This document discusses various antifungal drugs and their mechanisms of action. It describes Amphotericin B as a polyene antibiotic that binds to ergosterol in fungal cell membranes to form pores, and Griseofulvin as a heterocyclic benzofuran that disorients fungal microtubules. Key classes of antifungal agents are defined, and the pharmacology and uses of Amphotericin B and Griseofulvin are explained in detail.

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Faculty of Pharmacy
Anti Fungal Drugs
At the end of this lecture, the student will be able to:
• Classify anti-fungal drugs
• Describe the pharmacology of
– Amphotericin B
– Griseofulvin

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Faculty of Pharmacy
Contents
• Introduction to fungi
• Classification of antifungal agents
• Pharmacology of antibiotics as antifungal agents

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Faculty of Pharmacy
Introduction
• Fungal infections – Mycoses
• Fungi has rigid cell wall composed of Chitin (instead of
peptidoglycan)
• Cell membrane which contain ergosterol (rather than
cholesterol in mammalian membrane)

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Faculty of Pharmacy
Classes of Fungi
• Yeasts – produces by budding
– Cryptococcus neoformans (meningitis)
• Yeast – like fungi – grows like yeast & partly as filaments
(hyphae)
– Candida albicans (oral/ vaginal thrush, systemic
candidiasis)
– Pityrosporom orbiculare (Tinea vesicolor)

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• Moulds - filamentous spores
– Trichophyton species
– Microsporum species
– Epidermophyton species
– Causes infection in skin, nail and hair
• Dimorphic fungi
– Can grow in the form of yeast or filament
– Histoplasma capsulatum
– Blastomyces dermatidis
Classes of Fungi

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Faculty of Pharmacy
Classification of Antifungal Agents
Antibiotics
• Polyene antibiotics – Amphotericin B, Nystatin, Hamycin, Natamycin
• Heterocyclic benzofurans – Griseofulvin
Antimetabolites – 5- Flucytosine
Azoles
• Imidazole – Topical – Clotrimazole, Miconazole
– Systemic - Ketoconazole
• Triazoles – systemic – Fluconazole, Itraconazole
Allyl amines – Terbinafine
Miscellaneous (Topical) – Ciclopirox, Tolnaftate, Clioquinol ,
caspofungin

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Faculty of Pharmacy
©M. S. Ramaiah University of Applied Sciences
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Antifungal Agents - MOA

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Amphotericin-B
• Polyene group of antifungal antibiotics – obtained from
Streptomyces nodosus
• Has large number of double bonds
• Large lactone ring
• Amphoteric in nature- Hydroxyl rich part is polar & double
bond rich part is non polar
• Insoluble in water, unstable in aqueous medium

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Amphotericin B

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Amphotericin-B- MOA
• High affinity for ergosterol in fungi
• Binds to ergosterol and forms pores in cell membrane
• Forms pores, fungicidal in nature
• Vital constituents- macromolecules, K+, Na+, Mg2+, H+ leak out
• Pore formation characteristic of the amphoteric nature
• Hydrophobic site complexes with ergosterol outside the pore
• Polar portion makes a lining around the pore
• Great specificity for fungal cells because human cells have
cholesterol in the cell membrane, some binding which occurs
leading to toxicity
• Resistance- Replacement of ergosterol with other sterols in
fungal cell membrane, failure to penetrate the fungal cell

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Pharmacokinetics of Amphotericin-B
• Absorbed only in fungal stomach infection
• Not useful in systemic fungal infections by oral route, given by
iv infusion
• Wide distribution, except CSF
• Intrathecal – treatment of fungal infection in brain
• 90% protein bound, t1/2- 15d
• Binds to cholesterol of cell membrane, LDL, sterols in tissues
• Metabolism liver
• Excretion – biliary and urinary excretion, takes several days

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Formulations of Amphotericin-B
• Insoluble in water
• Formulated as a colloidal suspension with sodium desoxycholate
for iv infusion
• Liposomal Amphoterecin B- drug incorporated in small lipid
vesicles
• Lipid complex of Amphoterecin B- non liposomal complex which
complexes drug in with two phosphlipids
• Active drug from these formulations can be selectively transferred
to ergosterol containing fungal cell membrane without affecting
the cholesterol of the host cell thus reducing nephrotoxicity

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Antifungal Spectrum and Uses of Amphotericin-B
• For Candida albicans infection (systemic & oropharyngeal)
• Mould infection in immuno-compromised patients
• Opportunistic fungal infection like Mucormycosis
• Histoplasmosis infection
• Coccidiodomycoses infection
• Blastomycoses
• Cryptococcal infection

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Adverse Effects
• Serious long term toxicity - Nephrotoxicity- renal tubular
necrosis, hypokalemia, hypomagnesemia secondary to renal
• Hypochromic normocytic anaemia
• Intrathecal administration may lead to arachnoiditis and seizures
• Rarely hepatic toxicity and jaundice
• Acute adverse effects with infusion
– Fever, chills, difficulty in breathing
– Vomiting
– Moderate hypotension
Remedy – Paracetamol, antihistiminic and hydrocortisone

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Griseofulvin – Heterocyclic Benzofuran
• Antibiotic obtained from Penicillinum griseofulvum
• Effective against dermatophytes but not against Candida
• Dermatophytes concentrate it through energy dependent active
process and binds to fungal microtubules
• Fungistatic - targets metaphase – causes abnormal metaphase
configuration but no arrest
• Disorients microtubules and prevents movement of daughter
nuclei
• Forms multinucleated stunted fungal hyphae
• Affinity for newly formed keratin

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©M. S. Ramaiah University of Applied Sciences
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Pharmacokinetics of Griseofulvin
Absorption
• From GIT – erratic
• Improved by micronisation or administration with fatty food
Metabolism
• Liver – dealkylation
• High affinity for keratin precursor cells, retained in skin, hair
and nails
• Plasma half life 24 h

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Therapeutic uses of Griseofulvin
• Systemic treatment of dermatophytose caused by
– Microsporum
– Trichophyton
– Epidermophyton
• Nail infections
• Dose – 500-1000 mg/day in 2 divided doses orally
• Skin and hair infections treated for 2-4 weeks
• Toe nails may need more than a year

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Adverse Effects of Griseofulvin
• Headache, vomiting, nausea
• Photosensitivity, peripheral neuritis
• Hepatotoxicity in patients with porphyria
• CYT inducer - ↓effectiveness of warfarin & oral
contraceptives
• Transient albuminuria & leucopenia
• Disulfiram like reaction with alcohol

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Faculty of Pharmacy
Summary
• Antifungal agents are classified into antibiotics, azoles,
allylamines, antimetabolites and topical agents
• Amphotericin-B is a polyene antibiotic that has affinity to
ergosterol of fungal cell membrane
• Amphotericin-B shows fungistatic action
• Griseofulvin is a heterocyclic benzofuran that prevents the
movement of daughter chromosomes
• Used in the treatment of dermatophytose and nail infections