ANTIFUNGALS IN

DERMATOLOGY
Presented by : Dr TAH NJI Joy
Third year Resident in Dermatology
Supervisor : PROF KOUOTOU A. E.
2 Objective

1. Give the major groups and specific examples of antifungal

drugs

2. Describe the mechanism of action of antifungal drugs

including their pharmacological effects

3. To outline the clinical application of the drugs in medicine

 Plan
3
Introduction

I. Generalities

II-Pharmacological study

III-Indications

IV. Contraindication and precautions for use

V. Side effects and drug interactions

VI. Monitoring

Conclusion
 Introduction
4

 Pathogenic funfi of humans are generally fillamentous molds or

intracellular yeasts

 Fungal cell walls contain chitin and polysaccharides making them rigid
and acts as a barrier to drug penetration

 Fungi cell membranes contains ergosterols which influences the

efficacy and the risk of drug resistance

 Most antifungal agents are fungistatic with infection clearance

depending on the host and a few are fungicidal.
 1. General
5

1.1.Definition

Antifungals: synthetic or natural chemical substances having a specific

action on fungi cell wall and components of their plasma membrane
 1. General
6

1-2-Interest

 Epidemiological

 moleculesa lotprescribed mainly Fluconazole in 72% (fungal infections

increasing considerably over the last 20 years)

 revolutiontaken infungal loadnotablydeep

 1. General
7

1-2-Interest

 Epidemiological (continued)

 phenomenonresistance

pantifungal rescription not in accordance with recommendations,

treatment duration not respected

hasfungal infections treated on pharmacist advice in 46.5% without

physical examination or sampling for mycological examination (each
 1. General
8

1-2-Interest

 Therapeutic:molecules inducing effectsbenign or even serious secondary

effects (teratogenic effects,nephro-hepatotoxicity…)monitoringclinical
andparaclinic
 1. General
9

1-3 Recall
 1. General
10

1-3 Recall
 1. General
11
1-2-Classification based on chemical structures
Antifungal families Molecules
Table I:antifungal classification
Polyenes AmphotericinB, Nystatin, Hamycin
Allylamines Terbinafine, butenafine
pyrimidines Flucytosine

Derivatives of azoles Itraconazole, Fluconazole, voriconazole…

Echinocandins Caspofungin, Mycafungin, Anidulafungin
Hydroxypyridone Ciclopiroxolamine
Hetrocyclic benzofurans Griseofulvin
 1. General
12
 Derivatives of Azoles
13  Most commonly used
 Synthetic antifungals with Broad spectrum
 Fungicidal or fungistatic depending on concentration of drug
 Classified into :
 Imidazoles:
• topical (econazole, miconazole, clotrimazole),
• Systemic/ oral: ketoconazole )
• New agents: butaconazole, oxiconazole, sulconazole
 Triazoles:
• Systemic: Itraconazole, Fluconazole, voriconazole
• Topical: tercoonazole
I- Azoles
 Chemistr y

 Ketoconazole, Miconazole, Fluconazole, Itraconazole,

Voriconazole

14
 Derivatives of Azoles
15

2-2-Mechanism of action

 inhibits fungal Cyp3A4

chromosome P450 needed for
ergosterol synthensis

 disrupts membrane function and

increases permiability

 fungistatic
 Derivatives of Azoles
16 2-1-pharmacokinetics
Molecules Absoption Metabolism Distribution Elimination

Fluconazole Digestive -Not metabolized Homogeneous Urinary in

absorption -inhibits fungal distribution in unchanged
Cyp3A4 chromosome tissues with good form
P450 CNS and GIT
diffuion
Itraconazole -Digestive Liver metabolism by Diffusiontissue biliary
peak in 3 to 4h isoenzymeCYP34A intense but weak in
Half-life30-50h CSF

Voriconazol - Digestive Metabolism hepatic by Nonlinear kinetics urinary

e - 1/2 life 6 – 9 h isozymes Cytochrome
P450
 Derivatives of Azoles
17 indications contraindications interactions Side effects

Mycoses cutaneous- - Hepatic Not -digestive disorders

mucosalsuperficial(yeast insufficiency associatedcarbamaz (nausea, pain)
s,dermatophytes,Malasse - Hypersensitivity epine, rifampicin, -skin disorders
zia furfur, mold) and - Heart failure simvastatin, (alopecia, bullous
deeps (Histoplasma - Pregnancy and domperidone, ergot drug addiction,
sp.,Blastomyces breast feeding alkaloid especially in HIV
dermatitidis,Paracoccidio cases)
ides brasiliensi, -disordershepato-
basidiobolomycosisAndr biliary
hinophtoromycosis) -nervous disorders
(headaches, anxiety,
confusion)
-hematological
disorders
(neutropenia,
thrombocytopenia)
-disorderscardiac:
lengtheningQT
-visual disturbances
sometimes
 Derivatives of Azoles
18 2-4-Molecules available
Classes DCI speciality Dosage forms dosage Lanes
Derivati -Miconazole -Daktarin® - oral gel,vaginal -2-3applications/jr Oral
ves lotion, powder and local
azoles gel2%
- ovule at 100 and - 1 ovule/day - Vaginal
400 mg

-Econazole -Pevaryl®, Ecorex® - Cream, milk, - 2appl/day - Local

powder 1%
-ovule 150 mg - 1 ovule /day - Vaginal

-Ketoconazole -KNZ®, Nizoral® -comp200mg - 1-2comp/day - Oral

-Kétoderm® -foaming gel 2% - 3appl/week - local
sachets;2% cream 15g
tube - 1 appl/day
 Derivatives of Azoles
19 2-4-Molecules available
Classes DCI speciality Dosage forms dosage Lanes

Derivati -Sertaconazole -Monazol® -cream 2% - 1 appl/day -local

ves -ovum 300mg - 1 egg/day -vaginal
azoles
-Fenticonazole - Lomexin® -2% cream T/15g - 1appl/day
- Terlomexin® -Terlomexincapsulevaginal - 1capsule/day - Same
200 mg B/3

- Isoconazole - Fazol® -cream - 2appl/day - Same

-ovule 300 mg - 1 egg/day

-Voriconazole -Vfend® - Inj50 and 200 mg 8-12 mg/kg/day -IV

- Grounddrinkable 9 mg/Kg/12h -Per os
20

 Mucosal infections: 2weeks

 Skin infections: 6wks
 Hair infections: 6-8weeks
 Nail infections; fingers: 3-6months, toes: 6-9months
 CNS infections
 Derivatives of Azoles
21 2-4-Molecules available
Classes DCI speciality Dosage forms dosage Lanes

Derivati -Fluconazole -Triflucan® -capsules 50 mg, 100 mg, Oral

ves 200 mg - 400at 800 mg/day
azoles -groundinject2mg/ml IV
-suspensiondrinkable - 6 to 12 mg/kg/day
50mg

-Itraconazole Sporanox®
-capsules100 mg B/30 - 100 to 400 mg/day Oral
-oral solution
10mg/mlfl150ml
-Posaconazole Noxafil® - 300-600 mg/day Oral
-comp100, 300mg
-suspdrink40mg - 20 ml/day
 2-Pharmacological study
22

2-1-Metabolism of antifungals

 Polyenes
Molecule Absorption Biotransformati Diffusion Elimination
on
AmphotericinB - Negligible Little known -Weak meningeal Bile+++
digestive diffusion Renal +/-
- Exclusive IV - Storage in
administration viscera
- Half-life2-4h
 2-Pharmacological study
23

2-1-Metabolism of antifungals

 Allylamines
Molecules Distribution Metabolism Diffusion Elimination
Terbinafine - Hepaticbyisozyme -Diffusionfastto dermis urinary
Absorptiondigestiv s cytochrome -concentration in
e70% P450 stratumcorneumand
-peak max in 2 regions rich in
hours sebumThenhair follicles,
-strong connection hair, nails and fatty tissue
to plasma proteins
 2-Pharmacological study
24

2-1-Metabolism of antifungals

 Pyrimidines

Molecule Absorption Biotransformation Diffusion Elimination

flucytosine - -90% General in all Renal in
Digestiveimportan unmetabolized organisms unchanged form
t -10% metabolized including LCR
-half-life3-6h into 5-Fluorouracil
by intestinal
bacteria
 2-Pharmacological study
25

2-1-Metabolism of antifungals

 Echinocandins
Molecules distribution biotransformation Elimination
Caspofungin: -IV Hepatic metabolism -Slow by protein
administrationexclusiv but very slow by degradation
e protein hydrolysisand -low fraction
- Tissue accumulation N-acetylation eliminated by urine in
and slow release the form of
- half-life 10 h metabolites
 2-Pharmacological study
26

2-1-Metabolism of antifungals

 Echinocandins(continued)
Molecules distribution biotransformation Elimination
Micafungin After IV: Remains unchanged In the stool
- Rapid distribution in tissues
- Strong plasma protein binding
Anidulafungin -poor oral absorption No metabolism by Data not
-strong binding to plasma proteins the liver available
(> 99%)
- long half-life (> 24 h)
 2-Pharmacological study
27

2-1-Metabolism of antifungals

 Griseofulvin
Distribution Biotransformation Diffusion Excretion
After oral, Liver: transformation Fixation on - Large part
- Peak plasma in 2-4 into 6- keratin(hair, body eliminated
hours dimethylgriseofulvin(ma hair and nails) unchanged in stools
- Increased intestinal in metabolite) making keratinized - Smallpart by renal
resorption if taken cells resistant to route
with fatty meals dermatophytes
- Half-life10-3 p.m.
 2-Pharmacological study
28

2-2-Mechanism of action

 Polyenes
 2-Pharmacological study
29

2-2-Mechanism of action

 Allylamines
 2-Pharmacological study
30

2-2-Mechanism of action

 Pyrimidines and

Griseofulvin
 2-Pharmacological study
31

2-2-Mechanism of action

 Echinocandins
 2-Pharmacological study
32

2-2-Mechanism of action

 Hydroxypyridones

 fungistatic action by entry inhibitionmetal

ions,phosphatesAndpotassiumInfungal cell

 fungicidal action by disturbance activityrespiratory chains of themushroom

 2-Pharmacological study
33

2-3-Biological effects
Biological effects Classes ormolecules concerned
Actionfungistaticby direct fixation and Hydroxypyridones, griseofulvin, pyrimidines,
alteration of ergosterol, the main steroidal
component of the mushroom wall

Fungicidal actionbymolecule attachment to Allylamines, Echinocandins,

the fungal wall generating abnormal derivativesazoles,Polyenes
permeability via formation of pores in this
wallfrom whereleak intracytoplasmic
components of the fungus and
thereforeherdead
 2-Pharmacological study
34
2-4-Moleculesavailable and how to use
Classes DCI specialties Dosage forms dosage Lanes

Polyenes Ampho- Fungizone® -Oral suspension at 100 -50 mg/kg/day Oral

tericin B mg/mL -1- 1.5 g/D
-Capsules 250 mg - 0.3 mg/kg in 2 to 6
-50 mg powder for perf hours Injectable
Ambisome® IV
-50 mg powder for perf - 3 mg/kg/day for 30
to 60 minutes
Nystatin Mycostatin® Perbone
-compcoated at 500,000 IU -8 to 12comp/ day
--powder for suspension -5-40 doses/day
drinkable at 100,000 IU NRSAndchildren Vaginal
-compvaginal 100,000 IU -1 or 2/daypdt20 days
 2-Pharmacological study
35
2-4-Moleculesavailable and how to use
Classes DCI speciality Dosage forms dosage Lanes

Allyla- Terbinafine Lamisil® -comp250 mg -250 mg/day in adults and Oral

mines B/14 and 28 children over 40 kg

-cream,solution -one or two applications/day - local

and gelat 1%
Pyrimi- flucytosine Ancotil ® -comp500mg -Oral
dines B/100 100at 200 mg/Kg/day
-solution for -IV
infusion 1% 250
ml bottle
 2-Pharmacological study
36 2-4-Moleculesavailable and how to use
Classes DCI speciality Dosage forms dosage Lanes

Echinoca - caspofungin Cancidas® -Powder for infusion 50 -50-70mg/day IV

ndines and 70 mg

- Micafungin Mycamine® -Powder for infusion 50 -50-100 mg/day Same

and 100 mg

- anidulafungin Ecalta® - Powder for infusion -100-200 mg/day Same

100 mg

Hydroxy- - Ciclopyroxo-the Mycoster® -creamAndspray 1% -2appl/day local

pyridone mine -8% film-forming -1appl/day
solution -1-3 times/week
-foaming gel 1%
 2-Pharmacological study
37

2-4-Moleculesavailable and how to use

Classes DCI speciality Dosage forms dosage Lane

s
Others Griseofulvin Greyfulin® scored tablets 250 -1 g/day:adult Oral
Griseopharm® and 500 mg B/20 -15 to 20 mg/kg/day:
child
 3-Indications
38
Classes Indications
Polyenes
- Amphotericin B -cutaneous leishmaniasisAndvisceral, IFI(cutaneous
- Nystatin cryptococcosis)
-digestive and vaginal candidiasis
Allylamines Candidiasis anddermatophytesskin
(Terbinafine)

Pyrimidines(flucyt severe systemic mycoses with sensitive germs (deep candidiasis,

osine) cryptococcosis,chromomycosis, certain aspergillosis)
Derivativesazoles(i Mycoses cutaneous-
midazolesAnd mucosalsuperficial(yeasts,dermatophytes,Malassezia furfur, mold)
triazoles) and deeps (Histoplasma sp.,Blastomyces
dermatitidis,Paracoccidioides brasiliensi,
basidiobolomycosisAndrhinophtoromycosis)
 3-Indications
39

Classes Indications
Echinocandins Invasive candidiasisin non-neutropenic patients
Aspergillosisinvasive
Hydroxypyridones DermatophytiesAndcandioseshairless skin and appendages
Malasseziases, seborrheic dermatitis
Others: dermatophyteshairless skin and appendages
Griseofulvin
40
 4-Contraindications and precautions for use
41
classes Contraindications Precautions for use
Polyenes
- AmphotericinB - Hypersensitivity -Check medicationstaken by the
patient
(nephrotoxic,hypokalemics,
ARV, IMS
- Nystatin - Hypersensitivity, fructose
intolerance,glucose and -avoid intestinal transit
galactose malabsorption modifiers, not recommendedin
syndrome womenpregnant, epileptic…
Allylamines (Terbinafine) - absolute:hypersensitivity, Hepatic and renal assessment to
severe hepatic or renal be carried out before and during
insufficiency treatment perbone
- Related: breastfeeding
 4-Contraindications and precautions for use
42

classes Contraindications Precautions for use

Pyrimidines(Flucytosine) - absolute: hypersensitivity -dosages to be adapted
- related: pregnancy according to renal clearance
-CBC and liver assessment
before and during treatment
Derivativesimidazoles - Hepatic insufficiency -monitoringregular liver and
- Hypersensitivity hematological assessment
- Heart failure
- Pregnancy and breast feeding

Echinocandins - Hypersensitivity Liver assessment monitoring

- Intolerancewith fructose
- Insufficiencysevere hepatic
 4-Contraindications and precautions for use
43

classes Contraindications Precautions for use

-avoid contact with eyes
Hydroxypyridones Hypersensitivity

-avoid exposure to the sun

Others: Griseofulvin Porphyrias, lupus
immediately aftersocket
erythematosus, - Monitor liver function and
CBC
hypersensitivity
 5-Side effects and drug interactions
44

Classes Side effects Drugs interactions

Polyenes
- AmphotericinB -very common: fever, - Not associated with
headache,nausea vomiting, hypokalemic diuretics,
hypokalemia Zidovudine (increased
-common: hepatic and renal disorders, hematotoxicity),
tachycardia aminoglycosides (increased renal
-uncommon: toxicity)
convulsions,thrombocytopenia…

- Nystatin - Allergies and minor digestive - None

disorders
Allylamines (Terbinafine) -very common: rash, urticaria Not associated with Rifampin
-frequent: headache (because plasma level decreases)
-uncommon: ageusia, nausea, diarrhea
 5-Side effects and drug interactions
45
Classes Side effects Drugs interactions
- Hematological disorders (leukopenia, Not associated with zidovudine
Pyrimidines(Flucyt thrombocytopenia) (increasehematotoxicity)
osine) - Liver damage, nausea, vomiting, diarrhea,
skin rashes

Derivativesazoles -digestive disorders (nausea, pain) Not associatedcarbamazepine,

-skin disorders (alopecia, bullous drug rifampicin, simvastatin,
addiction, especially in HIV cases) domperidone, ergot alkaloid
-disordershepato-biliary
-nervous disorders (headaches, anxiety,
confusion)
-hematological disorders (neutropenia,
thrombocytopenia)
-disorderscardiac: lengtheningQT
-visual disturbances sometimes
 5-Side effects and drug interactions
46
Classes Side effects Drugs interactions
Echinocandins -side effects linked to the -increase AUC of thecaspofunginby
infusion (redness, pain, etc.) cyclosporine
-fever, nausea and vomiting -decrease AUC by cytochrome P450
-hepatotoxicity inducers (rifampicin,inhibit.proteasesof
HIV,phenytoin,carbamazepine,dexameth
asone)
Allergic or irritative contact None
Hydroxypyridones
dermatitis

Others: Griseofulvin -headaches,nausea, bullous drug -Decreaseeffects hasanticoagulants

addiction,leukopenia, -Decreaseefficiencyœtrogensand
neutropenia, progestins
anemia,hepatotoxicity+/- -DecreasecpMethadone
 6-Monitoring
47

 Clinical monitoring elements: therapeutic compliance, progression of

cutaneous and mucosal damage, side effects of medications,

 Paraclinical monitoring elements: liver transaminases, renal assessment,

complete CBC, sample for mycological examination
 Conclusion
48

Antifungals:

 bandtherapy frequently used in dermatology

 Goodclinical examination andexplorationparaclinicadequate to avoid

prescriptionsabusive and unnecessary source ofresistance
 References
49

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2-JPBRION. OFof Anti-infectious therapeutics Grenoble March 252021

3-Paul M.Tulkens. Anti-infectious:antifungals

4-MASSANET P., JUNG B. et al. Antifungal treatments in intensive care during documented
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5-HAS (High Authority of Health). Commission of theTransparency.Reviewsof July 22, 2015.

VFEND® Extension of indication. [online]. Available on: www.has-sante.fr (Page consulted on
05/11/2016).
 References
50

6-HAS(High Health Authority) (a). Transparency Commission. Opinion of November 12,

2008.Mycamine50mg, powder for solution for infusion.Mycamine100mg, powder for solution for
infusion. [online]. Available on: www.has-sante.fr

7-HAS(High Health Authority) (b). Transparency Commission. Opinion of September 20, 2006.
SPORANOX® 100mg capsules. [online]. Available on: www.has-sante.fr

8-DATRYA., BART-DELABESSE E. Thecaspofungin: from the mechanism of action to therapeutic

applications.RevMed Interne., 2006, (27), pp.32-39.

9-CAZENAVE B., LANTERNIER F., LORTHOLARY O. New systemic antifungals. The letter from
the infectious disease specialist, 2010, 25 (5), pp.178-184