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    New Fungi

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    Clara Shinta Aruan
    Fungi journal

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    New Fungi

    Uploaded by

    Clara Shinta Aruan
    31 views38 pages
    Fungi journal

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    © © All Rights Reserved

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    PDF, TXT or read online from Scribd

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    Fungi journal

    Copyright:

    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
    Download as pdf or txt
    31 views38 pages

    New Fungi

    Uploaded by

    Clara Shinta Aruan
    Fungi journal

    Copyright:

    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
    Download as pdf or txt
    of 38

    Antifungal Drugs

    D. Kumaraswamy
    Department of pharmacology
    SRM MCH&RC
    FUNGAL INFECTIONS
    (MYCOSES)

    Deep/
    Superficial systemic
    Fungal infections (Superficial)

    z Dermatomycosis (bcc cup)


    z Tinea pedis (athletes foot)
    z Tinea corporis (skin ringworm)

    z Tinea cruris (groin)

    z Tinea capitis (scalp)

    z Tinea unguium (nails)

    z Tinea barbae (beard)

    z Tinea mannum(hand)

    z Candidiasis skin, mouth, vagina


    oropharynx
    DEEP MYCOSES
    aspergilus

    Blastomyces

    Candida

    Coccidiodes
    Cryptococcus

    Histoplasma
    Antifungal drugs- Classification (5)

    1. ANTIBIOTICS
    Amphotericin B, (AMB), Nystatin,
    Hamcyin, Natamycin
    Griseofulvin
    2. ANTIMETABOLITES:
    5-Fluorocytosine (5-FC)
    inhibition of nucleic acid synthesis
    Antifungal drugs- Classification
    3. AZOLES
    z Imidazoles: (Topical): Clotrimazole,
    Econazole, Miconazole, Oxiconazole
    (Systemic): Ketoconazole
    Trizoles: ( Systemic) Itraconazole, Fluconazole,
    Voriconazole
    Inhibition of ergosterol synthesis
    4. ALLYLAMINE: Terbinafine
    Inhibition of lanosterol and ergosterol synthesis
    5. OTHER TOPICAL AGENTS:
    Tolnaftate, Undecylenic acid, Benzoic acid,
    Quiniodochlor, Ciclopirox olamine, Sod. thiosulfate.
    Amphotericin B - MOA
    z In fungi: ergosterol in membranes: higher
    affinity than mammalian cholesterol for AmB
    z Ergosterol: Only present in fungal cell
    membrane and not in animal cell
    z Ergosterol: Polyenes combine with it, get
    inserted into the membrane and several
    molecules together orient themselves and
    form a micropore.
    The Fungal Cell Wall

    mannoproteins

    1,3
    1,6
    glucans

    Cell 1,3 glucan chitin


    membrane synthase
    ergosterol
    Ergosterol

    Ergosterol with
    pore

    Polyene
    Antifungal Spectrum

    z Candida albicans, Histoplasma capsulatum, Cryptococcus


    neoformans, Blastomyces dermatitidis, Coccidioides immitis,
    Aspergillus, Rhodotorula.

    z Resistance is rare and slow to develop


    z Pharmacokinetics
    z Poorly: crosses cell membranes, absorbed from the gut and
    penetration into the eye, CSF, and joint capsules

    Kidney > liver > spleen > lung > heart > skeletal muscle > brain > bone > CSF > eye

    z For treatment of meningitis, it must be given intrathecally

    Given only via IV injection or intrathecally Selective distribution


    into deep tissue sites, with slow release of drug
    z Classic amphotericin B deoxycholate (Fungizone)
    formulation: serious toxic side effects.
    Less toxic preparations:

    1) Liposomal amphotericin B
    2) Amphotericin B colloidal dispersion
    3) Amphotericin B lipid complex

    z milder acute reaction


    z better tolerated
    z lower nephrotoxicity
    z minimal anaemia
    z targeted delivery-liver & Spleen
    ADVERSE EFFECTS (AMB)
    z Acute: Infusion-related
    z Chills, fever, dyspnea, nausea, vomiting,
    bronchospasm, hypotension, convulsions
    z Chronic
    z Nephrotoxicity
    z impaired concentration, impaired urinary
    acidification, K & Mg wasting with hypokalemia
    and hypomagnesemia
    z Normochromic, normocytic anemia
    z ( erythropoietin)
    Drug interactions
    Griseofulvin

    z Fungistatic
    z A systemic antifungal used to treat topical
    ringworm infections, e.g., onychomycosis,
    Tinea capitis, Tinea pedis, etc.
    z many Trichophyton spp., Microsporum spp.
    and Epidermophyton spp. are susceptible
    z Dermatophyte infections
    z Oral absorption (better with small particle size)
    z Enzyme inducer
    Mode of Action - Griseofulvin

    z disrupts mitotic spindle during


    metaphase by interacting with fungal
    microtubules------ (-) fungal mitosis
    (metaphase arrest)
    z sufficient to inhibit growth of fungi (drug
    is static), preventing them from invading.
    Griseofulvin-Adverse actions

    z GI disturbances
    z Allergic reactions
    z Skin rash
    z Headache
    z Photosensitivity
    z Angioedema
    z Peripheral neuritis
    Griseofulvin-Adverse effects (CNS)

    z Lethargy
    z Mental confusion
    z Blurring of vision
    z Vertigo
    z Being an antimiototic--bone marrow
    suppression, leucopenia, neutopenia
    Griseofulvin-Uses
    2. ANTIMETABOLITES:
    5-Flucytosine (5-FC)
    z Flucytosine is
    converted into 5-
    flurouracil, which
    inhibits thymidylate
    synthetase leading to
    inhibition of DNA
    synthesis
    (antimetabolite action)
    z All susceptible fungi are
    capable of deaminating
    flucytosine to 5-
    flurouracil
    3. AZOLES

    Better CSF
    penetrability
    High volume of
    distribution
    Dermatophytes,
    candida and other
    deep mycoses
    Triazoles are greater
    efficacy/lesser side
    effect and drug
    interaction
    Mechanism of Action:

    Acetyl CoA Squalene

    Squalene-2,3 oxide
    Squalene-2,3
    epoxidase
    Lanosterol

    14- demethylase Azoles

    Ergosterol
    Effect of azoles on C. albicans

    Before exposure After exposure


    Ketoconazole

    z Spectrum: yeasts and moulds - poor absorption


    limits its role for severe infections, generally
    used in mucosal infections only
    z Pharmacokinetics
    z Variable oral absorption, dependent on pH (often
    given with cola or fruit juice)
    z T1/2 7-10 hours
    z Protein binding > 99%
    z Hepatic, bile and kidney elimination
    z H2 blockers, antacids--- decrease absorption
    9Hepatoxicity (2-8%)- increase in
    transaminases, hepatitis
    9Dose related inhibition of CYP
    P450- responsible for
    testosterone synthesis
    9Dose-related inhibition of CYP
    P450 -responsible for adrenal
    cortisol synthesis
    4. ALLYLAMINE: Terbinafine

    z It causes non-
    competitive inhibition
    of squalene epoxide
    enzyme, which is
    involved in the
    synthesis of
    ergosterol by fungi

    Squalene-2-3- epoxidase
    Mechanism of Action:
    Acetyl CoA Squalene

    Squalene-2,3 oxide
    Squalene-2,3
    epoxidase
    Allylamines

    Lanosterol
    14- demethylase

    Ergosterol
    4. ALLYLAMINE: Terbinafine

    z A highly lipophilic, keratinophilic


    z Effective orally against dermatophytes
    and candida
    z Useful in fungal infections of nails (6-12
    weeks)
    z Adverse effects:- gastric upset, rashes
    and taste disturbances
    z Rarely hepatotoxicity
    5. OTHER TOPICAL AGENTS:

    z White fields ointment = Benzoic acid


    (6%) + Salicylic acid (3%)
    z Tolnaftate: Tinea corporis, cruris
    z Ciclopirox: Dermatophytes, candida
    Malassezia furfur
    z Selenium Sulfide: Malassezia furfur
    z Haloprogin: Dermatophytes, candida
    4 3
    1a

    1b

    2
    What are the targets for antifungal
    therapy?
    Cell membrane
    Fungi use principally ergosterol
    instead of cholesterol

    DNA Synthesis
    Some compounds may be
    selectively activated by fungi,
    arresting DNA synthesis.

    Cell Wall
    Unlike mammalian cells, fungi
    have a cell wall

    Atlas of fungal Infections, Richard Diamond Ed. 1999


    Introduction to Medical Mycology. Merck and Co. 2001
    Cell Membrane Active Antifungals

    Cell membrane
    Polyene antibiotics
    - Amphotericin B, lipid
    formulations
    - Nystatin (topical)

    Azole antifungals
    - Ketoconazole
    - Itraconazole
    - Fluconazole
    - Voriconazole
    - Miconazole, clotrimazole (and
    other topicals)
    THANK YOU

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