INTRODUCTION

Topical glucocorticoids (GCs) are among the mostcommon medications employed in the treatment ofskin diseases. Like systemic GCs they have indisputableanti-inflammatory and immuno-suppressive efficacy.Because they are delivered in high concentration tothe affected site they may be used to treat localisedareas of dermatitis in order to minimise the adverseeffects associated with systemic GC therapy. However,their potential local and systemic side effects need tobe considered before they are employed. This third,final article will consider the place of topicalglucocorticoid therapy in the treatment of localisedinflammatory dermatitis and specific conditions suchas atopic dermatitis and otitis externa.

PHARMACOLOGY OF TOPICAL GLUCOCORTICOIDS

Mechanism of action

As with systemic GCs (Horvath & van den Broek,2009 UKVet Vol 14 No 6 48pp) topical GCsmodulate gene transcription by interacting withspecific DNA sequences and several transcriptionfactors (De Bosscher & Haegeman, 2009). Locally,therefore, they have the same anti-pruritic, anti-inflammatory, anti-allergic and immunosuppressiveactivity as systemic GCs (Horvath & van den Broek,2009 UKVet Vol 14 No 6 48pp). Although

indiscriminate in their influence on cells of theepidermis and dermis, their ability to down-regulatesynthesis of pro-inflammatory cytokines bykeratinocytes and their anti-proliferative effect onkeratinocytes and fibroblasts are of particularimportance in the treatment of cutaneous conditions.

Formulations of topical GCs

The number of topical GCs licensed for veterinaryuse in the UK is very limited (Table 1). Aconsiderably greater number and variety ofpreparations is available for use in humans and aselection of these is included in Table 1. Thediscussion here includes reference to GCs usedtopically in humans.

The efficacy of a topical GC is determined by anumber of factors: � its ability to diffuse out of the vehicle� its ability to penetrate the dead stratum corneumand diffuse into the living epidermis and dermis

� its dose and pharmacological potency.

Topical GCs are formulated in a variety of vehiclesand the same GC at the same concentration but in adifferent vehicle will have a different potency (Ayres& Hooper, 1978). This is because GCs diffuse more

SMALL ANIMAL � DERMATOLOGY ���UK Vet - Vol 14 No 8 October 2009 1

Christa Horvath-Ungerboeck DrVetMed MRCVSCLINIC OF INTERNAL MEDICINE AND INFECTIOUS DISEASES, UNIVERSITY OF VETERINARY MEDICINE, VIENNA,VETERINAERPLATZ 1, 1210 VIENNA, AUSTRIAAdri van den Broek BVSc DVR PhD FRCVS Professor of Veterinary ImmunodermatologyUNIVERSITY OF EDINBURGH, HOSPITAL FOR SMALL ANIMALS, EASTER BUSH VETERINARY CENTRE, ROSLIN, MIDLOTHIAN. EH25 9RG

The use of glucocorticoids in caninedermatology: Part 3 Topical glucocorticoids

TABLE 1: Formulations of topical glucocorticoids (products licensed in the UK for veterinary useare in bold type)

Potency

Low

Mid

potency

High

potency

Topical glucocorticoid

Hydrocortisone aceponate

(0.584 mg/ml) +Hydrocortisone (0.1-1%)Prednisolone acetate (5 mg/ml)

Dexamethasone acetate (0.9 mg/ml)*Prednicarbate (0.1%)

+Fluticasone proprionate (0.05%)Triamcinolone acetonide (0.1%)

Betamethasone valerate (0.1%w/w)

Formulation

spray

creamsuspension

suspension cream

creamcream or spray

gel

Products(s)

Cortavance® (Virbac Ltd)

several products availableSurolan Ear Drops andCutaneous Suspension®

(Janssen Animal Health)Aurizon® (Vetoquinol UK Ltd)Dermatop Cream® (Dermik,Sanofi-Aventis)Cutivate® (GlaxoSmithKline)Kenalog Cream®/Spray®

(Bristol Myers Squibb)Fuciderm Gel®

(Dechra Animal Products)

+ Human preparation - available under the cascade; * Human preparation - available under the cascade, requires import licence

readily from some vehicles than others. In general,diffusion from different vehicles is in the followingorder, from most to least readily:� solutions� gels� foams� lotions� creams and ointments.

Many topical GCs are available as ointments andcreams and, although containing less water,ointments are generally more potent than creamscontaining the same drug, possibly as a result of theirocclusive effect (Wiedersberg et al., 2008).

Percutaneous penetration is enhanced by fluorination(triamcinolone acetonide and dexamethasone), whichincreases GC lipophilicity, and by the addition of estersor acetal groups (betamethasone-17-valerate). Morerecently other GCs have been developed to improvethe risk/benefit ratio of topical GCs in humans andsome are included in Table 1. Hydrocortisoneaceponate, an ester of hydrocortisone, andprednicarbate, an ester of prednisolone, cause lessdermal atrophy and fewer systemic side effects thanequipotent betamethasone-17-valerate - this is due totheir slow diffusion through the epidermis into thedermis and slow rate of metabolism by fibroblasts(Wiedersberg et al., 2008). Fluticasone proprionate isanother product that combines good anti-inflammatory activity with a reduced risk of systemicside effects, due to rapid conversion to an inactivemetabolite by the liver (Spencer & Wiseman, 1997).

As a general rule, subject to vehicle andpercutaneous penetration, therapeutic potencyincreases with pharmacological potency and doseand is greatest with fluorinated GCs such astriamcinolone acetonide, dexamethasone acetate andbetamethasone-17-valerate.

INDICATIONS AND CONTRAINDICATIONS FOR

TOPICAL GLUCORTICOID THERAPY

Indications

Topical GCs play an integral part in the treatment oflocalised dermatoses but should only be used afterdefinitive diagnosis is made and measures have beeninstituted to eliminate or control the underlyingcondition and predisposing factors. In the absence ofany contraindication, the following conditions areexamples of the justifiable use of topical GCs:� focal areas of inflammation - pyotraumaticdermatitis, eosinophilic plaque, insect andarthropod bites, burns, contact dermatitis,cutaneous lupus erythematosus and intertrigo(Figs. 1-3)

� localised canine atopic dermatitis (CAD) and asan adjunct to systemic therapy in managingexacerbations of CAD (Fig. 4)

� otitis externa especially if due to an underlyingallergic condition (canine atopic dermatitis,cutaneous adverse food reaction).

SMALL ANIMAL � DERMATOLOGY ��� UK Vet - Vol 14 No 8 October 20092

Contraindications

Topical GCs should not be used in:� cutaneous viral, fungal and bacterial infections� demodicosis.

They should be used with caution in cases ofdiabetes mellitus, systemic infections and pregnancy.Their use will be determined by the risk of systemicabsorption (see below).

Fig. 1: Intertrigo in a French Bulldog.

Fig. 2: Close up of the French Bulldog in Fig. 1showing erythema and alopecia.

Fig. 3: Cutaneous lupus erythematosus in a GermanShepherd Dog.

Fig. 4: Interdigital erythema in an atopic WelshSpringer Spaniel.

SMALL ANIMAL � DERMATOLOGY���

UK Vet - Vol 14 No 8 October 2009 3

ADVERSE EFFECTS OF TOPICAL GLUCOCORTICOIDS

Localised adverse effects are more common thansystemic reactions. Both are determined by theamount of GC absorbed, which in turn is influencedby:� their formulation (vehicle, concentration andcharacteristics of the GC)

� the frequency and duration of application� the thickness of the epidermis and dermis� the degree of inflammation� skin integrity over the affected area, which maybe impaired by clipping

� the use of occlusive wraps.

Systemic side effects are also influenced by the sizeof the affected area and the grooming/lickingbehaviour of the patient.

Local cutaneous adverse effects

Epidermal and dermal atrophy are the principaladverse local effects of topical GCs, and result fromtheir anti-proliferative activity on keratinocytes andfibroblasts. Reduced fibroblast proliferation andcollagen production can also result in loss of skinelasticity, increased fragility of blood vessels and theirsusceptibility to trauma with the development ofbruises. In addition there may be localhypopigmentation, comedo formation, delayedwound healing and suppression of local immuneresponses, with exacerbation of local infections suchas demodicosis and bacterial and fungal infections.

Systemic adverse effects

The most important adverse effect with topical GCs isthe development of iatrogenic hyperadrenocorticism(Horvath & van den Broek, 2009 UKVet Vol 14 No 648pp). Rapid and significant adrenocorticalsuppression has been documented after once dailyapplication of betamethasone valerate, triamcinoloneacetonide and flucinolone to a clipped, 15 cm x 25 cmarea of healthy skin (Zenoble & Kemppainen, 1987)and after twice daily otic instillation of triamcinoloneacetonide or dexamethasone (Moriello et al., 1988;Ghubash et al., 2004; Reeder et al., 2008) Slightreductions in total leukocyte count, lymphocytes andeosinophils have also been recorded with the use of atriamcinolone acetonide spray (Deboer et al., 2002)and a small but significant increase in alkalinephophatase with otic betamethasone (Ginel et al.,2007). Occasionally, clinical signs such as polydipsiaand polyphagia are observed and, rarely, latent diabetesmellitus may be unmasked (Huang et al., 1999).

Because of the possibility of systemic side effects:� intradermal tests should be delayed until at leastfour weeks after withdrawal of medication, asreactions may be suppressed (Ginel et al., 2007)

� tests of adrenocortical function should besimilarly delayed.

Adverse effects in owners

As topical GCs are applied by hand, adverse effectsmay also occur in the owner. Therefore, it is essentialthat owners be instructed to wear gloves whenapplying creams etc. or to use an applicator stick, andto wash their hands after exposure.

USE OF TOPICAL GLUCOCORTICOIDS

IN THE MANAGEMENT OF SKIN CONDITIONS

A number of points should be considered beforeusing topical GCs:� a definitive diagnosis should first be made andmeasures instituted to treat any predisposing orunderlying condition(s)

� the affected area should be exposed and cleanedgently, with an anti-keratolytic agent if indicated,to facilitate application and penetration of thetopical GC

� the topical GC should be chosen carefully (seebelow)

� side effects should be minimised by avoidingextended use and the employment of anElizabethan collar to prevent ingestion of GC.

Induction, maintenance and withdrawal� potency (Table 1) should be matched with thenature and severity of inflammation; in general amore potent product is used initially andemployed for only a limited period beforeswitching to one less potent when theinflammation is under control

� as the epidermis acts as a reservoir for topical GCsfrom which they diffuse slowly into the dermis,initial twice daily application can be tapered toonce daily and then alternate day applications

� once the lesion has resolved treatment canusually be withdrawn without the developmentof iatrogenic hypoadrenocorticism.

Choosing an appropriate formulation� polypharmacy should be avoided unless there isa specific indication for inclusion of anantimycotic/antibacterial agent - this is difficultunless one employs formulations for humans

� the product chosen should minimise potentialside effects as far as this is consistent withcontrolling the inflammation

� sprays, shampoos and conditioners containinghydrocortisone are of value if large areas areinvolved especially if the hair coat is dense

� gels allow good percutaneous absorption and areof value in animals with dense hair coats.

Acute dermatoses

In acute dermatoses GCs in sprays, solutions and gelsare useful in reducing pruritus, especially if the haircoat is dense and clipping is undesirable; creams areuseful on acutely inflamed intertriginous skin.

Chronic dermatoses

In chronic dermatoses with lichenification,betamethasone valerate and triamcinolone acetonide

ointments/creams are of particular value because theseGCs penetrate the skin barrier well; the occlusiveeffect of ointments also enhances absorption

THE USE OF TOPICAL GLUCOCORTICOIDS

IN SPECIFIC SKIN CONDITIONS

Canine atopic dermatitis (CAD)

The requirement of a combination of therapies tocontrol the clinical signs of CAD (hypo-sensitisation, antihistamines, Chinese herbs, fattyacid supplementation, shampoos, NSAIDs orantidepressants) and the use of systemic GCs werediscussed in Part 2 (Horvath & van den Broek,2009b UKVet Vol 14 No 7 61pp). If the pruritus is localised to small areas, like the paws, thentopical GC therapy may be sufficient. If multiplesites are affected, treatment should include bathsand fatty acid supplementation together withtopical GCs.

The disadvantages of topical therapy are the expenseand time and effort needed for application. However,randomised, placebo-controlled, double-blindedtrials have demonstrated the efficacy of a 0.015%triamcinolone acetonide spray in the management ofdogs with known or suspected allergic pruritus(Deboer et al., 2002) and of a hydrocortisoneaceponate (HCA) spray (Cortavance®; Virbac) in themanagement of CAD. This latter study demonstrateda significantly greater reduction in CADESI andpruritus scores of dogs receiving HCA compared tothose receiving the placebo. The coat length did notinfluence the results and haematology, biochemistryand ACTH-stimulation showed no significantchanges (Nuttall et al., 2009). This study suggests thatalthough Cortavance® is not licensed for long-termuse, it may be useful in controlling exacerbations ofclinical signs.

Otitis externa

Otitis externa is common, with an estimatedincidence in dogs of 5-17%. All breeds, ages andsexes can be affected but it occurs more frequently insome breeds such as Cocker Spaniels (increasedamount of glandular tissue) and breeds withpendulous ears. Otitis externa may be caused byOtodectes cynotis and, less frequently, demodicosis andforeign bodies, or it may be seen in association withunderlying diseases such as canine atopic dermatitisand cutaneous adverse food reactions and, lessfrequently, hypothyroidism and ear canal neoplasia.

In all cases, in order to identify the underlying cause,it is essential to obtain a detailed history and carryout a thorough examination. Examination of theear should include otoscopy, under sedation ifnecessary, and cytology followed, if indicated, bycollection of swabs for bacterial culture andsensitivity tests. Topical GCs are important in themanagement of otitis externa and choice ofproduct (Table 2) should be based on the results ofexamination, including cytology.

Inflammation should be classified as acute orchronic: � in acute otitis less potent GCs are indicated - theanti-inflammatory effect of GCs will reduceexudation, oedema, pruritus and pain, facilitatinginstillation of the product and penetration of anyantimicrobial to the interface with the epithelium

� in chronic otitis the more potent GCs areindicated - the antiproliferative effect of GCs onkeratinocyte and fibroblast proliferation willreduce epithelia hyperplasia and dermal fibrosis.

Cytology should further define choice of product. IfMalassezia spp. or cocci (commonly Staphylococcuspseudintermedius) are detected the product must containthe appropriate antimicrobial, and the nature of theinflammation (acute or chronic) will determine thechoice of GC. If rods are detected, as they are oftenPseudomonas spp., culture and sensitivity tests should beundertaken. In all cases with rods it is preferable tochoose a less potent GC to minimise the GC-inducedreduction in leukocyte activity. UnfortunatelyAurizon®, which contains marbofloxacin, and istherefore suitable for Pseudomonas otitis, contains themore potent betamethasone valerate.

CONCLUSION

Topical GCs are integral in the treatment andmanagement of localised dermatoses, however theyshould only be used when a definitive diagnosis hasbeen made and any underlying causes have beenidentified and managed. The choice of productshould be determined by the nature of theinflammation and should always take into account itspossible local and systemic adverse effects andduration of application should be as brief as possible.

REFERENCES

AYRES, P. J. and HOOPER, G. (1978) Assessment of the skin

penetration properties of different carrier vehicles for topically

applied cortisol. British Journal of Dermatology 99(3):307-17.

DE BOSSCHER, K. and HAEGEMAN, G. (2009) Minireview: latest

SMALL ANIMAL � DERMATOLOGY ��� UK Vet - Vol 14 No 8 October 20094

Product

Aurizon®

(Vetoquinol UK Ltd)

Otomax®

(Intervet/Schering- PloughAnimal Health)Canaural Ear

Drops®

(Dechra VeterinaryProducts)Surolan Ear Drops

and Cutaneous

Suspension®

(Janssen AnimalHealth)

Antibacterial

marbofloxacin (3 mg/ml)

gentamycin (2640 IU/ml)

diethanolaminefucidate (5 mg/gm)framycetin sulphate (5 mg/gm)polymixin Bsulphate (0.5293 mg/ml)

Antifungal

clotrimazole (10 mg/ml)

clotrimazole (8.8 mg/ml)

nystatin(100,000units/gm)

miconazolenitrate (23 mg/ml)

GC

dexamethasoneacetate (0.9 mg/ml)betamethasonevalerate (0.88 mg/ml)

prednisolone(2.5 mg/gm)

prednisoloneacetate (5 mg/ml)

TABLE 2: Veterinary ear products containing GCs

SMALL ANIMAL � DERMATOLOGY ���UK Vet - Vol 14 No 8 October 2009 5

perspectives on antiinflammatory actions of glucocorticoids.

Molecular Endocrinology 23(3):281-91.

DEBOER, D. J. , SCHAFER, J. H., SALSBURY, C. S., BLUM, J. R. ,

BEALE, K. M., VITALE, C. B., MUSE, R., MORIELLO, K. A.,

GARFIELD, R. A., KEEFE, T. J. and McARTHUR, T. R. (2002)

Multiple-center study of reduced-concentration triamcinolone

topical solution for the treatment of dogs with known or

suspected allergic pruritus. American Journal of Veterinary

Research 63(3):408-13.

GHUBASH, R., MARSELLA, R. and KUNKLE, G. (2004) Evaluation

of adrenal function in small-breed dogs receiving otic

glucocorticoids. Veterinary Dermatology 15(6):363-8.

GINEL, P. J., GARRIDO, C. and LUCENA, R. (2007) Effects of otic

betamethasone on intradermal testing in normal dogs. Veterinary

Dermatology 18(4):205-10.

HUANG, H. P., YANG, H. L., LIANG, S. L., LIEN, Y. H. and CHEN,

K. Y. (1999) Iatrogenic hyperadrenocorticism in 28 dogs. Journal

of the American Animal Hospital Association 35(3):200-7.

MORIELLO, K. A., FEHRER-SAWYER, S. L., MEYER, D. J. and

FEDER, B. (1988) Adrenocortical suppression associated with

topical otic administration of glucocorticoids in dogs. Journal of

the American Veterinary Medical Association 193(3):329-31.

NUTTALL, T., MUELLER, R., BENSIGNOR, E., VERDE, M., NOLI,

C., SCHMIDT, V. and REME, C. (2009) Efficacy of a 0.0584%

hydrocortisone aceponate spray in the management of canine

atopic dermatitis: a randomised, double blind, placebo-controlled

trial. Veterinary Dermatology 20(3):191-8.

REEDER, C. J., GRIFFIN, C. E., POLISSAR, N. L., NERADILEK, B.

and ARMSTRONG, R. D. (2008) Comparative adrenocortical

suppression in dogs with otitis externa following topical otic

administration of four different glucocorticoid-containing

medications. Veterinary Therapeutics 9(2):111-21.

SPENCER, C. M. and WISEMAN, L. R. (1997) Topical fluticasone

propionate: a review of its pharmacological properties and

therapeutic use in the treatment of dermatological disorders.

BioDrugs 7(4):318-34.

WIEDERSBERG, S., LEOPOLD, C. S. and GUY, R. H. (2008)

Bioavailability and bioequivalence of topical glucocorticoids. Eur J

Pharm Biopharm 68(3):453-66.

ZENOBLE, R. D. and KEMPPAINEN, R. J. (1987) Adrenocortical

suppression by topically applied corticosteroids in healthy dogs.

Journal of the American Veterinary Medical Association

191(6):685-8.

C O N T I N U I N G P RO F E S S I O N A LD E V E L O P M E N T S P O N S O R E D B YB AY E R A N I M A L H E A LT H

1. Which of the following GCs has been shown not to

suppress adrenocortical function in dogs when

applied to the skin:

a. betamethasone valerate

b. hydrocortisone aceponate

c. triamcinolone acetonide

d. dexamethasone

e. prednicarbate

2. Which of the following GCs has been shown to

suppress adrenocortical function when instilled

into the ear canal:

a. triamcinolone acetonide

b. dexamethasone

c. hydrocortisone acetate

d. prednicarbate

e. betamethasone valerate

3. Which of the following is likely to result from

topical use of GCs:

a. hyperpigmentation

b. lichenification

c. dermal atrophy

d. leukotrichia

e. hypopigmentation

4. Topical GCs are of value in managing which of the

following conditions:

a. pyotraumatic dermatitis

b. systemic lupus erythematosus

c. localised demodicosis

d. superficial pyoderma

e. localised atopic dermatitis

5. Which of the following parameters may be

affected by topical GCs:

a. plasma glucose

b. alkaline phosphatase

c. blood urea

d. serum calcium

e. eosinophil count

These multiple choice questions are based on the abovetext. Answers appear on page 71.