Antifungal agents

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Antifungal agents

• Pawitra Pulbutr
• M.Sc. In Pharm (Pharmacology)

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Antifungal agents

• Systemic antifungal for systemic infection
• Systemic antifungal for mucocutaneous infection
• Topical antifungal agents

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Systemic antifungal for systemic infection

• Amphotericin B
• Flucytosine (5-FC)
• Azoles
• Ketoconazole
• Itraconazole
• Fluconazole
• Voriconazole

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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

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• 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

Antifungal activity
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ADRs

• Immediate reaction
• Infusion related toxicity
• Fever, chills, muscle spasms, vomiting,
  headache, hypotension
• Slower infusion
• Premedication with ibuprofen, paracetamol,
  diphenhydramine, hydrocortisone

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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
  gtgtgt hypokalemia
• Sodium loading gtgtgt decrease prerenal toxic

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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
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Flucytosine (5-FC)

• water soluble pyrimidine analog
• 5-FU like structure
• Well GI absorption gt 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.

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Azole compounds

• Imidazole
• ketoconazole
• miconazole
• clotrimazole
• Triazole
• itraconazole
• fluconazole
• voriconazole

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Mechanism of action

• Inhibit fungal CYP 450
• sterol 14 a demethylase
• Inhibit ergosterol synthesis
• Imidazole less specific to fungal enzyme
• Imidazole may inhibit human enzyme
• Drug interaction Enzyme inhibitor
• ADRs Inhibit steroid hormone synthesis

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Clinical uses

• Broad spectrum
• Candiasis
• Cryptococcosis
• Blastomycosis
• Histoplasmosis
• Dermatophytosis ringworm
• Pseudallescheria boydii infection
• Aspergillosis
• Sporothricosis

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Systemic drug for mucocutaneous infection

• Griseofulvin
• Terbinafine

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Griseofulvin

• 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

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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)

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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

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Nystatin

• 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

New York State Health Lab
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Topical Azole

• Clotrimazole
• Miconazole
• Econazole
• Isoconazole
• Ketoconazole
• Tinea corporis, Tinea pedis, Tinea crusis
• Vaginal candidiasis, Oral thrush, Cutaneous
  candidiasis
• Seborrheic dermatitis
• Pityriasis vesicolor

• Cutaneous application
• Vaginal suppository (Clotrimazole)
• Oral troches

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Topical allylamine

• Terbinafine
• Naftifine
• Tinea crusis, Tinea corposis, Tinea pedis
• Less effective to Candida, tinea vesicolor
• Irritation

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• 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

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THE END