Antifungal agents
Pawitra Pulbutr
M.Sc. In Pharm (Pharmacology)
วัตถุประสงค์เชิงพฤติกรรม
• เข้าใจและอธิบายถึงกลไกการออกฤทธิ์, การดื้อยา, เภสัชจลนศาสตร์, อาการไม่
พึงประสงค์ท่เี กิดจากการใช้ยา, การนาไปใช้ประโยชน์ทางคลินิก รวมทัง้ ข้อดี
และข้อเสียของยาต้านเชื้อรา
Antifungal agents
Systemic antifungal for systemic infection
Systemic antifungal for mucocutaneous
infection
Topical antifungal agents
Systemic antifungal for
systemic infection
• Amphotericin B
• Flucytosine (5-FC)
• Azoles
• Ketoconazole
• Itraconazole
• Fluconazole
• Voriconazole
Amphotericin B Mechanism of action
 Cell membrane binding
 Target = Ergosterol of fungal cell membrane
 Pore forming action
 Increase cell membrane permeability
 Selective fungicidal
Resistance
 Decrease ergosterol binding
 decrease ergosterol number
 decrease ergosterol affinity
Antifungal activity
• Most broadest spectrum
• Candida albicans
• Cryptococcus neoformans
• Histoplasma capsulatum
• Blastomyces dermatitidis
• Coccidioides immitis
• Aspergillus fumigatus
• Paracoccidioides brasilliensis
• Penicillium maeneffei
• Mucormycosis (Rhizopus, Rhizomucor, Cunninghamella)
• Not to … Candida lusitaniae, Pseudallescheria boydii
ADRs
• Immediate reaction
• Infusion related toxicity
• Fever, chills, muscle spasms, vomiting,
headache, hypotension
• Slower infusion
• Premedication with ibuprofen, paracetamol,
diphenhydramine, hydrocortisone
ADRs
• Slower reaction
– Drug toxicity
– Renal damage
• decrease renal perfusion, prerenal failure …
reversible
• renal tubular injury, tubular dysfunction …
irreversible
• renal tubular acidosis, severe Mg++ & K+
wasting >>> hypokalemia
– Sodium loading >>> decrease prerenal toxic
Amphotericin B formulation
• Conventional
• Amphotericin B desoxycholate (DOC)
• Lipid formulation
•Amphotericin B Colloidal Dispersion (ABCD)
•Amphotericin B Lipid complex (ABLC)
•Small unilamellar vesicle formulation of
amphotericin B (AmBisome®)
Less bind to mammalian cells… Less nephrotoxicity
Expensive
Flucytosine (5-FC)
 water soluble pyrimidine analog
 5-FU like structure
 Well GI absorption > 90%
 Well distribution … including CSF
 Renal excretion … glomerular filtration …
 Mechanism of action
 Uptake into fungi by cytosine permease
 Converted into 5-FU … converted to …
 5-fluorodeoxyuridine monophosphate (F-dUMP)
… inhibit DNA synthesis
 5-fluorouridine triphosphate … inh. RNA syn.
Azole compounds
• Imidazole
• ketoconazole
• miconazole
• clotrimazole
• Triazole
• itraconazole
• fluconazole
• voriconazole
Mechanism of action
• Inhibit fungal CYP 450
• sterol 14 α demethylase
• Inhibit ergosterol synthesis
• Imidazole … less specific to fungal enzyme
• Imidazole … may inhibit human enzyme …
• Drug interaction … Enzyme inhibitor
• ADRs… Inhibit steroid hormone synthesis
Clinical uses
 Broad spectrum
 Candiasis
 Cryptococcosis
 Blastomycosis
 Histoplasmosis
 Dermatophytosis … ringworm
 Pseudallescheria boydii infection
 Aspergillosis
 Sporothricosis
Systemic drug for
mucocutaneous infection
Griseofulvin
Terbinafine
Griseofulvin
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Unclear mechanism of action … fungistatic
– inhibit mitotic spindle function … Inhibit
fungal mitosis
Accumulation in keratin
New skin … Non-infected
Oral … well absorption with fatty meal
Skin/ Nail/ Hair fungal infection
Late onset… 2-6 week
Microsized & Ultramicrosized preparation
Terbinafine (Lamisil®)
 Synthetic allyamine … well oral absorption …
extensive first pass metabolism
 Mechanism … Inhibit ergosterol synthesis
 Inhibit fungal squalene epoxidase
 Accumulation of toxic sterol squalene
 Fungicidal & Keratophilic
 Clinical uses
 Dermatophytes
 Onychomycosis
 250 mg/ day 6 weeks (finger) or 12 weeks (toe)
Topical antifungal therapy
• Superficial & Cutaneous fungal infection
• Stratum corneum, Squamous mucosa,
Cornea
• Dermatophytosis (ring worm)
• Cutaneous candidiasis
• Tinea vesicolor, Piedra
• Fungal keratitis
• Not effective for onychomycosis, tinea
capitis (head), subcutaneous mycosis
Nystatin
New York State Health
Lab
 Polyene macrolide
 Pore forming at cell membrane
 Amphotericin B like mechanism
 Topical only for candidiasis only
 Non GI, mucus absorption
 Clinical uses … local candida infection
 Oral suspension / Vaginal tablet
 Oral thrush (swish & swallow), Vaginal
candidiasis, Intertriginous candidal infection
Topical Azole
• Clotrimazole
• Cutaneous
application
• Miconazole
• Econazole
• Isoconazole
• Ketoconazole
• Vaginal suppository
(Clotrimazole)
• Oral troches
• Tinea corporis, Tinea pedis, Tinea crusis
• Vaginal candidiasis, Oral thrush, Cutaneous candidiasis
• Seborrheic dermatitis
• Pityriasis vesicolor
Topical allylamine
 Terbinafine
 Naftifine
 Tinea crusis, Tinea corposis, Tinea pedis
 Less effective to Candida*, tinea vesicolor*
 Irritation
Systemic antifungal for systemic infection
Amphotericin B
5-FC
Azole .. Ketoconazole, itraconazole, fluconazole, voriconazole
Systemic antifungal for mucocutaneous
infection
Griseofulvin
Terbinafine
Topical antifungal agents
Nystatin
Topical azole
Topical allylamine
Miscellaneous