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, 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
Antifungal Agents: FAQs
How do Antifungal Agents work?
Antifungal Agents work by targeting specific components within fungal cells, disrupting their normal functioning. This targeted approach ensures effective treatment with minimal impact on host cells.
Are there any side effects associated with Antifungal Agents?
While generally safe, Antifungal Agents may cause mild side effects such as nausea or skin irritation. Severe reactions are rare but consult a healthcare professional if any concerns arise.
Can Antifungal Agents be used for preventive purposes?
In certain cases, especially for individuals prone to recurrent fungal infections, prophylactic use of Antifungal Agents may be considered. However, this should be done under medical supervision.
How long does it take for Antifungal Agents to show results?
The timeline for results varies depending on the type of infection and the chosen medication. Improvement is often noticeable within a few days, but complete resolution may take weeks.
Can Antifungal Agents be used during pregnancy?
Pregnant individuals should consult their healthcare provider before using Antifungal Agents, as safety considerations may vary depending on the specific medication and trimester.
Are there any natural alternatives to Antifungal Agents?
While some natural remedies may offer relief for mild fungal infections, they may not be as potent as Antifungal Agents for severe cases. Consultation with a healthcare professional is recommended.
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