Antifungal agents

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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

Contents

• Introduction to fungi
• Classification of antifungal agents
• Pharmacology of antibiotics as antifungal agents

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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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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Classes of Fungi

• 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

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

Antifungal Agents - MOA

©M. S. Ramaiah University of Applied Sciences

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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

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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, t_1/2- 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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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

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

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Pharmacokinetics of Griseofulvin

• 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

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

Azoles

• Synthetic antifungal drug
• Broad spectrum fungistatic and fungicidal activity
• Imidazole group- 2 nitrogen in the azole ring
• Triazole group – 3 nitrogen in azole group
• Imidazole for systemic infections – Ketoconazole
• Other drugs for superficial fungal infection

Azoles

• Clotrimazole
• Ketoconazole
• Fluconazole
• Itraconazole
• Voriconazole
• Posaconazole

Mechanism of Action of Azoles

Ketoconazole

• Metabolism : Ketoconazole inhibits CYP450 enzymes, especially CYP3A4, CYP2C9; CYP2C19
• Raises the blood levels of several drugs including: Phenytoin, Digoxin, Carbamazepine, Omeprazole, Diazepam, Cyclosporine, Haloperidol, Nifedipine and other DHPs Warfarin, HIV protease inhibitors & sulfonylureas, Statins, Cisapride, Terfenidine, Quinidine, Cyclosporine, Tacrolimus

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Adverse Effect of Ketoconazole

• Nausea, vomiting, anorexia – minimised by taking drug with food
• Headache, paresthesia, rashes, hair loss
• Reversible elevation in hepatic enzymes
• Inhibits the formation of synthesis of testosterone & estradiol
• Gynacomastia & menstrual irregularities

Uses of Ketoconazole

• For dermatophytes infection – drug accumulates in stratum corneum
• For silent coccididiomycosis
• Oropharyngeal candisiasis in AIDS patients

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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

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