Title: Antifungal agents

Introduction

The development of antifungal agents has lagged behind that of antibacterial agents. This is a
predictable consequence of the cellular structure of the organisms involved. Bacteria are
prokaryotic and hence offer numerous structural and metabolic targets that differ from those of
the human host. Fungi, in contrast, are eukaryotes, and consequently most agents toxic to fungi
are also toxic to the host. Furthermore, because fungi generally grow slowly and often in
multicellular forms, they are more difficult to quantify than bacteria. This difficulty complicates
experiments designed to evaluate the in vitro or in vivo properties of a potential antifungal
agent.
Despite these limitations, numerous advances have been made in developing new antifungal
agents and in understanding the existing ones. This chapter summarizes the more common
antifungal agents. Three groups of drugs are emphasized: the polyenes, the azoles, and one
antimetabolite.
Definition
 An antifungal agent is a drug that selectively eliminates fungal pathogens from a host
with minimal toxicity to the host or
 Antifungal drugs are those drugs which inhibit or retard fungal growth.

Sites of action of antifungal drugs

SITE OF ACTION DRUGS drugs

Cell membrane
Ergosterol binding Amphotericin B, Natamycin and
Nystatin
Ergosterole synthesis inhibitors Allylamines (Amorolfine,Terbinafine etc.)
(Squalene, epoxidase inhibitor)
Ergosterol synthesis inhibitors(lanosterol Azoles (Ketoconazole, Miconazole etc.)
to ergosterol)
Cell wall
β glucan synthase inhibitor Echinocandins
Intracelluler
Pyrimidine analogue Flucytosine
Mitotic inhibitors Gresiofulvin
Other sites Benzoic acid , salicylic acid, tolnaftate,
castor oil etc.

 The antifungal drugs fall into two groups:

 antifungal antibiotics and
 synthetic antifungals.

Antifungal antibiotics
1. Amphotericin B
 Source – Streptomyces nodosus
 Mechanism of action – Increases permeability of cell membrane by binding to
ergosterol
 Antimicrobial spectrum – broad spectrum
 Resistance – when less ergosterol in membrane
 Pharmacokinetics – poorly absorbed from GIT, do not cross BBB
 Adverse effects - Nephrotoxicity
 Drug interaction :
a. with miconazole antagonistic effect
b. with flucytosine synergistic effect
 Dose – Dog -0.25 to 0.50 mg/kg, 3 times weekly
 Cat – 0.1 to 0.50 mg/kg, 3 times weekly
2.Nystatin
 Source – Streptomyces noursie
-Streptomyces aureus
 Mechanism of action –It binds to ergosteol and forms pores in cell membrane
3.Natamycin
 Source - Streptomyces natalensis.
  Mechanism of action –Binds to ergosterol and cause leakiness of cell
membrane.
4. Griseofulvin
 Source – Penicillium griseofulvinum
 Mechanism of action – inhibit mitosis by interfering spindle fiber
Formation.
 Resistance – due to reduced drug uptake
 Pharmacokinetics – low water solubility, bind with keratin layer
 Adverse effects – in cat leucopenia, neurotoxicosis and increased hepatic
enzyme activity, avoid in pregnant animals
 Drug interaction – not used with phenobarbitone and warfarin,
hepatotoxic with ketoconazole
 Synthetic Antifungal Agents
1. Flucytosine
 Mechanism of action :
1. It is converted to 5 furouracil which inhibit thymidylate synthetase enzyme
2. It inhibits transcription as 5FUTP( 5 flurouracil ribose triphosphate)
 Adverse effects:
 Bone marrow depression, convulsion in cat, alopecia in dog
 Not to be given in pregnant animal
 Clinical Use: Active against Cryptococcus neoformans, some Candida species, and the
dematiaceous molds that cause chromoblastomycosis.
 Drug interaction:
 Flucytosine + Amphotericin B show synergistic effect
 Not combined with immunosuppresent drugs
2.Azoles
 The antifungal activity of azole drugs results from the reduction of ergosterol synthesis
by inhibition of fungal cytochrome P450 enzymes.
 Azoles are synthetic compounds that can be classified as imidazoles and triazoles.
The imidazoles consist of
 ketoconazole,
 miconazole, and
 clotrimazole.
The triazoles include :
 itraconazole and
 fluconazole.
 Imidazoles
Ketoconazole
 Inhibit steroid synthesis in host
 Absorbed at acidic pH, so antacids will lower the drugs absorption when taken orally.
  Use : Ketoconazole is used in treatment of mucocutaneous candidiasis and
nonmeningeal coccidioidomycosis. It is also used in the treatment of seborrheic
dermatitis and pityriasis .versicolor (Topical/ shampoo).
 Dose :
Dogs – 5 to 20 mg/kg, 2 times daily
Cats – 5 to 20 mg/kg, 2 times daily
Clotrimazole and miconazole
 Clotrimazole and miconazole are available over-the-counter and are often used for
vulvovaginal candidiasis.
 Oral clotrimazole troches are available for treatment of oral thrush and are a
pleasant-tasting alternative to nystatin.
 In cream form, both agents are useful for dermatophytic infections, including tinea
corporis, tinea pedis, and tinea cruris.
 Absorption is negligible, and
 adverse effects are rare.

 Triazoles
Itraconazole
 Itraconazole is available in an oral formulation
 its absorption is increased by food and by low gastric pH.
 Undergoes extensive hepatic metabolism.
 Itraconazole is the azole of choice in the treatment of dermatophytoses and
onychomycosis and is the only agent with significant activity against Aspergillus species.
Fluconazole
 Fluconazole has good cerebrospinal fluid penetration.
 Can be given by the intravenous or the oral route.
 Fluconazole has the least effect on hepatic microsomal enzymes. Thus, has a wide
therapeutic window.
  Fluconazole is the azole of choice in the treatment and secondary prophylaxis of
cryptococcal meningitis. It is also effective for mucocutaneous candidiasis.
3.Terbinafine
 Synthetic allylamine antifungal agent
 Terbinafine inhibits ergosterol synthesis by inhibiting squalene epoxidase, (an enzyme
that is part of the fungal cell membrane synthesis pathway).
 DoseDog and cat – 3 to 10 mg/kg, once daily
4.Amorolfine
 Amorolfine inhibits enzymes, which depletes ergosterol and causes ignosterol to
accumulate in the fungal cytoplasmic cell membranes.
5.Benzoic acid and salicylic acid
 In combination are used as antifungal ointment known as “Whitfield’s ointment”.
Other antifungal drugs
Castor oil
 Has an organic unsaturated fatty acid Undecylenic acid which acts against fungal skin
infections.
 Mechanism of action is unknown
Tolnaftate
 Inhibits ergosterol biosynthesis
 Combined with salicylate because poor penetration
iodides
 It is the first antifungal agent
 Mechanism of action – not known, may cause enhanced immune response and leading
to fungus removal.
lufenuron
 Mainly used in flea treatment because inhibit chitin synthesis in larval forms.
 Due to ability to inhibit chitin formation used against fungal infections
Propionic acid
 Topical antifungal agent
 Used as 0.1 to 1% solution
Antimetabolite
 Antimetabolites are drugs that interfere with one or more enzymes or their reactions
that are necessary for DNA synthesis.
 They affect DNA synthesis by acting as a substitute to the actual metabolites that would
be used in the normal metabolism (for example antifolates interfere with the use of folic
acid).

Some other antifungal drugs include

 Gentian violet
 Sulphur
 Copper sulfate
 Cliquinole
 Dichlorophen
 Ciclopirox etc.
 Summery

References

 Medical Microbiology. 4th edition(Antifungal Agents,byDennis M. Dixon and Thomas

J.Walsh)
 Pharmacology lecture notes for Health Science Students(EPHTI,THE CARTER CENTER)
 Antifungal drugs ( notes Prepared byDr Arpita Shrivastav asst.professor veterinary
college rewa).