antifungal agents ( systemic and topical)

This ppt gives a overall view of classification of antifungal agents with mechanism of action, adverse effects , spectrum and dosage of each individual drug

1. ANTIFUNGAL AGENTS

2. Classification
I. Antibiotics
A. Polyenes B. Heterocyclic benzofuran
AmphotericinB (AMB) Griseofulvin
Nystatin C. Echinocandins
Hamycin Caspofungin, Micafungin,
Natamycin Anidulafungin
II. Antimetabolites
Flucytocine(5-FC)
III. Azoles
A. Imidazoles(topical) B. Imidazoles(systemic)
Clotrimazole Ketoconazole
Econazole C. Triazoles(systemic)
Miconazole Fluconazole, Itraconazole, Voriconazole
Oxiconazle Posaconazole
IV. Allylamine
Terbinafine
V. Other topical agents:Tolnaflate, Undecylenicacid, Benzoic acid,
Quiniodochlor, Ciclopriroxolamine, Butenafine, Sod. thiosulfate

3. Pharmacology of PolyeneAntibiotic
AmphotericinB (AMB)
Amphotericin(also called amphotericinB) is a mixture of
antifungal substances derived from cultures of Streptomyces
nodosus

4. Chemistry
1.AmphotericinBisaheptaenemacrolidecontainingseven
conjugateddoublebondsinthetranspositionand3-amino-
3,6-dideoxymannose(mycosamine)connectedtothemain
ringbyaglycosidicbond.
2.Theamphotericbehaviorforwhichthedrugisnamedderives
fromthepresenceofacarboxylgrouponthemainringand
aprimaryaminogrouponmycosamine;thesegroupsconfer
aqueoussolubilityatextremesofpH.

5. Mechanism of action
1. AMB acts by inhibiting fungal cell membrane function.
2. The site of amphotericinaction is the fungal cell membrane,
where it interferes with permeability and with transport
functions.
3. It forms binds toergosterolof fungal cell membrane to from
large pores (ion channels) in the cell membrane leading to loss of
intracellular K
+
ions.

6. Antifungal Spectrum
AmphotericinB is used to treat systemic disseminated fungal
infections caused by
1. Candida spp., Cryptococcus neoformansand
2. Dimorphic fungi (Aspergillusspp) like
Histoplasmacapsulatum
Coccidioidesimmitis
Blastomycesdermatitidis, and
Sporothrixschenckii.
It is the gold standard for treating disseminated infections
caused by several organisms including Aspergillusand Candida.

7. Pharmacokinetics
Absorption:AmphotericinBisprimarilyanintravenousdrug;
absorptionfromtheintestinaltractisminimal.
Distribution:90%ofthedrugisboundtoprotein.Itsinitialhalf-life
isabout24hours;thesecondeliminationphasehasahalf-lifeof15
days.Drugconcentrationsinpleuralfluid,peritonealfluid,synovial
fluid,aqueoushumor,andvitreoushumorapproachtwo-thirdsofthe
serumconcentrationwhenlocalinflammationispresent.Meningeal
andamnioticfluidpenetration,withorwithoutlocalinflammation.
Metabolism:About60%ofdrugismetabolizedinliver
Excretion:About5%ofamphotericinBisexcretedintheurineas
activedrug,withdrugstilldetectableintheurine7ormoreweeks
afterthelastdose.

8. Adverse effects
1. Renal toxicity: Some degree of reduction of renal function
occurs in more than 80% of patients receiving the drug.
2. Impaired hepatic function
3. Thrombocytopenia
4. Anaphylactic reactions
5. Others
a) Injection frequently results initially in chills, fever, tinnitus
and headache, and about one in five patients vomits.
b) The drug is irritant to the endothelium of the veins, and local
thrombophlebitisis sometimes seen after intravenous injection.
c) Intrathecalinjections can cause neurotoxicity, and topical
applications cause a skin rash.

9. Interactions
1. Flucytocinehas supra additive action with AMB.
2. Rifampinand minocyclinepotentiate AMBaction.
3. Aminogycosides, vancomycin, and cyclosporine enhance renal
toxicity of AMB.
Uses
1.Candidaesophagitisrespondstomuchlowerdosesthandeeply
invasivemycoses.
2.IntrathecalinfusionofC-AMBisusefulinpatientswith
meningitiscausedbyCoccidioides.
3.IntravenousadministrationofamphotericinBisthetreatment
ofchoiceformucormycosisandisusedforinitialtreatmentof
cryptococcalmeningitis,severeorrapidlyprogressing
histoplasmosis,blastomycosis,coccidioidomycosis,and
penicilliosismarneffei,aswellasinpatientsnotrespondingto
azoletherapyofinvasiveaspergillosis,extracutaneous
sporotrichosis,fusariosis,alternariosis,andtrichosporonosis.
Brands:MYCOL50mgi.v

10. Pharmacology of Antibiotic Heterocyclic benzofuran
Griseofulvin:Produced by the mold Penicilliumgriseofulvin,
Strucutre

11. Mechanismofaction
1.Griseofulvininhibitsmicrotubulefunctionandtherebydisrupts
assemblyofthemitoticspindleandformsmultinucleatecells
asthedruginhibitsfungalmitosis.
2.Inadditiontoitsbindingtotubulin,griseofulvininteractswith
microtubule-associatedprotein.

12. Antifungal Spectrum
1. Griseofulvinis fungistaticin vitrofor various species of the
dermatophyteslike
Microsporum
Epidermophyton,and Trichophyton
2. The drug has no effect on bacteria or on other fungi.

13. Pharmacokinetics
1.Griseofulvinisgivenorally.Itispoorlysolubleinwater,and
absorptionvarieswiththetypeofpreparation,inparticularwith
particlesize.
2.Itistakenupselectivelybynewlyformedskinand
concentrateditthekeratin.
3.Theplasmahalf-lifeis24h,butitisretainedintheskinfor
muchlonger.
4.ItpotentlyinducescytochromeP450enzymesandcauses
severalclinicallyimportantdruginteractions.
Adverseeffects
1.Gastrointestinalupsets,headacheandphotosensitivity.
2.Allergicreactions(rashes,fever)mayalsooccur.
3.Thedrugshouldnotbegiventopregnantwomen.

14. Interactions
1.GriseofulvininduceshepaticCYPs,therebyincreasingtherate
ofmetabolismofwarfarin.
2.Thedrugmayreducetheefficacyoflow-estrogenoral
contraceptiveagents,probablybyasimilarmechanism.
Uses
1.Mycoticdiseaseoftheskin,hair,andnailsdueto
Microsporum,Trichophyton,orEpidermophyton
2.Fortineacapitisinchildren,efficacyisbestfortineacapitis
causedby Microsporumcanis,Microsporumaudouinii,
Trichophytonschoenleinii,andTrichophytonverrucosum.

15. 3.Griseofulvinalsoishighlyeffectiveintineapedis,thevesicular
formofwhichismostcommonlyduetoT.mentagrophytes
andthehyperkeratotictypetoT.rubrum.
4.Griseofulvinisalsoeffectiveforringwormoftheglabrousskin;
tineacrurisandtineacorporiscausedbyM.canis,
Trichophytonrubrum,T.verrucosum,andEpidermophyton
floccosum;andtineaofthehands(T.rubrumandT.
mentagrophytes)andbeard(Trichophytonspecies).’
Brands:GRISOVIN-FP,WALAVIN,GRISORAL250mgtab

16. Pharmacology of Imidazole
Ketoconazole

17. Mechanism of action
1.Ketoconazoleactsbyinhibitingfungalcellmembranesynthesis.
2.Importantmoleculartargetintheergosterolsynthesispathway
is14a-steroldemethylase,amicrosomalcytochromeP450
enzymethatconvertslanosteroltoergosterol.
3.Theazolesareantifungalagentsthatinhibitfungal14a-sterol
demethylase.Theresultingdecreaseinergosterolsynthesisand
accumulationof14a-methylsterolsdisruptthetightlypacked
acylchainsofthephospholipidsinfungalmembranes.
4.Destabilizationofthefungalmembraneleadstodysfunctionof
membrane-associatedenzymes,includingthoseintheelectron
transportchain,andmayultimatelyleadtocelldeath.

18. Antifungal spectrum
1. Azoles as a group have clinically useful activity against Candida
albicans,
Candida tropicalis
Candida parapsilosis
Candida glabrata
Cryptococcus neoformans
2.Blastomyces dermatitidis
3. Histoplasmacapsulatum
4.Coccidioidesspp., Paracoccidioidesbrasiliensis,and ringworm
fungi (dermatophytes).
5. Aspergillusspp., Scedosporiumapiospermum(Pseudallescheria
boydii), Fusarium, and Sporothrixschenckiiare intermediate in
susceptibility.
6.These drugs do not have any useful antibacterial or antiparasitic
activity.

19. Adverse effects
1.The main hazard of ketoconazoleis liver toxicity, which is rare
but can prove fatal. Liver function is monitored before and
during treatment.
2.Other side effects that occur are gastrointestinal disturbances
and pruritus.
3. Inhibition of adrenocorticalsteroid and testosterone synthesis
has been recorded with high doses, the latter resulting in
gynaecomastiain some male patients.
Interactions
1. Ciclosporinand astemizoleall interfere with cytochromeP450
drug-metabolisingenzymes, causing increased plasma
concentrations of ketoconazoleor the interacting drug or both.
2. Rifampicin, histamine H
2receptor antagonists and antacids
decrease the absorption of ketoconazole.

20. Uses
1.Ketoconazoleremainsusefulinthetreatmentofcutaneous
andmucousmembranedermatophyteandyeastinfections,
butithasbeenreplacedbythenewertriazolesinthe
treatmentofmostseriousCandidainfectionsand
disseminatedmycoses.
2.Ketoconazoleisineffectiveinthetreatmentofcryptococcosis,
aspergillosis,andmucormycosis.
3.Widespreaddermatophyteinfectionsonskinsurfacescanbe
treatedeasilywithoralketoconazole.
Brands:FUNGICIDE,,KETOVATE200mgtab.
NIZORALANTIDANRUF2%shampoo

21. Pharmacology of Triazole
FLUCONAZOLE

22. Pharmacokinetics
1. It is 94% absorbed orally. Bioavailability not affected by
food or gastric pH.
2. Its t
1/2is 25-30 hr.
3.Fungicidal concentration is obtained in nails, vagina &
saliva.
4. Excreted unchanged in urine.
Mechanism of action
Same as that of KTZ

23. Adverse effects
1.Few side effects than KTZdue to more selectivity for
cytochromeP450.
2.Nausea, vomiting, abdominal pain, rash and headache.
3.Elevation of hepatic transaminasein AIDS patients.
4.Contraindicated in pregnancy and lactation.
Interactions
1. Plamsalevels of phenytoin, astemizole, cisapride, warfarin,
Zidovudineand sulphonylureashave been observed.

24. Uses
1.Fluconazoleisadrugofchoiceinesophagealand
oropharyngealcandidiasisandformostinfectionscausedby
Coccidioides.
2.Asingleoraldoseusuallyeradicatesvaginalcandidiasis.
3.Fluconazoleisthedrugofchoicefortreatmentandsecondary
prophylaxisagainstcryptococcalmeningitisandisan
alternativedrugofchoice(withamphotericinB)intreatment
ofactivediseaseduetoCryptococcusneoformans.
Brands
SYSCAN,ZOCON,FORCAN50,100,150,200mgcaps
200mg/100mli.v.infusion