TOPICAL CORTICOSTEROIDS

INTRODUCTION

• In 1952, Sulzberger and Witten first treated eczematous dermatitis with topical hydrocortisone.

• This success marked a cornerstone in dermatology and the birth of a wonder drug

Structure of corticosteroid

• CS have a basic skeletal structure of

cyclopentanoperhydrophenanthrene ring

(17-C) formed by fusion of 3 six

membered rings and one five membered

ring.

•Modification by addition or alteration of

function groups at certain positions, have

led to compounds with variable anti-

inflammatory, GCs vs MCs activity and

adverse effect.

PHARMACOKINETICS• Distribution : After application, distributed throughout

local skin; drug absorbed systemically is rapidly removed

from circulation and distributed to muscle, liver, skin,

kidneys, intestines

• Metabolism : mainly in the skin by:

a) Oxidation b) Conjugation

• Small amount absorbed systemically is metabolised in the liver to inactive metabolites which are excreted by kidneys.

PK and the potency of TCS preparation depends on 3

factors: Structure , vehicle and the skin condition

1. Structure of TCS molecule: HC is the backbone of most

TCS molecules. The addition or alteration of functional

groups (-OH, ester, F, Cl, acetonide, ketone) at certain

position affects the lipophilicity, solubility, percutaneous

absorption, biotransformation and GCR-binding activity.

Fluoridation renders the steroid more potent than

chlorination.

Fluoridation at C-9 increases potency more than at C-6

position.

An ideal topical steroid should permeate the stratum

corneum, reach an adequate conc. in epidermis without

crossing the dermis to enter systemic circulation.

This is achieved by molecules with high lipophilicity.

2. The vehicle: Vehicle is the sum of the formulation ingredients in which the drug is presented to the skin. The ideal vehicle should be- cosmetically acceptable, biocompatible, chemically, microbiologically and physically stable and should be able to release the drug in the stratum corneum.

• The potent molecules may be made clinically ineffective or that the enhanced efficacy may be generated with weaker molecules, depending upon the vehicle used.

Important considerations for choosing a vehicle:

1. Solubility of agent in vehicle

2. Rate of release of agent from vehicle

3. Ability of vehicle to hydrate stratum corneum

4. Stability of therapeutic agent in vehicle, any

physical/chemical interactions b/w the two

• Vehicles, previously considered to be an inactive molecule,

also do some important functions -

Emollients: Smoothens the skin by filling spaces between skin

flakes, with droplets of oil and ↑ flexibility of skin.

Emulsifying agent: Stabilizes the emulsion and also helps in

even distribution

Solvents are used in lotions, solutions, gels and spray to create a

less viscous product.

Humectants attract water to stratum corneum (transepidermal)

Thickening agent can be used to make the preparation

stiffer.

Ointments- ↑ the hydration of stratum corneum and

occludes the drug thus increasing its potency.

• The other functions of vehicle includes its cooling

effect, antipruritic, moisturization, ↑ing the PC

absorption by making it more soluble, anti-oxidant,

preservative and reduces friction.

3. Role of Condition of Skin in Percutaneous Absorption:

The skin condition determines the bioavailability of drug.

Penetration is inversely α to the thickness of Stratum

corneum.

Penetration ↑ with inflammed or diseased skin and also

with ↑ hydration of stratum corneum and also with

temperature. Stratum corneum may also act as a reservoir

for TCS for upto 5 days, this retention is concentration &

formulation dependent.

Steroids are absorbed at different rates

from different parts of the body : • Forearm absorbs - 1%

• Armpit absorbs - 4%

• Face absorbs - 7%

• Eyelids and genitals absorb - 30% (maximum)

• Palm absorbs - 0.1%

• Sole absorbs - 0.05% (minimum)

Mechanism Of Action Of Glucocorticoids

The CS diffuse into the target cell & binds to the GCR(found

in almost all types of cells) in the cytoplasm

The CS-GCR complex undergoes necessary conformational

changes (dissociation of hsp-90 and p59 from hetero

tetrameric complex of GCR)

The resulting active complex traverses the nuclear envelope

and binds to the GRE of many genes

Gene regulation & transcription of various specific mRNA

occur.

Lipocortin

• CS inhibits transcription factors such as activator protein 1

and nuclear factor κB, that are involved in the activation of

pro-inflammatory genes.

• Genes that have anti- inflammatory role are upregulated by

CS and includes lipocortin and p11/calpactin-binding

proteins.

ANTI INFLAMMATORY ACTION

Direct effects( immediate)

Stabilize cell and lysosomal membranes: prevent release of

lysosomal contents & phospholipid precursors for synthesis

of PGs & PAF

Potentiates vascular response to catecholamines

Reduce vascular sm sensitivity to histamine & bradykinin

Inhibit mast cell sensitization induced by IgE

Inhibit release of histamine & other mast cell mediators

GCR mediated effects(delayed)

Induction of anti-inflammatory proteins- lipocortins,

vasocortin and vasoregulin

Lipocortins inhibit phospholipase A2 & block release of AA &

PAF from cell membrane; thus prevent formation of PGs, LKTs,

12-HETE (Hydroxy eicosa tetraenoic acid) and 15-HETE.

Lipocortins also prevent PAF induced wheal and flare rxns. &

leukocyte chemotaxis

Vasocortin and vasoregulin ↓vascular permeability

Lipocortins

Anti-inflammatory actions on specific cells

Polymorphonuclear leucocytes

• ↓ ability to adhere to vascular endothelium

• ↓ migration to sites of inflammation

• ↓ no. at sites of inflammation

• Reduce phagocytosis, bactericidal activity, release of acid

hydrolases and pyrogens

Monocytes• reduce number at sites of inflammation• reduce fungicidal activity and clearance of opsonized

particle • ↓ response to macrophage activating factor &

chemotaxis

Lymphocytes• ↓ response to concanavalin A induced T-cell blastogenesis• Induction of T cell apoptosis• ↓ response to tetanus toxoid• ↓ Antibody mediated cell mediated cytotoxity• ↓ NK cell activity

Langerhans cells

• Moderate potency TCS ↓ expression of Fc receptor , C3b receptor

and HLA DR positivity but no alteration in CD1a antigen expression

• Superpotent TCS cause loss of cells expressing langerhans cell

markers

Effects on immune cytokine production

↓ production of interleukin-1 (IL-1α and IL-1β), IFN-γ, TNF,

IL-2, IL-8 and GMCSF

Anti inflammatory properties are:

• Useful in skin conditions like atopic dermatitis and contact dermatitis in which excess inflammatory response occurs

• Deleterious where inflammation is host protective. Eg: dermatophyte infections

ANTIPROLIFERATIVE ACTION EPIDERMIS

• Number of keratinocyte mitoses seen diminished

• Stratum corneum thickness reduced

• Granular layer reduced or absent

• Basal layer of keratinocytes flattened

• Keratinocytes growth factors suppressed

• Keratinocyte ultrastructure (keratin filaments, keratohyalin granules,

membrane-coating granules) normal

• Basement membrane unaffected

• Melanocyte pigment production inhibited

DERMIS 1) EARLY ATROPHY

• Dermal volume reduced: ↓ water content, loss of

glycosaminoglycans

• Hypoactive fibroblasts : suppression of procollagen-I

mRNA transcription, reduced activity of prolyl 4- OHase &

lysyl oxidase, collagenase activity reduced, hyaluronate

synthetase activity suppressed

• Collagen & elastic fibers unchanged

2) LATE ATROPHY

• Dermal volume reduced

• Collagen & elastic fibers diminished & abnormally

aggregated

• Hypoactive fibroblasts

• Dermal vessels fragile due to loss of fibrous & ground

substance support

Antiproliferative effects are :

• helpful in proliferative dermatoses like psoriasis

• Injurious when used in the wrong disease, location

or potency or in excess quantity

INDICATIONSDermatitis/ papulosquamous Bullous dermatosis Atopic dermatitis Diaper dermatitis Dyshydrotic eczema Erythroderma Lichen planus Lichen simplex chronicus Nummular dermatitis Piytriasis rosea Psoriasis-intertriginous Psoriasis–plaque or

palmoplantar Seborrheic dermatitis

Bullous pemphigoid

Cicatricial

pemphigoid

Epidermolysis bullosa

acquisita

Pemphigoid gestationis

Pemphigus Foliaceus

CONNECTIVE TISSUE DISEASE Dermatomyositis Lupus

NEUTROPHILIC DERMATOSIS Behcet’s disease Pyoderma gangrenosum

OTHER DERMATOLOGIC DISEASES Alopecia areata Acne keloidalis nuchae Chondrodermatitis nodularis helicis CTCL- Patch stage Granuloma annulare Jessener’s lymphocytic infiltrate LSEA (lichen sclerosus et

atrophicus) Lichen planopilaris Morphea Sarcoidosis Vitiligo Well’s syndrome Pruritus- perianal, scrotal & vulvar

Responsiveness of Dermatoses to TopicalApplication of Corticosteroids

Highly responsive

Psoriasis (intertriginous)

Atopic dermatitis (children)

Seborrheic dermatitis

Intertrigo

Moderately responsive

Psoriasis (body)

Atopic dermatitis (adults)

Nummular eczema

Primary irritant dermatitis

Papular urticaria

Lichen simplex Chronicus

Least responsive

Palmoplantar psoriasisPsoriasis of nailsDyshidrotic eczemaLupus erythematosusPemphigusLichen planusGranuloma annulare

Necrobiosis lipoidica diabeticorumSarcoidosisAllergic contact dermatitis,acute phase insect bites

ESTIMATING TCS POTENCY• Assays measure anti-inflammatory and/or

antiproliferative properties of TCS• Stoughtan vasoconstriction assay – most commonly

used• Involves:1) Preparing test corticosteroid in 95% alcohol2) Applying to volar surface of normal volunteer’s

forearm3) Allowing alcohol to evaporate, occlusive dressing for

16 hours4) Washing off the area

5) Assessing vasoconstriction 2 hrs later: 0 = none 1 = mild 2 = moderate 3 = intense6) Statistical analysis based on sum of signed ranks of

difference• Correlates well with clinical efficacy( except aclometasone

oint.,hydrocortisone cream) and is reproducible• Best evaluation with vasoconstriction assay in

combination with a second assay on spontaneously occuring skin diseases in human volunteers

Commonly used Glucocorticoid assays Assays of Anti-inflammatory potency

LAB ANIMALS:

• Mitotic index suppression– hairless mouse• Antigranuloma assay- rat• Croton oil inflammation assay- rat• 6-chloro-2,4-dinitrobenzene inflammation– guinea pig

HUMAN VOLUNTEERS:

Vasoconstrictor Assay Artificially induced inflammation Spontaneously occurring skin disease

Assay of Atrophogenicity

LAB ANIMALS OR CELL CULTURES: • Inhibition of fibroblast growth in vitro• Neutral red release assay • Mouse tail epidermis • Guinea pig epidermis

HUMAN VOLUNTEERS:• Micrometer calipers• HPE• X ray radiography• Pulsed ultrasound

Potency ranking of selected TCS preperation

US classification :

Class1- SuperpotentBetamethasone dipropionate 0.05% optimized vehicle-Gel/ointClobetasol propionate 0.05%- cream/gel/oint/spray/foamHalobetasol propionate 0.05% - cream/oint

Class2- PotentBetamethasone dipropionate 0.05%- creamMometasone furoate 0.1%- oint

Class3- Potent, upper mid strengthBetamethasone valerate 0.1%- ointFluticasone propionate 0.005%- oint

Class4- Mid strengthBetamethasone valerate 0.12%- foamHydrocortisone probutate 0.1%- creamHydrocortisone valerate 0.2%-ointTriamcinolone acetonide 0.1%- ointMometasone furoate 0.1%- cream/lotion

Class5- Lower mid stengthBetamethasone dipropionate 0.05%- lotionBetamethasone valerate 0.12%- cream/lotionFluticasone propionate 0.005%- creamHydrocortisone valerate 0.2%- creamHydrocortisone butyrate 0.1%- lipocreamTriamcinolone acetonide 0.1%- cream/lotion

Class6- Mild strength Desonide 0.05%- cream/lotion/ointment Alclometasone dipropionate 0.05%- cream/oint Flucinolone acetonide 0.01%- cream/solution Betamethasone valerate lotion 0.1%

Class7- Least potent Topicals with dexamethasone, flumethasone, hydrocortisone, methylprednisolone and prednisolone

British classificaton

Class IV Very potent (up to 600 times as potent as HC)• Clobetasol propionate • Betamethasone dipropionate

Class III Potent (50-100 times as potent as HC)• Betamethasone valerate• Betamethasone dipropionate• Diflucortolone valerate• Hydrocortisone 17-butyrate • Mometasone furoate• Methylprednisolone aceponate • Halometasone 0.05%

Class II Moderate (2-25 times as potent as HC)• Clobetasone butyrate • Triamcinolone acetonide

Class I Mild• Hydrocortisone 0.5-2.5%

SIDE EFFECTS LOCAL SIDE EFFECTS1) Atrophy:• Most common• Lax, depressed, wrinkled, shiny skin with

telangiectasias, purpura, striae, stellate pseudoscars, prominent deep vessels and hypopigmentation

• Corticoid purpura: fragile skin with tears/bruises• Atrophy of epidermis within 7 days of superpotent TCS

with occlusion; 2 weeks of less potent/ superpotent without occlusion

• Most signs of cutaneous atrophy (except striae) resolve by 1 to 4 weeks of stoppage

2) Flaring up/increased incidence of infections: Esp. if used - on flexural sites - with polythene occlusion e.g. : Tinea incognito, crusted scabies, candidiasis, prolongation of herpes/molluscum, Staphylococcal folliculitis

3) Steroid face: erythema and telangiectasia with atrophy of dermal conn. tissue and resultant loss of vascular supprt

4) Acneiform eruptions: dense, inflamed, monomorphic eruption of erythematous follicular papules and pustules

5) Rosacea – esp.in fair skinned6) Peri-oral dermatitis7) Hypertrichosis, hypopigmentation8) Delayed wound healing, genital ulceration

9) Burning, itching, irritation, dryness10) Granuloma gluteale infantum like reaction11) Reactivation of Kaposi sarcoma

12) Rebound syndrome: • Initial improvement f/b lack of response ; subsequent

flare after TCS stopped.• Skin is atrophic, erythematous with burning sensation

esp. on facial, genital and perioral skin

13) Tachyphylaxis: can occur if restarted within 1 week, so a gap of 1 week should be given before restarting

14) Vehicle related side effects:• Itching, burning, stinging, irritant contact dermatitis• Very occlusive vehicles – folliculitis, miliaria, exacerbation of acne/rosacea

Potential Contact Sensitizers in Topical Corticosteroids

• Parabens• Propylene glycol• Benzyl alcohol• Chlorocresol• Ethylenediamine hydrochloride• lsopropyl palmitate• Polysorbate 60• Stearyl alcohol• The corticosteroid itself

15) Allergic contact dermatitis:• Generally DTH; occasionally Type I• Can be due to: i) preservatives/stabiliser used ii) steroid molecule (eg. Hydrocortisone)• Suspect if : steroid responsive dermatoses fails to respond/ worsens with TCS or evolves into a chronic inflammatory condition which heals with stoppage of incriminated steroid

• TCS have divided into 4 gps based on their antigenic behaviour and cross reactivity as elucidated by patch testing

a) Hydrocortisone type b) Triamcinolone acetonide type c) Betamethasone type d) Hydrocortisone-17-butyrate type• 85% cross reactions within same group• Patch testing with ethanol as vehicle advisable

TCS CROSS REACTION GROUPS

GROUP A HydrocortisoneHydrocortisone acetateTixocortole pivalateMethylprednisolonePrednisolone

GROUP BTriamcinolone acetonideBudesonideDesonideFlucinolone acetonideFlucinonide

GROUP CBetamethasoneBetamethasone sod.PO4DexamethasoneDexamethasone sod.PO4

GROUP DHydrocortisone-17-butyrateAclometasone dipropionateBetamethasone valerateBetamethasone dipropionateHydrocortisone-17-valerateClobetasone-17-butyrateClobetasone-17-propionate

16) Ocular side effects:• TCS have 36-40 times ↑ penetration in eyelid• Can cause: cataract, glaucoma, slow healing of ulceration, exacerbation of herpetic ulcers, ↑ susceptibility to fungal/bacterial infections, ocular hypertension

SYSTEMIC SIDE EFFECTS1) Suppression of hypothalamo-pituitary axis

2) Iatrogenic Cushing’s syndrome

3) Growth retardation in infants and children

• Risk factors: young age, liver and renal disease, amount of TCS

applied, extent of skin surface treated, frequency of application,

length of treatment, potency of drug and the use of occlusion

CONTRAINDICATIONS ABSOLUTE• Known hypersensitivity to TCS• Known hypersensitivity to a component of the

vehicle

RELATIVE• Bacterial,mycobacterial,fungal,viral infection• Infestation• Ulceration

CAUTION! USAGE IN PREGNANCY

• FDA : Category C – when potential benefits justify possible risk to fetus

• Animal studies : fetal abnormalities with large amt, occlusive dressings, potent agents, prolonged periods

• Human studies : not documented

DURING LACTATION• Use with caution at sites other than breast or nipple• Not known if CS are distributed in breast milk

ELDERLY PATIENTS:

• Thin skin : ↑ penetration• Clearance from skin may be reduced• May have pre-existing skin atrophy secondary to

aging• ↑purpura

To be used : 1) infrequently 2) for brief periods 3) under close supervision

PEDIATRIC USE

• Effective with few side effects if : a) low potency preparation b) brief period c) without occlusion

• ↑ risk of side effects as:1. ↑ skin surface area to body weight ratio - ↑

systemic absorption2. ↓ ability to metabolise potent glucocorticoids

rapidly3. Occlusion in diaper region – greater penetration

4) Premature infants – thinner skin – greater penetration5) Can suppress HPA axis – - Addisonian crisis; - Chronic suppression – growth retardation - Near puberty – premature

epiphyseal closure

• Clobetasol & betamethasone to be used in children of age > 12 yrs

• Fluticasone can be used in children of age > 3months• Mometasone can be used in children of age >2 yrs.

CHOOSING A TCS PREPARATION1) CHOOSING THE DESIRED POTENCY BASED ON :

• Thin, acute inflammatory skin lesions – low to medium

• Chronic, hyperkeratotic, lichenified, indurated –

high/very high strength

• Face, intertriginous and inframammary – low strength

OR occ. Short term use(<2 weeks) of more potent

• Recalcitrant lesions of face/intertriginous – may require

more potent prep./ longer duration

• Palms/soles – high/ very high strength

• BSA involved : low to medium strength when large body surface to be

covered

• AGE : children/elderly

• DURATION : duration of very-high strength TCS should not

exceed 3 weeks whenever possible.

- Medium/high strength TCS – side effects rare before 3 months (except

face/intertriginous) ; intermittent therapy preferrable for longer

duration

- Low strength – side effects rare ; prefer intermittent therapy for

long term use esp. if ↑ BSA

• TCS should be discontinued when the disease has resolved ; they are not for disease prevention

• Sudden cessation during acute phase avoided – may cause rebound worsening of skin disease

• Long term therapy may be required for chronic skin diseases responding to treatment but with monitoring for side-effects and tachyphylaxis

2) CHOOSE THE PROPER VEHICLE:• Location• Moisturizing/ drying effect required• Potential for irritation• H/o allergic reactions• Type of disease

3) DETERMINING THE REQUIRED AMOUNT:• One gram of cream will cover an area of skin approximately 10

X 10 cm(100cm²) assuming a layer 100 microns thickness. The same amount of ointment will cover an area

• Based on Finger Tip Units

One fingertip unit (FTU) is the amount of topical steroid that is

squeezed out from a standard tube with a 5 mm nozzle from the very end of the finger to the distal finger crease

5 – 10 % higher

• One FTU is enough to treat an area of skin twice the size of the flat of an adult's hand with the fingers together.

• One FTU is : 0.43g in females : 0.49g in males

• OD/BD applications recommended for most ; more frequent application on palms/soles

• A/D therapy or weekend-only application effective in selected chronic conditions

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