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, 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
• 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
