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

Antifungal Agents

•       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
     –   Produced 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

Mechanism of Action of Antifungal Agents

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

•       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