dr. Dwi Indria Anggraini, MSc., SpKK.

Dep. Of Pharmacology and Pharmacy

Faculty of Medicine, Lampung University
 Topical Systemic

• Imidazoles • Allylamines:  Terbinafine  

• Allylamines  and   • Triazoles
Benzylamines   • Itraconazole
• Polyenes   • Fluconazole  
• Other  Agents   • Voriconazole
• Ciclopiroxolamine   • Imidazoles:  
• Tolnaftate   Ketoconazole
• Undecylenic  acid   • Miscellaneous:  
Griseofulvin  
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Properties of an Ideal Topical Antifungal Agent
• Broad spectrum
• Fungicidal
• Absence of resistance within the targeted fungi
• Keratinophilic with penetration of the cornified
envelope without systemic absorption
• Nonirritating and hypoallergenic
• Possess anti-inflammatory properties
• Once-per-day application (or less)
• Short duration of therapy
• Multiple formulations (cream, solution, etc.) and sizes
• Inexpensive
 Impede   synthesis   of  a  component   of  the  
fungal  cell  wall  through   inhibition  of  
lanosterol 14α-­‐demethylase (lanosterol to  
ergosterol).

Depletion   of  ergosterol results   in  

membrane   instability   and  
hyperpermeability

Changes   incompatible   with  

growth  and  survival  of  the  fungus.  

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¡ Strong  keratinophilic à penetration  of  the  
SC  >>>
¡ High  affinity  for  keratin  à low systemic  
absorption
¡ Urinary  excretion  à 0.3%–1.0%  of  the  
applied  dose.  
¡ In  the  inflamed  skin,  absorption  of  imidazoles
does  not  usually  exceed  4%  of  the  applied  
dose.
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Dermatophytoses
• Tinea  pedis/tinea  manum
• Tinea  cruris
• Tinea  corporis
• Tinea  faciei  (the  unbearded  face)  
Pityriasis  versicolor  

Mucocutaneous  candidiasisa  
• Cutaneous  candidiasis  
• Vulvovaginal  candidiasis
• Oral  candidiasis  (thrush)
Seborrheic  dermatitis  
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Econazole,  ketoconazole,  and  oxiconazole  are  approved  for  
once-­‐daily  dosing

Application  should  include  normal  skin  for  a  radius  of  2  cm  

beyond  the  affected  area.  

Duration  of  treatment  with  imidazoles  has  varied.  

• tinea  corporis   and  tinea  cruris  :  + 2  weeks

• tinea  pedis  :  up  to  4  weeks
• treatment   should   be  continued   for  at  least   1  week   after  all  symptoms   have  
abated
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 Risks  And   • Irritant  reactions
Precautions • Allergic  reactions

• Drug  reactions  are  rare

• Increased  serum  tacrolimus  levels  were  observed  in  
Complications renal  transplant  recipients  who  used  clotrimazole  
troches  for  mucocutaneous  candidiasis.
• Concerns  of  resistance  must  also  be  considered.

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Impede  synthesis  of  ergosterol through  
inhibition  of  squalene epoxidase (converts  
squalene to  squalene oxide).  

Depletion  of  ergosterol àmembrane  

instability  and  hyperpermeability.  

Fungicidal  (accumulation  of  intracellular  

squalene leads  directly  to  cell  death)  

¡ Terbinafine à 10–100-­‐fold  increased   potency   in  vitro  than  naftifine

¡ Anti-­‐inflammatory   activity
¡ Limited   antibacterial   properties

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¡ Highly  lipid  soluble  
¡ Efficiently  penetrate  the  SC
¡ Butenafine:  within  the  SC  at  minimum  inhibitory  
concentration  for  at  least  72  hours  after  app.
¡ Terbinafine may  persist  at  a  similar  level  for  up  to  
7  days  after  app.
¡ Low  Systemic  absorption  à urinary  excretion  
3%–5%  of  the  applied  dose.

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¡ Dermatophytoses
§ Tinea pedis/tinea manum
§ Tinea cruris
§ Tinea corporis
¡ Tinea faciei (the  unbearded face)  
¡ Pityriasis versicolor

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Nystatin  binds  irreversibly  to  membrane  sterols  
present  in  susceptible  species  of  Candida.

The  polyene  molecules  demonstrate  a  higher  affinity  

for  fungal  sterols,  including  ergosterol

This  irreversible  binding  alters  membrane  

permeability,  causing  leakage  of  essential  intracellular  
components  and  fungal  death.  

Fungistatic in  low  concentrations;  

fungicidal  at  high  concentrations.
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 • Nystatin  is  insoluble  in  water
• Not  absorbed  from  intact  skin,  the  gastrointestinal  tract,  or  the  
vagina.  
PKs

• Topical  nystatin  is  used  to  treat  mucocutaneous candidiasis  

caused  by  C.  albicans,  and  other  susceptible  species  such  as  C.  
parapsilosis,   C.  krusei,  and  C.  tropicalis.  
Indications • Nystatin  is  not  effective  against  dermatophytes  or  Pityrosporum.

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¡ Available  as  a  powder,  cream,  ointment,  
suspension,  and  pastille.  
¡ To  treat  oral  candidiasis  (thrush),  the  suspension  or  
pastille  is  used  4-­‐5  times  daily,  usually  for  2  weeks.  
¡ To  treat  cutaneous  infection,  the  powder,  cream,  
and  ointment  are  used  twice  daily  for  approximately  
2  weeks.  

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 Risks Complications

• Irritant   • Few
reactions • Resistance  
• Allergic   may  be  
contact   encountered  in  
dermatitis some  Candida
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 CICLOPIROX  OLAMINE

• Interrupts  active  membrane   transport  of  essential   cellular   precursors,   particularly  

trivalent   cations à disrupts  cellular   function,  leading   to  demise   of  the  fungus  à if  
concentrations   of  the  drug  are  high   enough,  the  membrane   integrity   of  the  fungus  may  
actually   be  impaired.
• Antiinflammatory and  antibacterial   activities.
• Remains  in  high  concentration   within  the  epidermis   and  upper  dermis.  
• Penetrates   keratin   easily à for  onychomycosis; capable   of  penetrating   the  nail  plate  
material.  
• 10%  of  the  administered   dose  is  excreted   in  the  urine.  
• Indication:
• Dermatophytoses and  onychomycosis,   candidiasis,   pityriasis versicolor,   seborrheic  
dermatitis.

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 TOLNAFTAT

•Impair  ergosterol synthesis  via  inhibition  of  squalene

epoxidase
•Fungistatic or  fungicidal,  depending  upon  the  concentration.
•No  antibacterial  properties.  
•Systemic  absorption  à negligible
•Indication: dermatophytosis and  PV

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 UNDECYLENIC  ACID

•The  organic  acid  interacts  with  components  fungal  cell  wall.  

•In  C.  albicans,  the  inhibition  of  germ  tube  formation  has  been  
recently  identified,  and  a  similar  effect  has  been  noted  in  
conidia  formation  in  Trichophyton rubrum.
•Available  as  a  zinc,  calcium,  or  copper  salt.  
•As  tissue  pH rises,  this  salt  fails  to  dissociate,  and  the  
antifungal properties  of  the  medication  diminish.
•Systemic  absorption  is  negligible
•Used  for  the  treatment  of  dermatophytosis and  candidiasis.  

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• Indicated for extensive fungal skin infections,
tinea pedis, onychomycosis, and tinea capitis.
• Preventive therapy for the immunosuppressed.
• Major classes of antifungal medications used in
outpatient settings:
• allylamines (terbinafine),
• triazoles (itraconazole, fluconazole)
• imidazoles (ketoconazole),
• griseofulvin,
• polyenes (nystatin, amphotericin B)
• ciclopiroxolamine.
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¡ Terbinafine is  
not  contra  
indicated  with  
any  specific  
drug  

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¡ Inhibits  14-­‐α-­‐demethylase in  the  fungal  
membrane  à arrest  of  fungal  cell  growth
¡ Extensively  metabolized,  primarily  by  the  
CYP3A4  iso-­‐enzyme  system.  
Hydroxyitraconazole is  the  main  metabolite.
¡ +54%  excreted  in  the  feces;  34%  in  the  urine.  
¡ PKs  are  not  affected  in  patients  with  renal  
insufficiency.
¡ Liver  cirrhosis  à absorption  is  slightly  increased  
and  the  half-­‐life  is  prolonged  (reduced  1st-­‐pass  
metab).  

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¡ PKs  are  similar  for  both  IV  and  oral  adm.
¡ Near  complete  absorbtion,  is  not  dependent  
on  stomach  acidity.
¡ Long  half-­‐life  of  25–30  hours,  and  a  steady-­‐
state  level  is  reached  after  7  days  of  once-­‐
daily  administrations.  

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¡ Second-­‐generation  triazole agent
¡ Oral  and  intravenous  formulations
¡ Invasive  fungal  diseases,  particularly  invasive  
aspergillosis
¡ Risk  and  Precaution:
§ Cutaneous  adverse  effects  
§ Photosensitivity  reactions
§ Pseudoporphyria
§ Steven-­‐Johnson  syndrome  and  life-­‐threatening  toxic  
epidermal  necrolysis,  
§ Skin  cancers

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¡ fungistatic in  vitro
¡ narrow  spectrum  of  
antimycotic activity.  
¡ disrupts  microtubule  
mitotic  spindle  formation  
à mitotic  arrest  at  the  
metaphase  stage

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¡ Absorption  is  enhanced  by:
§ concurrent  intake  of  a  fatty  meal  
§ smaller  particle  size  formulation
§ mainly  metabolized  by  the  liver  à excretion  

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¡ Griseofulvin induces  
CYP3A4  à lower  
plasma  levels  of  drugs  
metabolized  by  this  
pathway.
¡ Decreased  
anticoagulation  by  
warfarin
¡ Decreased  
effectiveness  of  oral  
contraceptive  pills.  

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¡ Imidazoles
¡ ADRs >>  à no  longer  used  as  a  first-­‐line  agent  for  the  
treatment  of  dermatophyte or  yeast  infections.  

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Terima  Kasih  ...