anti fungal drugs[1]

8/3/2019 Anti Fungal Drugs[1]

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Dr Azza Baraka
http://upload.wikimedia.org/wikipedia/commons/9/99/Amanita_phalloides_1.JPG


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There is increase in incidence ofopportunistic fungal infection ( dueto wide spread use ofimmunosuppressants andemergence of AIDS) ranging fromtrivial cutaneous infection to

systemic diseases which demandprolonged treatment with toxicagents


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Fungal infections (Mycoses):

Systemic infection

Mucocutaneous(superficial) infection


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Systemic candidiasis

Cryptococcsis

Aspergillosis

Blastomycosis

Histoplasmosis


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Candidisis (Yeast)

Dermatomycosis

(Molds)


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Tinea corporis
http://dermatlas.med.jhmi.edu/derm/IndexDisplay.cfm?ImageID=-664370511


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onchmycosis


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Alter membrane permeability:

Azoles Polyenes Allylamines

Disrupt cell wall:Echinocandins(caspofungin).

Block nucleic acid synthesis:

Flucytosine

Disrupt microtubular functions:

Griseofulvin


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Systemically administered (oral or parenteral)

AFDS for systemic (invasive) fungal infections.

Oral AFDs for mucocutaneous (superficial)

fungal infections.

Topically applied AFDs for mucocutaneous

fungal infections.


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AMPHOTERICIN B

FLUCYTOSINEAZOLES

Echinocandins


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It has a broad antifungal spectrum.

It is often used as the initial induction

regimen for serious fungal infectionsand then replaced by a less toxic drug.


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D

Na+

Cytoplasmic membrane

Fungal cell

SqualeneLanosterolErgosterol

Fungal celldeath

Amphotericin Binds to ergosterol and form pores

in the membrane


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No

Only ergosterol is affected by this drug


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IV infusion

Poorly absorbed from GIT

Intrathecal for fungal meningitis


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Infusion related

HypotensionAttenuated by :

Slowing infusion ratePremedication with: Antihistamines ,antipyretic

Fever

chills muscle spasmvomiting


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Nephrotoxicity

Anemia : renal erythropoietin formation


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Fluocytosine is converted to 5-fluorouracil (5-FU)


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Permease

5-FC

5-FC

Deaminase

5-FU

DNA & RNA synthesis

Inhibition

5-FUTP

5-FdUMP


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Narrow spectrum antifungal


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Flucytosine is often used orally incombination with other antifungal

drugs to avoid development ofresistance and for synergistic actions


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YesBecause Mammalian cells have low level of enzymes that

convert Flucytosine to 5-FU

Does resistance occur to FC?

Yes

Decrease activity of fungal enzymes thatconvert Flucytosine to 5-FU


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Orally


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Reversible BMS: anaemia, leucopenia, thrombocytopenia

Alopecia

Elevatedhepaticenzymes


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A-Imidazoles: KetoconazoleB-Triazoles:1st generation: Itraconazole,Fluconazole2nd generation: Voriconazole

2nd generation triazoles differ from 1st

generation triazoles in having an extendedspectrum of activity and being active

against fluconazole-resistant species.


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SqualeneLanosterol

Fungal celldeath

Blocked by azole

P450Ergosterol

Loss of membrane selectivity & loss of important cell contents


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Broad spectrumanti-fungal


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1. Triazoles have a broader antifungal spectrum thanimidazoles.

2. Triazoles achieve better distribution into body fluids.3. Triazoles have greater affinity for fungal compared

with mammalian P450 enzymes so produce lesseffect on human steroid synthesis . Thus their safetyprofile is significantly improved over imidazoles.

4. Triazoles have broad application in therapy of bothsuperficial and systemic fungal infections. Whereas,the use of imidazoles is limited to treating superficialfungal infections.


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Both imidazoles and triazoles might causehepatotoxicity ranging from mild transientelevations in transaminases to clinical hepatitis

and liver failure. These reactions areidiosyncratic, so there is no cross-sensitivitybetween azoles.

Imidazoles might cause endocrinal

disturbances due to inhibition of synthesis ofgonadal and adrenal steroids as a result ofinhibition of human P450.


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The major drawback associated with azole userelates to their metabolism by the hepaticcytochrome P450 (CYP) enzyme system.

Because azoles also inhibit CYP enzymes,plasma levels of any drug metabolized bythese enzymes may be elevated .

The potential for drugdrug interactions isgreatest for itraconazole and voriconazole, butlower for fluconazole, as these azoles are notmetabolized to the same extent by the CYP

system .


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Echinocandins have poor oral absorption so givenIV.

As effective as Amphotricin B but toxicity associatedwith echinocandins is infrequent because their action

is specific to fungal cell walls. They are not metabolized via the cytochrome

P450 enzymes, so there are minimal drugdruginteractions.

Adverse effects include histamine release reactions(irritation at infusion site, headache, rash) and fever.


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1. Azoles2. Griseofulvin3. Terbinafine


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It is an allylamine.


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Squalene Lanosterol Ergosterol

Squalene

epioxidase

Terbinafine

Squalene


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Dermatophyte infection

It accumulates in Keratinized tissues(skin)

>effective thangriseofulvin or azoles


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GIT upsetHeadache


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Treatment of Dermatophyteinfection as tinea infections of theskin. After oral absorption it is takenup selectively by newly formed skinand concentrated in keratin.

Azoles and terbinafine are moreeffective alternatives.


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Oral.

binds to keratinresistant to fungalinfections.

No eradication of infection.


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Fungal cell

Inhibit microtubule functions

Support , transport , division

GG


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1.Allergic reactions2.Hepatoxicity

3.BMS


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Griseofulvin is a P450 inducer.


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NYSTATIN

Topical Amphotericin B

Topical Terbinafine Topical Azoles


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Not absorbed from GIT

It is only used topically andis never administeredparentrally because of its

serious systemic toxicity.


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D

Na+

Cytoplasmic membrane

Fungal cell

SqualeneLanosterolErgosterol

Fungal celldeath

Nystatin Binds to ergosterol and form pores in the

membrane


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Candida albicans

Nystatin

Oropharyngeal thrushVaginal candidiasis

Skin candidal infection

N.B. never systemic.


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1-Mycotic corneal ulcers &keratitis.

2- Fungal arthritis.

3- Candiduria.


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Local irritation,hypersensitivity.


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Topical azoles

Ketoconazole Miconazole Clotrimazole

Candida AlbicansDermatophytes


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ORAL(KETOCONAZOLE, ITRACONAZOLE,FLUCONAZOLE) or PARTENTRAL(ITRACONAZOLE, FLUCONAZOLE) for

systemic infections ORAL(KETOCONAZOLE, ITRACONAZOLE,

FLUCONAZOLE) or Topical(KETOCONZOLE, MICONAZOLE,

CLOTRIMAZOLE) for mucocutaneousinfections


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Terbinafine,

Cream or gel.Local irritation,

erythema, burningsensation.


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DERMATOPHYTESCompounds like benzoic acid

(Whitfield oint.) still can be usedfor mild infections.Topical imidazoles (miconazole)

are usually preferred.If multiple areas (esp. in scalp ornails) or if failed topical; oral

itraconazole or terbinafine.


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anti fungal drugs[1]

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