ANTIFUNGALAGENTS ANTIFUNGAL AGENTS

ANTIFUNGALAGENTS ANTIFUNGAL AGENTS

Drugsthatactonfungi A.Altercellmembranepermeability

1.Azoles 2 T bi fi 2.Terbinafine 3.Polyenes

B.Blocksnucleicacidsynthesis B. Blocks nucleic acid synthesis

Flucytosine
C.Disruptsmicrotubulefunction

Griseofulvin

ANTIFUNGALAGENTS ANTIFUNGAL AGENTS

A.AZOLEAntifungalAgents:Ketoconazole,Fluconazole,Itraconazole, Voriconazole V i l 1.Ketoconazole Substitutedimidazole derivative Mechanismofaction:altersmembranepermeabilitybyblockingthesynthesis M h i f ti lt b bilit b bl ki th th i ofergosterol,theprimarycellularsteroloffungi Pharmacokinetics AbsorbedfromtheGIT Absorbed from the GIT Peakplasmalevel 12hours Itrequiresacidicenvironmentfordissolution Biphasicelimination:half life 2hoursduringthefirst10hoursafter Biphasic elimination: halflife 2 hours during the first 10 hours after administrationand8hoursthereafter Indications:activeagainstblastomycosis,paracocciiodomycosis, histoplasmosis,chronicmucocutaneous candidiasis,andresistant dermatophyte i f ti d t h t infection

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PharmacologicEffects:actsmoreslowlythanotherantifungalagents Lesseffectiveinacuteandsystemicfungalinfections PoorpenetrationatBBB Preparation:tablet Preparation: tablet AdverseEffects 1.nauseaandvomiting 2.hepatotoxicity 2 h i i 3.hypersensitivityreactions 4.gynecomastia 5.transientblockadeoftestosteronesynthesisandadrenalresponseto corticotropin 6.blocksseveralcytochrome P450relatedenzymesteps y y p

ANTIFUNGALAGENTS ANTIFUNGAL AGENTS

B.Fluconazole Isabitriazole Mechanismofaction:inhibitscytochrome P450dependentenzymes, blockingthesynthesisofergosterol Pharmacokinetics: morewatersolublethanketoconazole andhighly Ph ki ti t l bl th k t l d hi hl bioavailable Peakplasmalevel:12hours;halflife 30minutes Excretedunchangedintheurine Excreted unchanged in the urine CSFconcentrationsapproach5090%serumconcentration Indications: systemicfungalpathogenssuchasAspergillus,B.dermatitides,C. p albicans,C.neoformans,C.immitis,H.capsulatum Effectiveagainstoropharyngeal andesophagealcandidiasis,systemiccandidal infections,andcryptococcal meningitis Preparation: oralandIV

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AdverseEffects:bettertoleratedthanketonazole LesstoxicthanAmphotericinBorflucytosine Itmayincreaseserumconcentrationofphenytoin,cyclosporine,andoral hypoglycemicagentsandpotentiatestheeffectofWarfarin yp g y g p 3.Itraconazole drugofchoiceforsystemicblastomycesandsporothrix andforcutaneouschromoblastomysis ItisanalternativeagentforinfectionscausedbyAspergillus,Coccidioides, It is an alternative agent for infections caused by Aspergillus Coccidioides Cryptococcus,andHistoplasma Inesophagealcandidiasis usedinresistantcasestofluconazole Activeindermatomycoses Active in dermatomycoses Voriconazole newazolewithwiderspectrumoffungalactivitythan itraconazole

ANTIFUNGALAGENTS ANTIFUNGAL AGENTS B.Flucytosine

Fluorinatedpyrimidine Mechanismofaction:convertedwithinfungalcellsto5fluorouracil,ametabolic antagonistthatleadstoinhibitionofthymidylatesynthetase t i t th t l d t i hibiti f th id l t th t Pharmacokinetics: wellabsorbedfromtheGIT WidelydistributedthroughoutthebodyincludingtheCSF Excretedintheurineunchanged Excreted in the urine unchanged Indications: effectiveagainstC.neoformans,somestrainsofCandida(C. albicansresistant) NoteffectiveasAmphotericinB MostcommonlyusedincombinationwithAmphotericin M l di bi i i hA h i i AIDShavingCryptococcalmeningitis Preparation: capsule AdverseEffects:fatalbonemarrowdepression,GIupset,skinrash,hepatic Adverse Effects: fatal bone marrow depression GI upset skin rash hepatic dysfunction

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C.Griseofulvin ProducedbyPenicilliumgriseofulvum Poorlysolubleinwater P l l bl i t Mechanismofaction:bindspolymerizedmicrotubules,disruptingmitotic spindles Fungistatic Indications: activeagainstdermatophytes,includingMicrosporum, Epidermophyton,Trichophyton g y Ineffectiveagainstyeast Becauseofitsaffinityforkeratin,usefulfortreatingmycoticdiseasesoftheskin, hair,andnailssuchastineacapitis,tineapedis,cruris,corporisandcircinata Giveorally:topicalusehaslittleeffect Preparations: tablets,capsules,oralsuspension AdverseEffects:relativelylowtoxicity

ANTIFUNGALAGENTS ANTIFUNGAL AGENTS

D.Nystatin Polyeneantibiotic MechanismofAction:bindstosterolswhichenrichedinmembraneoffungi andyeast;fungistaticandfungicidal Appearstoformchannelsinthemembranethatallowsmallmoleculesto leakoutofthecell Pharmacokinetics: notabsorbedappreciablyfromtheGIT Notabsorbedfromtheskinormucousmembrane Notgivenparenterally Poorlysolubleanddecomposesrapidlyinwater Indications: Candida infections of the skin mucous membranes and Candidainfectionsoftheskin,mucousmembranesand intestinaltract,oralthrushandvaginitisbytopicalapplication,intestinal candidadiasisoral Preparations:ointment,oralsuspension,tablets,dropsandpowder Preparations: ointment oral suspension tablets drops and powder AdverseEffects:GIdisturbances

ANTIFUNGALAGENTS ANTIFUNGAL AGENTS

E.Amphotericin B Polyene antibiotic MechanismofAction:similartoNystatin p g g g p Indications:broadspectrumantifungalagentagainstHistoplasma Capsulatum,C.neoformans,Coccidioides immitis,Candidaspecies, Blastomyces dermatatidis andsomestrainsofAspergillus andSporotricum

theconcentrationdetermineswhetheritisfungistatic or the concentration determines whether it is fungistatic or fungicidal

Pharmacokinetics: poorlyabsorbedfromtheGI

IVadministrationresultsinaplasmahalflifeofabout24hours f f f
Excretedveryslowlyintheurine TherapeuticUses:mosteffectivedrugforsystemicfungalinfection Usedforthetreatmentoflifethreateningfungalinfection

ANTIFUNGALAGENTS ANTIFUNGAL AGENTS

C.neoformans associatedwithAIDS ParasiticlesionofAmericanleishmaniasis mayrespondtoAmphotericin B Intrathecal infusioninthetreatmentoffungalmeningitis p y p p j Preparations: lyophilizedpowderusedforinjections

topicalformulations
AdverseEffects: hypersensitivityreactions,normochromicnormocytic anemia, feverchills,headacheandGIdisturbanceswithIVadministration fever chills headache and GI disturbances with IV administration

thrombophlebitis
F.Naftidine syntheticantifungalagentisanallylamine h i if l i ll l i MechanismofAction:decreasesthesynthesisofergosterol byinhibiting squalene peroxidase

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PharmacologicEffects:fungicidalagainstdermatophytes

Fungistatic againstyeasts
Usedtotreattinea pedis,cruris,corporis Itisnoteffectiveforfungalinfectionsofthehairandnails It is not effective for fungal infections of the hair and nails Preparation: cream AdverseEffects:burning,dryness,rednessanditchiness G.Miconazole andCotrimazole Imidazole derivatives Topicalagents p g InhibitthegrowthofcommonDermatophytes includingTrichophyton, Epidermophyton floccosum,C.albicans,Malassezia furfur,ringwormand otherskininfections,vulvovaginal candidiasis, , g ,

ANTIFUNGALAGENTS ANTIFUNGAL AGENTS

Parenteralused systemicfungalinfectionscausedbyCandidiasis, CoccodiomycosisandCryptococcosis H.HaloproginandTolnaftate Haloprogin fungicidaltoEpidermophyton,Pityrosporum,Microsporum, p g g p p y , y p , p , Trichophyton,andCandida Tolnaftatetreatmentformostcutaneousmycoses,ineffectiveagainst y yeast Freeoftoxicityorallergicreaction