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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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