Topical antifungals

1. TOPICAL ANTIFUNGALS
1

2. ANTIFUNGAL DRUGS
 Work by exploiting differences between mammalian
and fungal cells to kill the fungal organism without
dangerous effects on the host.
 Both fungi and humans are eukaryots .
 Difficult to find or design drugs that target fungi
without affecting human cells. (side effects)

3. IDEAL ANTIFUNGAL AGENT
 Broad spectrum of action.
 Fungicidal at therapeutic conc.
 Keratinophilic with penetration of cornified layer
without syst absorption.
 Nonirritating and hypo-allergic.
 Possess anti inflammatory property.
 Once per day application.
 Availability in multiple formulations.
 Inexpensive
Until now no one current agent possesses all these.

4. Fungal cell membranes have a unique
sterol, ergosterol, which replaces
cholesterol found in mammalian cell
membranes

5. 5

6. HISTORY
 Before the 1940s antifungal therapy comprised of
 Castellini’s paint
 Whitfield’s ointment
 Gentian voilet
 These nonspecific agents were generally irritating, staining and
minimally effective.
 The explosive increase in fungal infections and recurring treatment
failures during world war 2,led for search for improved therapeutic
measures.

7. IMIDAZOLES
 Clotrimazole
 Econazole
 Ketoconazole
 Miconazole
 Oxiconazole
 Sertaconazole
 Sulconazole
 Luliconazole
 bifonazole
 fenticonazol
 Terconazole
 Tioconazole

8. ALLYAMINES &
BENZYLAMINES
ALLYAMINES
 Naftifine
 Terbinafine
BENZYLAMINES
 Butenafine

9. POLYENES
 Nystatin
 Amphotericin B
 Amorolfine
MORPHOLINES

10. OTHERS
 Tolnaftate
 Undecylenic acid
 Ciclopirox olamine
 Zinc pyrithione 1% , Selenium disulphide 2.5%
 Resorcinol
 Azelaic acid
 Benzoyl peroxide

11. INDICATIONS
 DERMATOPHYTES
 Tinea pedis/tinea manum
 Tinea cruris
 Tinea corporis
 Tinea faciei
 Tinea unguium
 P VERSICOLOR (malassezia furfur)
 MUCOCUTANEOUS CANDIDIASIS
 Cutaneous
 Vulvovaginal
 Oral (thrush)
 Perleche
 SEBORRHEIC DERMATITIS
(associated with pityrosporum ovale)

12. MECHANISM OF ACTION
α
Polyenes

13. POLYENES
 First agents developed with antifungal activity
 Contain a macrolide ring with number of conjugated double
bonds, hence the name poly-ene
 Nystatin -Discovered in 1949 – first specific antimycotic
for human use.
 derives its name from the new york state health laboratory
 Polyene antibiotic derived from Streptomyces noursei and
streptomyces albidus
 Structure and mode of action similar to Amphotericin B but
d/t high systemic toxicity used for topical treatment.
 Insoluble in water, not absorbed from intact skin, GIT,
vagina

14. NYSTATIN & AMPHOTERICIN B
 Fungistatic at low conc.
 Fungicidal at high conc.
 Candida spp.
 Not effective against dermatophytes or
pityrosporum

16. INDICATIONS
 Cutanoeus and mucocutaneous candidiasis
 Ineffective for dermatophytes, no antibacterial, antiviral,
antiprotozoal effects
 Nystatin: available as cream, ointment, oral suspension and powder
(1lakh U/gm or /ml) ,MYCOSTATIN VAGINAL tab10's (25.13 INR)
Manufacturer:SPPL
 Amphotericin B: Fungisone oral suspension, 100 mg/ml, use 1 ml 4
times a day, applying directly to tongue, then swish and swallow
 Adverse effect: Nystatin
 Burning, pruritus , pain
 Eczema
 hypersensitivity reactions

17. Azoles
Imidazoles
Ketoconazole
Miconazole
Clotrimazole
Triazoles
Itraconazole
Fluconazole
Voriconazole
Posaconazole

18. MECHANISM OF ACTION
Inhibition of fungal
cytochrome P450
dependant enzyme
Lanosterol 14 alpha
demethylase
Reduction of
ergosterol
synthesis

19. IMIDAZOLE
 Block biosynthesis of ergosterol
 Depletion of ergosterol – improper membrane function
– incompatible with growth and survival
 Interferes with cyt P450 dependent enzyme,
lanosterol 14 α demethylase ( converts lanosterol to
ergosterol)
 Fungistatic
 Active against wide range of fungal organisms including
candida and pityrosporum yeasts as well as
dermatophytes
 Also have antibacterial properties – can suppress the
growth of staph. Aureus
 Absorption percutaneous <1% , inflammed skin < 4%

20. MICONAZOLE
 Penetrates Str.C well – detected upto 4 days after single
application
 Indications: Dermatophytes- t. rubrum, t. mentogrophytes,
E. floccosum, C. albicans, Malassezia furfur
 Also active against gm+ve bacteria – erythrasma, impetigo,
ecthyma ( moderately effective)
 Twice daily application is recommended in all clinical
situations except for t. versicolor where once daily
application is recommended
 Should include normal skin of a radius 2cm beyond the
affected area.
 Adverse effects: irritation, burning, maceration, allergic
dermatitis

21.  DAKTARIN gel 2 % x 20g (40.75 INR)
 DAKTARIN cream 2 % x 15g (9 INR)
Manufacturer: J & J (Ethnor)
 MICOGEL cream2 % x 15g (19.5 INR)
Manufacturer:Cipla

22. CLOTRIMAZOLE
 Activity: Trichophyton, epidermophyton, microsporum spp.,candida (
nearly that of nystatin), gm +ve bacteria
 Oropharyngeal candidiasis: oral trouches 4-5 times a day 2 weeks
 Vaginal candidiasis : once daily tablet insertion for 1-2 days
 AE: erythema, stinging, blistering, pruritus, urticaria

23. AVAILABILITY
 ABZORB powd1 % w/w x 100g (66.6 INR)1 % w/w x 75g (45.7 INR)
Manufacturer:Ranbaxy (Consumer HC)
 CANAZOLE cream1 % w/w x 15g (19 INR) Manufacturer:Lupin
 CANDID gel 1 % w/w x 15g (53 INR)
 CANDID cream 1 % w/w x 15g (48.2 INR)
 CANDID lotion 1 % w/v x 15ml (47.8 INR)
 CANDID powd 1 % w/w x 100g (64.3 INR)1 % w/w x 30g (35.1 INR)
 CANDID DPS ear drops10ml (30.9 INR)
 CANDID MOUTH PAINT mouth paint 1 % w/v x 15ml (52.2 INR)
 CANDID-TV lotion60ml (105.5 INR) ( CLo. 1%, Sel. Sul 2.5%) Manufacturer:Glenmark
 CANDICLO-V KIT pessary200 mg x 3's (46 INR)
 CANDICLO-V KIT cream1 % w/w x 1's (46 INR)
Manufacturer:Sterling Lab (Medi-Genix)

24. KETOCONAZOLE
 Broad spectrum of activity against dermatophytes and yeasts
 Indications: dermatophytes, candida albicans , m.furfur
 Seborrheic dermatitis: 2% shampoo/ cream
 erythema, stinging, pruritus, contact dermatitis ( keto, sodium
sulfite, propylene glycol)
 NIZRAL shampoo 2 % x 50ml (150 INR)
NIZRAL cream 2 % w/w x 15g (75 INR)
NIZRAL soln 2 % w/v x 50ml (150 INR)
Manufacturer: J & J (Ethnor)
 KOIZ SOAP soap 2 % x 50g (44 INR) Manufacturer: Dewcare
 KZ Powder Manufacturer H&H Pharma

25. OXICONAZOLE
 Rapidly absorbed into the stratum corneum.
 Fungicidal conc. Within 5 hrs
 Persistence of drug in Str. C -4 days( single application)
 Reservoir effect – persistence at therapeutic levels X 7 days
 ZODERM cream 1 % x 30g (79.3 INR)
 ZODERM-E cream: 20g (37.89 INR) 30g (79.3 INR) oxiconazole 1 %
w/w, benzoic acid 0.2 % w/w
 ZODERM-E lotion: 30g (69.05 INR) oxiconazole 1 % w/w, benzoic
acid 0.2 % w/w. Manufacturer: GSK

26. SERTACONAZOLE
 Relatively lipophilic – greater reservoir effect
 Activity : t. rubrum, t. mentogrophytes, E. floccosum,
C. albicans, Malassezia furfur, gm +ve bacteria
 Second mech of action: direct membrane damage
 Allergic contact dermatitis
 ONABET CRM cream 2 % w/w x 10g (80 INR)
Manufacturer: Glenmark
 ONABET-V1 tab 500 mg (110 INR)

27. LULICONAZOLE
 developed in Japan
 Advantages: lipophilic with residual effect and once
daily application
 LULIFIN cream1 % w/w x 10g (130 INR)
Manufacturer:Ranbaxy

28. Name Concentration Frequency of
application
Pregnancy cat
(w)
Clotrimazole 1% Twice C (B)
Ketoconazole 1% & 2% Twice/ once C (B)
Miconazole 2% Twice C (B)
Oxiconazole 1% Once B (B)
Sertaconazole 2% Twice C (C)
Luliconazole 1% Once B
Duration : 2 wks. For tinea cruris/corporis; up to 4 wks In tinea pedis

29. ALLYLAMINES AND BENZYLAMINES
 Fungistatic and fungicidal activity
 Fungicidal against dermatophytes and static against c. albicans
 Act on an earlier step of ergosterol synthesis than the azoles and
their inhibition is cyt. P450 independent
 Inhibit fungal synthesis of ergosterol by inhibiting squalene
epoxidase
 Also results in toxic accumulation of squalene within the organism
which is fungicidal.
 Terbinafine, naftifine, butenafine
 Activity : dermatophytes, m. furfur, molds, dimorphic fungi, candida

30. MECHANISM OF ACTION
It interferes with ergosterol
biosynthesis by:
Inhibiting the fungal
enzyme squalene
epoxidase
Accumulation of the sterol
squalene

31. TERBINAFIN AND NAFTIFINE
 Lipophilic – efficient penetration and high
concentration in the stratum corneum and hair follicles
 Active against dermatophytes, molds certain dimorphic
fungi, C albicans
 Terbinafine 10-100 times more potent than naftifine
 After topical application, 3-5% of terbinafine is
absorbed – metabolites in urine 2-3 days afterwards
 Residual therapeutic effect after stopping the
medications
 possess anti-inflammatory activity.
 AE: burning, irritation, pruritus, dryness
 Strains of trichophyton rubrum resistant to squalene
epoxidase inhibitors have been reported

32. BUTENAFINE
 Only member of benzylamine family.
 Structurally similar to allylamines and also acts by
inhibiting squalene epoxidase.
 Residual therapeutic effect after stopping the
medications ( butenafine – strong keratin binding)
 Possess antiinflamatory action.
 AE: burning, irritation, pruritus, dryness
 FINTOP cream 1 % w/v x 15g (68.5 INR)
Glenmark (Gracewell)
 BUTOP cream 1 % w/w x 15g (42 INR)
Cipla
32

33. Agent Frequency of application Duration of appliacation
Naftifine Cream – once Use 2 wks. Beyond
resolution of symptoms
Gel – twice
Terbinafine T pedis (interdigit) –
twice
At least 1 wk
T pedis (plantar) – twice At least 1 wk
T elsewhere – once/twice At least 1 wk, up to 4
wks
Butenafine T pedis - once to twice At least 1 wk if twice; at
least 4 wks if once
T elsewhere – once At least 2 wk
P versicolor – once At least 2 wk

34. AVAILABILITY
 TYZA CRM cream 1 % w/w x 10g (51.92 INR)
Manufacturer: AHPL
 BUTOP cream 1 % w/w x 15g (42 INR) (
Cipla)
 ZIMIG CRM cream 1 % w/w x 10g (62.75 INR)
(GSK)
 SEBIFIN cream 1 % w/w x 10g (57 INR)
1 % w/w x 15g (80 INR)
(Ranbaxy )

35. MORPHOLINES
 Inhibits two separate stages in the synthesis of ergosterol and is
fungicidal.
 Marketed as 5% amorolfine laquer for treatment of onychomycosis
and amorolfine cream for dermatophytosis
 Active against dermatophytes and other filamentous fungi that
cause onychomycosis – Scytalidium species and scopulariopsis
species. Also active against dimorphic fungi, C. albicans , C.
neoformans.
 Water resistant laquer- once/ twice weekly application.
 Cure rates are approximately 50% at 6 mths.
 Acts synergistically with azoles and allylamines

36. AVAILABILITY
 LOCERYL NAIL LAQUER nail lacquer 5 % w/v x 5ml
(1125 INR) Manufacturer: Galderma
 Loceryl cream 0.25%

37. THERAPEUTIC SHAMPOOS
 Are surfactant or “wetting agents” , have hydrophilic and
hydrophobic portions on each molecule.
 MOA- Degrease the skin of scalp thro the emulsification of sebum
– promoting wetting of scalp – enhances effect of active ingredient.
 Results in washing away flakes of scale – facillitating separation of
scales into smaller, less visible flakes.
 In seb dermatitis – decreases high skin surface lipid levels.
( as surface lipid layer provides substrate required for growth of
pityrosporum yeast)
 Antifungal shampoos, acts by suppression of sup fungal inf.

38.  In addition, selenium sulfide has significant
cytostatic effect on hyperproliferative
keratinocytes.
 Zn pyrithione and selenium sulfide reduce cell turnover rate
significantly.
 Possibly selenium sufide has direct antimitotic effect.
 Ketoconazole shampoo has antiinflammatory action.
 Ketoconazole, suppress pityrosporum more effectively than
either Zn pyrithione and selenium sulfide.
 Relapse rate may b delayed with ketoconazole compared to
other.

39. INDICATIONS
FDA APPROVED
SCALING SCALP AND DANDRUFF
 Selenium sulfide 1 and 2.5 %
 Zn pyrithione
 Ketoconazole 1 , 2%
SEBORRHEIC DERMATITIS
 Ketoconazole2%
 ciclopirox 1%
 Selenium sulfide 2.5%

40. OFF LABLE DERMATOLOGICAL
USES
Adjuvant t/t in tinea capitis
 Ketoconazole2%
 Selenium sulfide 2.5%

41. APPLICATION TECHNIQUE
 Applied after wetting hairs and massaged vigorously
allowing shampoo to contact the scalp for 5 min.
 Some products are stay on applications for overnight
and washed off in morning.
 Safe for daily use, although effective by as little as
once or twice weekly.
 In contrast to ketoconazole shampoo, which plateau at
two to three times weekly use, selenium sufide and zn
pyrithione continue to improve scaling with increased
use upto daily.

42. ADVERSE EFFECTS
 Therapeutic shampoos C/I in persons allergic to
active ingredient, preservatives, fragrances.
 Saftey in pregnancy- no significant risk to fetus.
 Safety in children- ketoconazole safe and effective
in infants with cradle cap
 But with precaution, as amt of skin surface in
proportion to body wt is greater in infants.
 Allergic and irritant contact dermatitis- drying,
burning, stinging, irritation.
 Possible allergens- anionic detergents,fragrences,
formaldehydes etc.
 Selenium sulfide leave residual smell, discolor hair ,
make hair more oily

43. CICLOPIROX OLAMINE
 Hydroxypyridone antifungals with Diff. mode of action
 Does not directly inhibit sterol synthesis
 Binds with high affinity to trivalent cations such as Fe3+ -
essential for the function of numerous enzymes, including
cytochromes – disruption of several metabolic pathways
(mitochondrial electron transport)
 Broad spectrum activity against dermatophytes, yeasts and
moulds.
 Also effective against gm +ve and gm –ve bacteria including
MRSA
 Antiinflammatory activity (inhibits prostaglandin and leukoteine
syn in PMNs)

44. CICLOPIROX OLAMINE
 Available as
 Cream 0.77%
 Nail lacquer 8%
 Shampoo 1% and 1.5%
 Daily use of 8% nail laquer x 9-12 mths required for
onychomycosis
 AE: burning sensation/ pruritus
 Because of the broad antibacterial activity, inherent
anti-inflammatory action and highly effective
antifungal activity Ciclopirox has proven to be very
successful in the treatment of interdigital tinea pedis
with secondary bacterial infection (dermatophytosis
complex) .

45. Indications Remarks
Cutaneous candidiasis Twice daily for 2 – 4 weeks
Dermatophytes
P versicolor
T pedis Continue 1 month or longer
Seb dermatitis Twice weekly for indefinite
durations
onychomycosis Lacquer : daily for 9-12 mths

46. AVAILABILITY
 ONYLAC nail lacquer 8 % w/v x 3.3ml (210 INR)
Manufacturer: Cipla
 8X SHAMPOO shampoo x 60ml (129.25 INR)
Manufacturer: Cipla
 BATRAFAN cream 10 mg x 1 g x 15g (28.18 INR) 10 mg
x 1 g x 30g Manufacturer: Sanofi Aventis
Form Packing (Max Retail Price)
 OLAMIN cream 1 % w/w x 15g (43.8 INR)
 OLAMIN scalp soln 1.5 % x 50ml (175 INR)
(Micro Gratia)

47. SELENIUM SULFIDE
 antiseborrheic, antifungal for topical application
 2.5% lotion - available by prescription, 1% - otc
 T. versicolor and Seborrheic Derm. of scalp.
 Effective adjuvant with griseofulvin for t. capitis
 Cytostatic effect on cells of epidermis and follicular epithelium
 Shedding of fungi in stratum corneum d/t reduction in corneocyte
adhesion
 Also some fungicidal activity against P. ovale

48. SELENIUM SULFIDE
 Preg Cat C
 Treatment should be continued for at least 1 week
after all symptoms have abated.
 AE: Irritant contact dermatitis, Allergic contact
dermatitis, urticaria

49. AVAILABILITY
 SELDRUFF PLUS susp: selenium sulphide 2.5 % w/v,
clotrimazole 1 % w/v; 60ml (45 INR) Manufacturer:
Wings Pharma
 SELSUN shampoo 2.5 % w/v x 120ml (59 INR) 2.5 %
w/v x 60ml (35 INR) Manufacturer: P. Upjohn

50. TOLNAFTATE
 Thiocarbamate derivative
 Inhibitor of squalene epoxidase
 Spectrum of activity similar to allyamines
 TINADERM soln 10 mg x 20ml (15.65 INR)
 TINADERM cream 10 mg x 10g (32.07 INR)
Manufacturer: Fulford
 TANACIDAL soln : 10 mg x 10ml (17.27 INR)
BPL Pharma

51. UNDECYLENIC ACID
 Obtained from destructive distillation of castor oil.
 Fungistatic , antiviral, antiseptic properties
 Can be used in concentrations upto10% in solutions,
oint, powders, and emulsions for topical application.
 Should not be applied to mucous membranes as can
cause severe irritation.
 Traditionally used for T. pedis (low cure rates)
 May cause sensitisation rarely

52. OTHER TOPICAL ANTIFUNGALS
 Whitfield’s oint
 6% benzoic acid, 3% salicylic acid
 Superficial dermatophyte infection
 Not cosmetically acceptable
 Resorcinol
 Suppresses Pityrosporum yeasts
 Mild irritant , prolonged application can lead to myxoedema
 Methaemoglobinemia has been reported after topical use in children
 Gentian Violet
 Triphenylmethane dye active against Gm +ve bacteria and fungi
 Used in Vg pessaries and as 1-3% lotion for yeast infections
 Castellani’s paint- basic fuschin – used in T. pedis

53. OTHER TOPICAL ANTIFUNGALS
 Zn Pyrithione 1%
 Has antipityrosporum effect by suppression of sup fungal inf.
 Systemic absorption occure to some extent, but hav high safety
margin, with just minor skin irritation.
DANCLEAR shampoo: ketoconazole 2 % w/v, zinc pyrithione 1 %
w/v, aloe 0.5 % DANCLEAR shampoo 50ml (69.95 INR) 90ml (115
INR) Manufacturer: Zydus (Liva)
 Clioquinol
 broad spectrum antibacterial and antifungal
 Synthetic hydroxyquinoline
 Used in T. pedis
 Mechanism of action is unknown
 Disadvantage: staining and sensitising properties.

54. SYSTEMIC / TOPICAL
Choice depends upon the-
 Extent & severity
 Site
 Co-morbid conditions or potential drug interaction
 Anticipated efficacy of treatment
 Cost and access to medication
 Ease of use
 Depending upon the site
 TOPICAL- Infection confined to glabrous skin
 SYSTEMIC - Extensive /recalcitrant ds or involvement of
hair and nails

55. ADVANTAGES
 Fewer Side effects
 Fewer drug interactions
 Localization of treatment
 Generally lower cost

56. DERMATOPHYTES
 Allylamines/ Benzylamines have greater activity than azoles
 Allylamines/ Benzylamines – fungicidal
 Azoles- fungistatic
 Allyamines/Benzylamines significantly lower relapse rate than
azoles
 In vitro antidermatophyte potency
Butenafine = terbinafine ( highest)
Ciclopirox
Naftifine
Azole ( lowest)
Retention effect
with fungicidal
activity
responsible for
shorter duration
of therapy and
lower relapse
rates with Allyl/
Benzyamines

57. CANDIDIASIS
 In vitro activity
 Ciclopirox> azoles>> butenafine > naftifine = terbinafine

58. ANTIINFLAMMATORY
PROPERTIES
 Allylamines/ Benzyl amines have been found to
possess greater anti- inflammatory action than azoles
 Azoles:
 Most inhibit chemotactic ability of PMNs ( C, M, E, K)
 Bifonazole – also inhibits calmodulin – required for PG
synth and Histamine release from mast cells
 Elevated levels of calmodulin – psoriatic plaques
 Bifonazole – seb derm and sebopsoriasis
 Ketoconazole- inhibits 5 lipooxygenase decreases
production of leukoterine B4 – used in seb. Derm

59. ANTIINFLAMMATORY PROPERTIES
 Naftifine
 Inhibits PMN chemotaxis – Inhibits pseudopod formation
 Impedes production of reactive O2 intermediates
 Inhibits 5- lipooxygenase
 Ciclopirox olamine
 Inhibits both 5-Lipo and Cyclo- oxygenase

60. ANTIBACTERIAL EFFECTS
 Gm +ve and Gm-ve
 Clotrimazole
 Econazole
 Miconazole
 Oxiconazole
 Setraconazole
 Terbinafine
 Ciclopirox olamine
 In vitro Gm-ve activity of Ciclopirox superior to that
of other antifungals

61. THANK YOU