Antifungal agents

ANTIFUNGAL AGENTS Dr.Elza Joy MunjelyJR-I Depmt. Of Pharmacology Govt. Medical College,Kottayam.

Fungi- Eukaryotes

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Cell wall- beta glucan and chitin

Cell membrane ergosterol

Yeasts Crypyococcus neoformansYeast like fungi-Candida albicansMoulds-DermatophytesDimorphic fungi-Blastomyces dermatitidis,Histoplasma capsulatum,Coccidioides immitis,Sporothrix

Pathogenic Fungi Classification

Fungal infections Mycoses

SUPERFICIAL-Black piedraCUTANEOUS-TineaSUBCUTANEOUS-SporotrixSYSTEMIC- Blastomycosis,Histoplasmosis,Coccidioidomycosis,CryptococcosisOPPORTUNISTIC Mucor,Aspergillus,Candida

Classification based on mechanism of action Acting on fungal cell wall : Echinocandins.

Acting on fungal cell membrane : Polyenes,Azoles & Allylamine

Inhibition of nucleic acid synthesis: 5Flucytosine.

4.Acting on mitotic spindle: Griseofulvin.

5.Topical: Ciclopirox, Tolnaftate, Haloprogin, Undecylenic acid, Topical azoles.

MECHANISM OF ACTION

Cell wall

ANTIFUNGALSALTERATION OF CELL MEMBRANE / WALL PROPERTIESBLOCK NUCLEICACID SYNTHESISINHIBIT MICROTUBULE FUNCTIONPorin-FormationSynthesis inhibitors

Polyene antibiotics Amphotericin B Nystatin

FlucytosineGriseofulvin1.Azoles 2.Allylamines3.Glucan synthesis inhibitors

Mechanism of action of Echinocandins

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Cell Membrane

MOA of Polyenes

Amphotericin BBinds ergosterol in fungal cell membraneForm pores in cell membrane Cell contents leak outCell death

PrecursorsSqualeneLanosterolergosterol14--demethylaseSqualene epoxidase

Fungal cell membrane

AZOLES & ALLYLAMINES

Allylamines

Azoleantifungals

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ANTIMETABOLITES

MOA of flucytosine

Antimitotic

MOA of GriseofulvinBinds to polymerised microtubules and inhibit mitosis

SqualeneLanosterolErgosterolSqualene epoxide14--demethylase5-FC5-FU5-FdUMPdUMPdTMPDNACytosinedeaminaseThymidylatesynthetase

microtubules

Pore formationPermeaseFungal cellwall cell membrane

ECHINOCANDINSAMPHOTERICIN BALLYLAMINESAZOLESGRISEOFULVINFLUCYTOSINEFUNGAL CELL

Polyene antibiotics Amphotericin B: Streptomyces NodosusAmphoteric

Lactone ring Lipophilic partHydrophilic part

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Antifungal spectrum AspergillusBlastomyces dermatitidisCandida albicans Cryptococcus neoformansCoccidioides immitisHistoplasma capsulatumMucor spp.-

Broadest spectrum of action

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Liposomes in the therapy of infectious diseases and cancer 1989: 105Antiprotozoal spectrumLeshmania

Naegleria fowleri

Mechanism of resistance Replacement of ergosterol by other sterols in fungal plasma membrane.

Resistance is not a problem clinically24

PharmacokineticsPoorly absorbed orally

Insoluble in water so colloidal suspension prepared with sodium deoxycholate(1:1 complex)

t = 15 days

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Lpd formulations of amphotericin B

(ABLC; Abelcet)

(ABCD; Amphocil or Amphotec)

(L-AMB; Ambisome)Amphotericin B Lipid Complex(ABLC)Amphotericin B Colloidal Dispersion(ABCD)Liposomal Amphotericin B

Ribbon-like particles Carrier lipids: DMPC, DMPG J Liposome Res 1993; 3: 451

AMB Lipid complex (ABLC): ABLC

35% AMB incorporated in ribbon like particles of dimyristoyl phospholipids35% AMB incorporated in ribbon like particles of dimyristoyl phospholipids

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ABCDAMB colloidal dispersion (ABCD):

Disc shaped particles containing 50% each of AMB & cholesteryl ester in aqueos dispersion 28

The LIPOSOME.. Hospital Practice 1992; 30: 53Liposomal AMB (Small unilamellar vesicles) :

10% AMB incorporated in SUV made up of lecithin

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Adverse events: Acute reaction: Long term toxicity: Nephrotoxicity: CNS toxicity :AnaemiaHepatotoxicity rarely

Acute reaction: Chills, fever, headache, pain all over, nausea, vomiting, dyspnoea lasting 2-5 hrs because of release of IL & TNFcan be treated with hydrocortisone 0.6mg/kg

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Systemic mycotic infections invasive aspergillosis Rapidly progressive Blastomycosis & CoccidiomycosisMucormycosis.Disseminated rapidly progressing Histoplasmosis Cryptococcus neoformans-intra thecalGiven as IV Available as 50mg vial suspended in 10 ml water and then diluted with 500 ml glucose

Uses

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Liposomes in the therapy of infectious diseases and cancer 1989: 105

Release frommacrophageMacrophageRelease in bloodcompartmentEndocytosisLiposomeLysosomeFusionLiposomedegradationEndocyticvesicleReserve drugs for resistant kala azar

Deliver AMB to RES of liver speen so useful in leshmania & immunocompromised

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Topical uses

Intestinal Monoliasis: OrallyVaginitisOtomycosis: 3 % drops Mycotic infections of the bladder (bladder irrigation)

Nystatin

S.Noursei locallyUses: Intestinal moniliasis Vaginitis Prevention of oral candidiasisOral, cutaneous, conjunctival candidiasis

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Hamycin:S. PimprinaHindustan antibioticsTopical use in thrush, cutaneous candidiasis, trichomonas & monilial vaginitis, otomycosis by aspergillus

Natamycin:

Broad spectrum Used topicallyFusarium solani keratitis, trichomonas & monilial vaginitis

AZOLESSynthetic Broad spectrum Fungistatic or fungicidal depending on conc of drug imidazoles & triazoles

Imidazoles:

Two nitrogen in structure Topical: econazole, miconazole, clotrimazole Systemic : ketoconazole Newer : butaconazole, oxiconazole, sulconazole

Triazoles Three nitrogen in structure Fluconazole, itraconazole, voriconazoleTerconazole

SYSTEMICTOPICALKetoconazoleFluconazoleItraconazoleVoriconazoleClotrimazoleMiconazoleEconazoleOxiconazoleSertaconazoleTerconazoleSulconazoleTioconazoleButaconazole

Imidazoles

Miconazole & clotrimazoleTopical use: Miconazole 2 % and clotrimazole 1 % Uses: Dermatophyte infectionsCandida: oral pharyngeal, vaginal, cutaneous Adverse events: Local irritation

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First orally effective broad spectrum antifungalacidic environment favours absorption Csf penetration less

Ketoconazole

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Adverse events of ketoconazole

steroid, testosterone & estrogen synthesisGynaecomastia, oligospermia , loss of libido & impotence in males Menstrual irregularities & amenorrhoea in females

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Drug Interactions of ketoconazole

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Dangerous interaction with terfenadine,astemizole and cisapridePolymorphic ventricular tachycardia

Ketoconazole and steroid hormone synthesis Inhibitcholesterol side-chain cleavage enzyme17-hydroxylase -which converts cholesterol topregnenolone 17,20-lyase ,which convertpregnenolone intoandrogens 11-hydoxylase, which converts11-deoxycortisol tocortisol.

Uses of ketoconazoleDermatophytosis: conc in stratum corneum Monilial vaginitis : Systemic mycosisTopical: T.pedis, cruris, corporis, versicolor

200 mg OD Also tried in dermal leshmaniasis 48

Other uses of ketoconazoleProstate cancerPrecocious pubertyCushing syndromeHirsuitism

Triazoles

Fluconazole

Broad spectrumCandida, cryptococcosis, coccidiodomycosis DermatophytosisBlastomycosis Histoplasmosis Sporotrichosis Oral, IV as well as topical Not effective against aspergillosis & mucormycosis

Pharmacokinetics of fluconazole Not affected by food or gastric pH crosses BBB Fungal meningitis

Adverse events of fluconazoleGIT upset Less adverse effects than ketoconazoleNo anti androgenic & other endocrine effects

Uses of fluconazoleCandida: vaginal candidiasis- 150 mg oral dose Oral candidiasis- 2 weeks treatment required Tinea infections & cutaneous candidiasis: 150 mg weekly for 4 weeks tinea unguim : 12 months Systemic fungal infections:Meningitis: preferred drug Eye drops for fungal keratitis

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Itraconazole Broad spectrum of activity also against aspergillus Does not inhibit steroid hormone synthesis and no serious hepatoxicity

Pharmacokinetics of itraconazoleAbsorption enhanced by food & gastric acidity Accumulates in vaginal mucosa, skin, nails CNS penetration is poor Metabolized in liver

Uses of itraconazoleDOC for paracoccidomycosis & chromoblastomycosis , histoplasmosis & blastomycosis Also used in oesophageal, oropharyngeal vaginal candidiasis DermatophytosisOnychomycosis Aspergillosis

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Adverse events of itraconazoleHypokalemia Increase plasma transaminaseDrug interactions: Oral absorption by antacids, H2 blockers

VoriconazoleHigh oral bioavailabilityGood CSF penetration Doesnt require gastric acidity for absorption

Uses of voriconazole

DOC for invasive aspergillosis Most useful for esophageal candidiasis First line for moulds like fusarium Resistant candida infections

Adverse effects of voriconazole Adverse events: Transient visual changes like blurred vision , altered color perception & photophobia Prolongation of QT

PosaconazoleBroadest spectrum azoleLiquid oral formulationDose : 800mg/dayPotent inhibitor of CYP-3A4

Indications -Posaconazole

Prophylaxis of invasive candidiasis

Salvage therapy for invasive aspergillosis

Mucor mycosis & zygomycosis the only azole active!

RavuconazolePhase II clinical trialSpectrum- Candida sp Aspergillus DermatophytesOral

Water solubilityAbsorptionHalflife(hrs)EliminationFormulationsKetoconazolelowvariable7-10HepaticOralitraconazolelowvariable24-42HepaticOral/IVFluconazolehighhigh22-31RenalOral/IVVoriconazolehighhigh6HepaticOral/IVPosaconazolelowhigh25HepaticOral

VORICONAZOLEPOSACONAZOLERAVUCONAZOLEFormulationsORAL/IVORALORALT 1/2 6 hrs25 hrs100 hrsAdverse effects liver enzVisual S/EGI upsetHepatotoxicDrug interactionsHigh least

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TerbinafineOrally & topically effectiveFungicidal Pharmacokinetics:Well absorbed orallyHighly keratophilic & lipophilic poor BBB permeability t1/2- 15 days

Adverse events and uses Adverse events: Taste disturbancesRarely hepatic dysfunction Uses: Dermatophytosis OnychomycosisCandidiasis

Other allylamines NaftifineDermatophytes,T.versicolor,cutaneous candidiasisButenafine

5 flucytosineNarrow spectrum Prodrug, pyrimidine analogAdverse events: Bone marrow toxicity , Alopecia, rarely hepatitisUses: in combination with AMB in cryptococcal meningitis

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Advantages of combination: Entry of 5 FCReduced toxicity Rapid culture conversion Reduced duration of therapy Decreased resistance

GriseofulvinPenicillium griseofulvumFungistatic systemic drug for superficial fungal infectionsActive against dermatophytesDermatophytes concentrate it actively hence selective toxicity

Pharmacokinetics:

Increased absorption by fatty food keratinized tissuet1/2=24 hrs

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Adverse events: Headache most common CNS symptoms: confusion, fatigue, vertigoPeripheral neuritisphotoallergyTransient leukopenia, albuminuria

Uses: Systemically only for dermatophytosis, ineffective topically Duration of treatment depends on site, thickness of keratin and turnover of keratin. Treatment must be continued till infected tissue is completely replaced by normal skin,hair, nail.Dose: 125-250 mg QID

Duration of treatment Body skin = 3 weeksPalm, soles = 4- 6 weeksFinger nails = 4- 6monthsToe nails = 8 12 months

Interactions: Warfarin , OCPPhenobarbitone, Disulfiram like reaction

EchinocandinsSpectrum Candida Aspergillus NOT active againt Cryptococcus

PKHighly PPBMetabolites are eliminated by kidneys & GITAvailable only as i/v formulations

EchinocandinsAdv Broad -spectrum activity against all Candida speciesRelatively low toxicity- among the safest

CaspofunginFDA approved in 2001Dose single loading dose 70mg followed by daily dose of 50mg iv over 1 hrUse Invasive forms of candidosisCandidemia Invasive aspergillosis

MicafunginFDA- approved in 2005Candida esophagitis- 150 mg/dayCandidemia -100mg/day Prophylaxis of fungal infections in those receiving stem cell transplant- 50mg/day D/IMicafungin - the levels of nifedipine,cyclosporine and sirolimus

AnidulafunginFDA approved in2006Candida esophagitis- 100mg 1st day followed by 50mg/day Candidemia- 200mg 1st day followed by 100mg/day

Adverse Effects Flushing , phlebitis-Anidulafungin Increase in liver enz.GI disturbances Caspofungin

Topical agents used in dermatophytosis Tolnaftate: Tinea infections.Not effective in hyperkeratinized lesions Salicylic acid aids its effect by keratolysis

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Topical agents used in dermatophytosis Ciclopirox olamine: Tinea infections, pitryasis versicolor ,dermal candidiasis, vaginal candidiasis Penetrates superficial layers

Topical agents used in dermatophytosis Undecylenic acid: 5% (Tineafax) Generally combined with zinc (20%) used in tinea cruris and nappy rashSodium thiosulfate: (Karpin lotion) Reducing agent known as hypo Effective in pitryasis versicolor only 20 % solution for 3-4 weeks

Active against malasessezia furfur

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Topical agents used in dermatophytosis Benzoic acid: Used in combination with salicylic acid Whitfields ointment: ( benzoic acid 6% + salicyclic acid 3 %)Salicyclic acid due to its keratolytic action helps to remove infected tissue & promotes penetration of benzoic acid in fungal infected lesion Adverse events: irritation & burning sensation (Ring cutter ointment)

Topical agents used in dermatophytosis HaloproginDermatophytosisMainly-T.pedis

Topical agents used in dermatophytosis Quinidiochlor; Luminal amoebicide Weak antifungal & antibacterial External application : dermatophytosis , mycosis barbae, pitryasis versicolor Selenium sulfide: T. versicolor Potassium iodide: Dermatophytic infection

Spectrum of actionNystatin: Candidiasis only Griseofulvin: Dermatophytosis only Terbinafine : Dermatophytosis & candidiasis Caspofungin: Aspergillosis & candidiasis

Important characteristicsBroad spectrum: AMB, KTZ, FLU, ITRNephrotoxic/ Anemia: AMBLeucopenia: 5 FC GIT upset: All Over all toxicity: highest for AMB lowest for fluconazole, itraconazole