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Antifungal AgentsAntifungal AgentsSystemic and TopicalSystemic and Topical
Dr Khairani Idah Mokhtar (PhD)Dr Khairani Idah Mokhtar (PhD)School of Dental SciencesSchool of Dental SciencesUSM Health CampusUSM Health Campus
Acknowledgement:Dr Asia Rehman (PPSG)Dr Mohd Suhaimi Ab. Wahab (Dept. of Pharmacology, PPSP)
Lecture OutlineLecture Outline FungalFungal Classification of antifungal drugClassification of antifungal drug Mechanism of actionsMechanism of actions Adverse effectsAdverse effects
Fungi -eukaryotesFungi -eukaryotes Morphologically:Morphologically:
– unicellular (yeasts) unicellular (yeasts) – multicellular (molds/hyphae)multicellular (molds/hyphae)– alternate between the two forms alternate between the two forms
(dimorphic fungi)(dimorphic fungi)
The Trichophyton fungus, photographed under an electron microscope at more than 4,000 times its original size, causes ringworm of the scalp (tinea capitis). The fungus is reproducing by flowering. © Oliver Meckes/Photo Researchers, Inc.Read more: http://www.humanillnesses.com/original/E-Ga/Fungal-Infections.html#ixzz0cZ8Ktrb3
Tinea capitis or fungal of scalp http://www.provlab.ab.ca/mycol/tutorials/derm/3case.htm
DrugDrug ApprovalApprovalNystatinNystatin 19541954Amphotericin B deoxycholateAmphotericin B deoxycholate 19581958GriseofulvinGriseofulvin 19591959Miconazole, clotrimazole (topical)Miconazole, clotrimazole (topical) 19691969FlucytosineFlucytosine 19721972Miconazole (IV)Miconazole (IV) 19791979KetoconazoleKetoconazole 19811981FluconazoleFluconazole 19901990Itraconazole (capsules)Itraconazole (capsules) 19921992Terbinafine (topical)Terbinafine (topical) 19931993Terbinafine (oral), ABLCTerbinafine (oral), ABLC 19961996ABCD, Liposomal Ampho B, Itraconazole ABCD, Liposomal Ampho B, Itraconazole (oral solution)(oral solution)
19971997
CaspofunginCaspofungin 20012001VoriconazoleVoriconazole 20022002MicafunginMicafungin 20052005AnindulafunginAnindulafungin 20062006
History of antifungal drug development
Fungal infections:Fungal infections: Superficial- skin, hair, nail, mucous Superficial- skin, hair, nail, mucous
membranesmembranes
Systemic-affecting body as whole Systemic-affecting body as whole e.g in AIDS patientse.g in AIDS patients
Life-threateningLife-threatening Compromised host “opportunistic Compromised host “opportunistic
mycoses”mycoses” Causative fungus: Candida*, Aspergillus, Causative fungus: Candida*, Aspergillus,
CryptococcusCryptococcusCandida albicans-oral lesion, oral thrush Candida albicans-oral lesion, oral thrush
(candidiasis), denture stomatitis(candidiasis), denture stomatitis
Antifungal drugsAntifungal drugs
2 categories:2 categories: Systemic drugsSystemic drugs – oral or parenteral – oral or parenteral
– Systemic infectionsSystemic infections– Mucocutaneous infectionsMucocutaneous infections
> 8 agents. Most common:> 8 agents. Most common: amphotericin B, fluconazole,amphotericin B, fluconazole, itraconazole, & itraconazole, &
ketoconazoleketoconazole
Topical therapyTopical therapy
>16 agents. Most common:>16 agents. Most common:clotrimazole, miconazole & nystatinclotrimazole, miconazole & nystatin
Antifungals - Antifungals - classificationsclassifications PolyenePolyene
– Amphothericin B Amphothericin B – NystatinNystatin
AzolesAzoles– ImidazolesImidazoles
KetoconazoleKetoconazole MiconazoleMiconazole ClotrimazoleClotrimazole
– TriazolesTriazoles ItraconazoleItraconazole FluconazoleFluconazole VoriconazoleVoriconazole
EchinocandinsEchinocandins– CaspofunginCaspofungin– MicafunginMicafungin– Anidulafungin Anidulafungin
GriseofulvinGriseofulvin Terbinafine (allylamines)Terbinafine (allylamines) FlucytosineFlucytosine
Image from http://www.doctorfungus.org/thedrugs/antif_pharm.htmImage from http://www.doctorfungus.org/thedrugs/antif_pharm.htm
Cell wall
Cell membrane
Targets for antifungal drugs
Cholesterol primarily in mammalian cell membrane, ergosterol predominant in many pathogenic fungal cell membrane
How do they work?How do they work?
Image from http://www.doctorfungus.org/thedrugs/antif_pharm.htmImage from http://www.doctorfungus.org/thedrugs/antif_pharm.htm
Polyenes and azoles -target ergosterol destroying the cell membrane’s integrity.
Allylamines (terbinifine)- inhibit ergosterol synthesis.
Echinocandins β-3-glucan synthesis inhibitor block the production of the β-(1,3)-glucan protein damaging the cell wall.
flucytosine inhibit DNA/RNA synthesis
griseofulvin inhibit fungal cell mitosis preventing cell proliferation and function.
Nikkomycin and Polyoxin target chitin synthase.
Mannoproteins are another potential target.
Polyene group; Polyene group; amphotericin B, amphotericin B, nystatinnystatin
Mechanism of action:Mechanism of action:– Interact with ergosterol – component of Interact with ergosterol – component of
cell membranecell membrane– Produce hydrophilic channelsProduce hydrophilic channels– Leakage of cell contents and Leakage of cell contents and
electrolytes electrolytes Intracellular ion lossIntracellular ion loss Disrupt osmotic function of membraneDisrupt osmotic function of membrane
– Alters cell metabolismAlters cell metabolism
http://www.doctorfungus.org/thedrugs/antif_pharm.htmhttp://www.doctorfungus.org/thedrugs/antif_pharm.htm
Mechanism of actionAlteration of cell permeability by pores formation. Causing leakage of intracellular components. Leads to cell death.
Amphothericin BAmphothericin B Broad spectrumBroad spectrum Powerful but toxicPowerful but toxic Candida sppCandida spp., aspergillus, ., aspergillus,
Histoplasma capsulatum, C. imitis, Histoplasma capsulatum, C. imitis, Blastomyces dermatitidis, Blastomyces dermatitidis, Cryptococcus neoformansCryptococcus neoformans
Amphothericin BAmphothericin B IntravenousIntravenous
– Test doseTest dose– Infusion over 6 hoursInfusion over 6 hours– 4 hrs vs 1 hr*4 hrs vs 1 hr*
Highly protein boundHighly protein bound Poor CSF penetration (2-3%)Poor CSF penetration (2-3%)
– May need intrathecal administrationMay need intrathecal administration Slow release from peripheral compartmentSlow release from peripheral compartment Slow excretion in urine and bileSlow excretion in urine and bile
*E C Oldfield et. Al., Randomized, double-blind trial of 1- versus 4-hour amphotericin B infusion durations. Antimicrob Agents Chemother. 1990 July; 34(7): 1402–1406
Amphothericin B – adverse Amphothericin B – adverse effectseffects
ImmediateImmediate– Infusion relatedInfusion related
Fever, rigors (6%), hypotensionFever, rigors (6%), hypotension Premed with PCM or steroid may helpPremed with PCM or steroid may help
DelayedDelayed– NephrotoxicNephrotoxic
80% with cumulative dose of >4 mg80% with cumulative dose of >4 mg Azotemia, RTAAzotemia, RTA Saline loading may reduce the riskSaline loading may reduce the risk
– Electrolyte disturbanceElectrolyte disturbance Hypokalaemia, hypomagnesemiaHypokalaemia, hypomagnesemia
– Normochromic normocytic anaemiaNormochromic normocytic anaemia Lipid formulationLipid formulation –reduce side effects –reduce side effects
Liposomal Ampho BLiposomal Ampho B liposome-encapsulated formulationliposome-encapsulated formulation
Ampho B in lipid delivery Ampho B in lipid delivery vehiclevehicle
Binding affinityBinding affinity– Less to host membraneLess to host membrane– More to fungal membraneMore to fungal membrane
Act as Ampho B reservoirAct as Ampho B reservoir Reduce toxicityReduce toxicity
– 5 X higher dose5 X higher dose FormulationsFormulations
– AmBisomeAmBisome– AmphotecAmphotec– AbelcetAbelcet
25 – 75 X more expensive25 – 75 X more expensive
nystatinnystatin Active against candida, cryptococcus, Active against candida, cryptococcus,
histoplasmahistoplasma Highly toxicHighly toxic Used mainly for superficial fungal Used mainly for superficial fungal
infections – candidainfections – candida Available as Available as
– tablets, tablets, – suspension, suspension, – vaginal pessaries, vaginal pessaries, – creamcream
Polyene: contains many double bonds
Nystatin Used for local effect.Not absorbed from skin or
mucous membranes. Uses; For infections caused by
Candida A. Thrush, denture stomatitis,
antibiotic stomatitis. Side effects;
– Nausea after oral administration.
Amphotericin BAvailable for I/V injectionNot absorbed from GIT & little Not absorbed from GIT & little
from broken skin.from broken skin. Uses; I/V for systemic fungal I/V for systemic fungal
infections.infections. Otherwise alternative to Otherwise alternative to
nystatin.nystatin. In dentistryIn dentistry; amphotericin B ; amphotericin B
lozenges / oral suspension for lozenges / oral suspension for local use.local use.
Side effects; (with parenteral (with parenteral use)use) Fever, nausea, vomiting, Fever, nausea, vomiting,
hypotension.hypotension. Nephrotoxic; increase in blood Nephrotoxic; increase in blood
urea.urea. Neurotoxic; seizures & Neurotoxic; seizures &
paresthesia.paresthesia.
Azoles –Azoles –synthetic compoundsynthetic compound
Mechanism of actionMechanism of action Reduce ergosterol synthesis Reduce ergosterol synthesis
– inhibit fungal cytochrome P450 enzymeinhibit fungal cytochrome P450 enzyme– 14-alpha-demethylase14-alpha-demethylase
– forms lanosterolforms lanosterol Creates a leaky cell membrane.Creates a leaky cell membrane. Impaired membrane function Impaired membrane function
interferes with fungal replication.interferes with fungal replication.– Leads to altered cell metabolism & death.Leads to altered cell metabolism & death.
Mechanism of actionInhibits demethylation of lanosterol to ergosterol by 14-alpha-demethylase (P450 enzyme)
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Azoles- classificationAzoles- classification ImidazolesImidazoles (2 N (2 N
atoms)atoms)– KetoconazoleKetoconazole
Given orallyGiven orally Systemic infection Systemic infection
– Miconazole, Miconazole, Clotrimazole Clotrimazole
For local applicationFor local application
TriazolesTriazoles (3 N atoms) (3 N atoms)– Higher affinity for Higher affinity for
fungal enzymefungal enzyme– Less toxic than Less toxic than
imidazolesimidazoles Fluconazole (oral, Fluconazole (oral,
IV)IV)– Good GIT Good GIT
absorptionabsorption– Good CSF Good CSF
penetrationpenetration ItraconazoleItraconazole
– Good absorptionGood absorption– Poor CSF Poor CSF
penetrationpenetration VoriconazoleVoriconazole
– Visual disturbance Visual disturbance in 30% of patientsin 30% of patients
*Triazoles safer than *Triazoles safer than imidazole, imidazole, flucanazoleflucanazole is is widely usewidely use
AzolesAzoles Oral and iv administrationOral and iv administration Less toxic than Ampho BLess toxic than Ampho B
– Clinical Use: Clinical Use: – many Candida species many Candida species
Cryptococcus neoformans Cryptococcus neoformans endemic mycoses such as blastomycoses, endemic mycoses such as blastomycoses,
histoplasmosishistoplasmosis dermatophytes dermatophytes Aspergillus:itraconazole Aspergillus:itraconazole
Adverse effectsAdverse effects relatively nontoxic relatively nontoxic Most common: minor gastrointestinal upset Most common: minor gastrointestinal upset Very rare: hepatitis Very rare: hepatitis
Drug Interactions: Azoles-- drug interactions due to Drug Interactions: Azoles-- drug interactions due to effects on cytochrome P450 enzyme systems effects on cytochrome P450 enzyme systems
Flucytosine (5-FC)Flucytosine (5-FC) Not commonly usedNot commonly used Derived from fluorouracil (5-FU)Derived from fluorouracil (5-FU) Mechanism of action:Mechanism of action:
– Taken up by fungal cell; believes it to be Taken up by fungal cell; believes it to be cytosinecytosine– It is then deaminated to 5-fluorouracil; an antimetabolite.It is then deaminated to 5-fluorouracil; an antimetabolite.– Interferes with DNA synthesis & cell death.Interferes with DNA synthesis & cell death.
No anticancer propertyNo anticancer property Narrow spectrumNarrow spectrum
– C. neoformans, Candida spC. neoformans, Candida sp Oral formulationOral formulation Adverse effectsAdverse effects
– Marrow suppressionMarrow suppression– Hepatitis Hepatitis
Griseofulvin Griseofulvin Mechanism of actions:Mechanism of actions:
– Binds to microtubules.Binds to microtubules.– Disrupts cell’s mitotic spindle structure.Disrupts cell’s mitotic spindle structure.– Arrest of cell division.Arrest of cell division.– Results in inhibition of fungal mitosis (reproduction).Results in inhibition of fungal mitosis (reproduction).
Effective only against tinea (ring worm) Effective only against tinea (ring worm) infections in skin, hair & nails. infections in skin, hair & nails.
Use for systemic treatment of dermatophytosisUse for systemic treatment of dermatophytosis Bound to keratin in newly form epidermis, Bound to keratin in newly form epidermis,
protect the skinprotect the skin Need to be given for 2-6 weeksNeed to be given for 2-6 weeks Replaced by itraconazole and terbinafineReplaced by itraconazole and terbinafine
EchinocandinsEchinocandins Caspofungin, Micafungin, AnidulafunginCaspofungin, Micafungin, Anidulafungin New antifungalsNew antifungals Mechanism of action:Mechanism of action:
– Blocks the synthesis of a major fungal cell Blocks the synthesis of a major fungal cell wall component, 1-3-beta-D-glucanwall component, 1-3-beta-D-glucan
Available only in intravenous formAvailable only in intravenous form Single daily doseSingle daily dose Use for resistant infectionUse for resistant infection Not much of side effectsNot much of side effects
-specific target to fungal cell wall-specific target to fungal cell wall
Summary:Summary: Amphothericin BAmphothericin B Azoles- fluconazoleAzoles- fluconazole
– Drug formulationsDrug formulations– Side effectsSide effects
Thank you for your Thank you for your attentionattentionReferencesReferencesKatzung’s Basic and Clinical Katzung’s Basic and Clinical Pharmacology, 11Pharmacology, 11thth Ed. 2008 Ed. 2008