Antifungal agents

Antifungal agents

Contents

• Introduction to fungi

• Classification of antifungal agents

• Pharmacology of antibiotics as antifungal agents

Objective

At the end of this lecture, the student will be able to:

• Classify anti-fungal drugs

• Describe the pharmacology of

– Amphotericin B

– Griseofulvin

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)

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)

• 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

Amphotericin-B

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

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

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

Griseofulvin

Griseofulvin MOA

Pharmacokinetics of Griseofulvin

• Liver – dealkylation

• High affinity for keratin precursor cells, retained in skin, hair and nails

• Plasma half-life 24 h

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

• 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

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

Summary

• Antifungal agents are classified into antibiotics, azoles, allylamines, antimetabolites and topical agents