ANTIFUNGAL AGENTS

Dr. R. Yogeswari, Ph.D.,

Assistant Professor,
Department of Veterinary Pharmacology and Toxicology,
Veterinary College and Research Institute,
Namakkal-2.
 LEARNING OBJECTIVES
Antifungal agents
 Classification

 Mechanism of action

 Spectrum

 Pharmacokinetics

 Side effects

 Clinical uses
 INTRODUCTION
 Fungi – Mould , Yeast and Dimorphic fungi
 INTRODUCTION
Fungal infections

 Superficial infection – keratinized skin layers and appendages–

Dermatophytes (Microsporum, Trichophyton and Epidermophyton),
infections of mucous membrane.

 Systemic infection – Candidiasis, Histoplasmosis, Cryptococcosis,

Aspergillosis etc.,
 INTRODUCTION
 Antifungal agents

Selection and use of antifungal drugs

 Clinical response

 Efficacy studies in animals

 CLASSIFICATION
I. Antifungal antibiotics
1. Polyenes – Amphotericin B, Nystatin, Natamycin
2. Heterocyclic Benzofurans – Griseofulvin
II. Antimetabolites - Flucytosine
III. Azoles
1. Imidazoles – Ketaconazole, Miconazole, Clotrimazole
2. Triazoles – Fluconazole, Itraconazole, Voriconazole
IV. Allylamines - Terbinafine
V. Echinocandins - Caspofungin
VI. Miscellaneous – Benzoic acid , Salicylic acid, Sulphur, iodides
 POLYENE ANTIFUNGAL AGENTS
Amphotericin B
 Streptomyces nodusus
 Fungicidal

Leakage of cellular content

Efflux of K+ and influx of H+ ions

Halts important enzymatic

processes in fungi Irreversible
cell damage
 Cont….
Spectrum:
 Systemic fungal infections (Candida, Histoplasma, Cryptococcus,
Blastomyces, Coccidioides, Aspergillus and Sporothrix spp.)

Resistance: Infrequent

Kinetics:
 Oral route – Poorly absorbed

 I/V route only

 Distribution - Uneven

 Eliminated unchanged in urine (20%) and faeces (45%).

 Cont….
Side effects:
 Renal function impairment – Vasoconstriction and binds to renal

tubular cell membrane.

 GI effects, anaemia and thrombophlebitis at injection site.

Use:
 Systemic fungal infection in cat, dog, horse and dog.

 Combined with flucytosine to reduce toxicity.

 Cont….
Nystatin:
 Streptomyces noursei

 High systemic toxicity

 Skin, oral, intestinal and vaginal candidiasis in dogs, cats and birds.
Thrush ?
Natamycin:
 Streptomycin natalensis

 Fungal keratits

 Both are fungicidal to yeast infection caused by Candida spp. and

Malassezia spp.
 GRISEOFULVIN
 Penicillium griseofulvum
 1939 – 1958
MOA:
Drug enters the cell through energy dependant
transport system

Interfere with polymerization of microtubules

Interfere with spindle formation

in dividing cells

Arrest the metaphase of the cell division

 Cont….
Spectrum:
 Narrow – only against dermatophytes.
Fungistatic

Resistance: Rare, decreased uptake of drug

Kinetics:
 Oral absorption – variable ( 25 – 100 %)
- Particle size (micronized / Ultramicronized)
- Fatty diet

 Metabolised in liver – Oxidation and glucuronide conjucation

 One half of the drug excreted as metabolites in urine and remainder as unchanged form in
faeces.
 Cont….
After absorption concentrated in skin, hair, nails

Drug binds to keratin precursor cells

Persist in new keratin

New growth of hair/ nails – free of fungal infections

Accompanied by shedding of older grown infected cells

Treatment
4-6 weeks for skin and
1 yr for toe/nails
infection
 Cont….
Side effects:
 GI disturbances, hepatotoxicity .
 Cats – Leucopenia, anaemia, teratogenic and carcinogenic.
 Along with ketoconazole - hepatotoxic

Microsomal enzyme inducer

Promotes biotransformation of concurrently administered drugs (eg: Warfarin)

Use:
Dermatophytic fungal infections in dogs, cats, calves and horses.
 ANTIMETABOLITE – 5-FLUCYTOSINE
 Fluorinated pyrimidine fungistatic antifungal agent
 Cont….
Spectrum:
 Narrow – Cryptococcus, Candida, Aspergillus and Sporothrix spp.

Resistance:
 Easily develop (lower cytosine deaminase level).
 Combination with amphotericin B - resistance

Kinetics:
 Oral absorption – completely absorbed
 Distributed widely (CNS, eye, joint)
 80 – 90% excreted in urine
Side effects:
Cont….
 Less toxic and well tolerated

 Bone marrow depression – renal disease patients

 GI signs and reversible hepatic effects.

 Teratogenic in laboratory animals.

Use:
 Cyptococcal meningitis - along with Amphotericin B

 Aspergillosis and Candidiasis in Psittacine birds.

 AZOLES
 Five membered heterocyclic compounds containing one or more
nitrogen atoms in the ring.
 Two subgroups : Imidazoles and Triazoles

Imidazoles
Triazoles
1. Ketoconazole
1. Fluconazole
2. Miconazole*
2. Itraconazole
3. Clotrimazole*
3. Voriconazole
4. Enilconazole*

 Fungistatic
 Cont….
Acetyl Co A

Squalene

Lanosterol
14 α – demethylase Azoles
Ergosterol

 Inhibition of ergosterol synthesis Altered membrane permeability

 IMIDAZOLES
Cont….
KETOCONAZOLE:
 Synthetic imidazole antifungal
 First azole given orally to treat systemic fungal infection

Spectrum:
 Broad –spectrum – Systemic mycosis and superficial Candidiasis and
dermatophyte infections.

Resistance:
 Altered steroid biosynthetic pathway
 MDR genes - reduce the levels of the drug
 Cont….
Other pharmacological effects:
 High oral dose – block testicular and adrenal androgen biosynthesis
- Weak androgen receptor antagonist.

Kinetics:
 Oral absorption - Variable (enhanced by acidic pH).
 Widely distributed.
 Metabolized in liver and excreted primarily in bile.

Side effects:
 GI disturbances and dose related hepatotoxicity
 Decrease libido and produce reproductive disorders.
 Teratogenic in laboratory animals.
 Cont….
Drug interactions:
 Inhibits cyp450 enzymes – Microsomal enzyme inhibitor
 Absorption decreased by concurrent administration of gastric antacids.

Clinical use:
 Systemic mycosis
 Superficial infections not responding to griseofulvin and other topical
antifungals.
MICONAZOLE: Cont….
 Primarily used as topical agent
 Penetrates well into the skin persist for 4 days in stratum cornium.
 Local dermatophytosis in dogs and cats / oral or vaginal thrush.

ENILCONAZOLE:
 Topical antifungal agent
 Nasal Aspergillosis
 Disinfect poultry equipments

CLOTRIMAZOLE:
 Topical antifungal agent
 Candidiasis, trichomoniasis and dermatophyte infections.
 TRIAZOLES
Cont….
 Triazoles have less effect on mammalian steroid synthesis than do imidazoles, longer half-
life and lower toxicity.

FLUCONAZOLE:
 Local and systemic Candida Spp. Systemic Cryptococcus, Histoplasma, Sporothrix and
Blastomyces spp. and dermatophytes.
 Well absorbed orally and well distributed.

 Also administered through IV route

 Excreted in urine and sweat.

 Side effects: Better tolerated than ketoconazole

 Not recommended in pregnant and lactating animals.

ITRACONAZOLE:
Cont….
 Local and systemic mycosis – broader spectrum
 Oral absorption – moderate to well (gastric acid increase absorption)
 Well distributed to body tissues and fluids.
 Metabolised in liver and excreted in faeces.
 First choice for dermatophyte infection in cats.
 Also shown efficacy against Malassezia dermatitis and refractory dermatophyte
infection.
 GI disturbances and dose dependant hepatotoxicity.

VORICONAZOLE: Invasive fungal infections

POSACONAZOLE: Otic fungal infections

ALLYLAMINES
 Terbinafine Cont….
 Active against yeast and wide range of dermatophytes

 Cidal against dermatophytes and static against yeast.

 Well absorbed orally and widely distributed.

 Metabolised in liver and excreted in urine (80%) and faeces (20%).

 Well tolerated and with few adverse effects.

 Used for dermatophyte infection in dogs, cats and birds and Malassezia yeast

infection.
 Butenafine
 Naftifine
 ECHINOCHANDINS
Inhibit synthesis of fungal cell wall - Penicillin of
antifungal drugs

Inhibit 1,3- β glucan

synthase enzyme
 Cont….
 Caspofungin

 Semi-synthetic lipopeptide drug - Glarea lozoyensis

 Only administered intravenously

 Used in the treatment of invasive candidiasis and aspergillosis.

 MISCELLANEOUS AGENTS
Benzoic acid:
 Bacteriostatic and fungistatic
 Trichophyton infection in cattle
Whitfield
Salicylic acid: ointment
 Keratolytic and fungistatic

Sulphur:
 Fungicidal, bactericidal, keratolytic and antipruritic

Copper sulphate:
 Fungicidal – Astringent and caustic

Iodide – Potassium iodide, povidone iodine

Sodium thiosulphate
SUMMARY
QUESTIONS ?
 Model Questions
1. Name the antifungal agent whose absorption is enhanced in the presence of fatty
diet ?

2. Which antifungal agent will enhance the toxicity of co-administered drugs by

inhibiting the microsomal enzyme ?

3. What is the drug of choice for thrush and fungal keratitis ?

4. What is the major side effect of amphotericin B ?

5. Name the antifungal agent that inhibit the mammalian steroid synthesis ?