Antifungal agents

Antifungal agents


       Introduction to fungi

       Classification of antifungal agents

       Pharmacology of antibiotics as antifungal agents


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

       Classify anti-fungal drugs

       Describe the pharmacology of

      Amphotericin B



       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


       Polyene antibiotics – Amphotericin B, Nystatin, Hamycin, Natamycin

       Heterocyclic benzofurans – Griseofulvin

Antimetabolites – 5- Flucytosine


       Imidazole – Topical – Clotrimazole, Miconazole

       Systemic - Ketoconazole

       Triazoles – systemic – Fluconazole, Itraconazole

Allyl amines – Terbinafine

Miscellaneous (Topical) – Ciclopirox, Tolnaftate, Clioquinol , caspofungin

Antifungal Agents - MOA


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, t1/2- 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


       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


      Moderate hypotension

Remedy – Paracetamol, antihistiminic and hydrocortisone


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




       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


       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







Mechanism of Action of Azoles


       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


       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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