacokinetics Mechanism of Actions Indications Adverse Effects

Caspofungin Absorption

Poorly absorb orally

Given in slow IV infusion within 1 hour

Distribution

97% bound to plasma protein

Metabolism

Unknown

Excretion

Unknown

Block the cell wall synthesis by

inhibiting 1.3-b-Glucan

Synthase activity

o Depletion of Beta Glucan

polymers in the Fungal cell

wall

o Weakened cell wall unable

the cell to withstand

osmotic stress

Candida

infection

Highly safe drugs

DNA/RNA Synthesis Inhibitor

Antimetabolites 5-Fluorocytosine

(5-FC/

Flucytosine)

Absorption

Very well absorb upon oral admin

Distribution

Distributed in all body compartments

including the CSF

Poorly plasma protein bound

Metabolism

Unknown

Excretion

Urine

Transported into fungal cytoplasm

by Cytosine Permease

Then converted into 5-FU

(anticancer) by Cytosine

Deaminase in the cytoplasm

The 5-FU is then phosphorylated

and at the end inhibit the RNA

and DNA function

Cryptococcus

neoformans

Candida spp

Can be metabolise into 5-

FU by bacteria residing

the GIT, this will lead to

chemotoxic effect

Thrombocytopenia

Leukopenia

Anemia

GIT upset

Vomiting

Mitotic Spindle Formation Inhibitor

Miscellaneous Group of Antifungal Drugs Griseofulvin Absorption

Very absorb upon oral admin

Improve if taken with fatty foods

Distribution

Keratophilic

o Deposited in the skin

o Prevent future infection

Metabolism

Hepatic metabolism

Excretion

Urine

Inhibit the formation of

mitotic spindle

o Inhibit the growth of

fungus through disrupting

Mitosis

Ring worms

infection

GIT upset

Confusion

Fatigue

Headache