Corticosteroid:Co t coste o dtopical and systemic

Aznan Lelo, Yunita Sari PaneAznan Lelo, Yunita Sari Pane

Dep. Farmakologi dan Terapeutik,Dep. Farmakologi dan Terapeutik,Fakultas Kedokteran

Universitas Sumatera UtaraUniversitas Sumatera Utara8&11, 4 Februari 2009, KBK, FK USU, Medan

DermatitisDiapers dermatitisAtopic dermatitis

Stasis dermatitisContact dermatitis

Symptoms of allergic drug reactionsSymptoms of allergic drug reactions

Skin reactionsSkin reactions(80%)AnaphylaxisAnaphylaxis (9 - 15%)Respiratory symptomsRespiratory symptoms (6 - 9%)Drug feverDrug fever (2 - 6%)

Stevens Johnson syndrome

Eczema TreatmentEczema TreatmentEmollients: ointments > creams > lotionsTopical corticosteroidsTopical Immunomodulators (TIMs): safe for short-term or intermittent long-termsafe for short-term or intermittent long-term

• Pimecrolimus (Elidel)• Tacrolimus (Protopic)

Systemic corticosteroidsSystemic corticosteroidsOral Antihistamines

• Sedating-AHisNon sedating AHis• Non-sedating-AHis

Oral Leukotriene receptor antagonists

• Monteleukast (Singulair)

STEROIDSTEROIDLipid characterized byLipid characterized by a carbon skeleton with four fused rings. All steroids are derived from the acetyl CoA biosynthetic pathway.SystemicTopicalp

Topical corticosteroids (TCS)Topical corticosteroids (TCS)

• First introduced in the 1950s and areFirst introduced in the 1950s and are currently the mainstay of prescription therapy for atopic dermatitistherapy for atopic dermatitis

• Safe and effective when used as recommendedrecommended

• Weakest steroid that will keep the d t l h ld b deczema under control, should be used

• Potent steroids should be used in short pulses, generally 2-3 weeks

TCS = Topical corticosteroids

Drug Topical preparation PotencyBeclomethasone 0.025 % cream PotentdipropionateBetamethasone benzoate Betamethasone valerate

0.025 % cream, ointment0.12 % cream, ointment

PotentBetamethasone valerate 0.12 % cream, ointmentClobetasol propionate 0.05 % cream Potent

Halcinonide 0.1 cream Potent

Triamcinolone actonide 0.1 % ointment PotentFluocinolone actonide 0.025% ointment Moderate

Mometasone 0.1 % cream, ointment Moderate

Fluticasone 0.05 % cream ModerateHydrocortisone acetate 2 5 % ointment ModerateHydrocortisone acetate 2.5 % ointment ModerateHydrocortisone acetate 0.1 – 1.0% ointment Mild

Classification of TCSClass Potency Steroid

Anti-inflam

Anti-mitosi Diseases Disadvantage

I Super- Betametason +++ +++ Liken simplex causes thin potent, fast acting

dipropionat 0,05 %

kronikHyperkeratosis eksemaMycosis

skin, not safe in kids short-term use only

fungoides. LE, resist. eczema

II Potent Triamsinolon asetonid 0 1%

+++ ++ Lichenified eczemaasetonid 0,1%

Betametasone valerate

eczema, psoriasisSeboroika eksema

III M d t Fl t ++ + B d tillIII Moderate safer for chronic use

Flumetason pivalat 0,02 %

++ + Body, extremities

still causes thinning over long-term

IV Mild Hidrokortison 1 %

+ - Face, flexures, children, aged people

Limited effectiveness

DiprosoneDiprosone (Betamethasone Propionate)

Appro ed in 2001Approved in 2001

Betamethasone Propionate 0.05% Class steroid

Diprosone Ointment, 0.05% a Class I steroidDiprosone Cream 0 05% a Class II steroidDiprosone Cream, 0.05% a Class II steroidDiprosone Lotion, 0.05% a Class III steroid

Mechanism of action of TCSMechanism of action of TCS1. Antiinflammatory effects

TCS affect inflammatory cells chemicalTCS affect inflammatory cells, chemical mediators and tissue responses which are all responsible for cutaneous inflammationp

2. Antiproliferative effects (anti-mitotic)TCS may reduce mitotic activity in the epidermis, leading to flattening of the basal cell layer and thinning of the stratum corneum and stratum granulosumcorneum and stratum granulosum

3. Atrophogenic EffectsTCS can promote atrophy of the dermisTCS can promote atrophy of the dermis through inhibition of fibroblast proliferation, migration, chemotaxis and protein synthesis

Topical Corticosteroids (TCS)Topical Corticosteroids (TCS)Antiinflammatory effectsy

- TCS inhibit nuclear factor kappa B (NFkB), which upregulates cytokines. Inhibition done by increasing production of NFkB inhibitor (IkB) and directly binding &production of NFkB inhibitor (IkB) and directly binding & inactivating NFkB

- Affects leukocytes, lymphocytes, monocytes, epidermal Langerhans’ cellsLangerhans cells

- Inhibit phospholipase A2 and then inhibit PGs & LTs- Vasoconstrictive- Antipruritic - Mast cell sensitization & IgE induced

mediator release inhibitedAntiproliferative & Atrophogenic effectsAntiproliferative & Atrophogenic effects

GLUCOCORTICOID(CORTISOL : HYDROCORTISONE)

MECHANISM OF ACTION

N l Cell membrane

Nuclear membrane

SteroidSteroid + receptor

Steroid + receptor

accceptor

Steroid receptor complex

receptor complex

chromatin

receptor

GLUCOCORTICOID(CORTISOL : HYDROCORTISONE)(CORTISOL : HYDROCORTISONE)

IMMUNOSUPPRESSIVE AND ANTI-INFLAMMATION EFFECT

ANTIGEN ANTIBODY COMPLEX INHIBITED BY ANTIGEN-ANTIBODY COMPLEX

PHOSPOLIPIDPHOSPOLIPASE A

INHIBITED BY GLUCOCORTICOID

ARACHIDONIC ACID

PHOSPOLIPASE A2

CYCLOOXYGENASELIPOXYGENASE

LEUKOTRIENE PROSTACYCLINTHROMBOXANESLEUKOTRIENE

PROSTAGLANDINS

PROSTACYCLINTHROMBOXANES

Systemic Effects of TCSSystemic Effects of TCS

• If a TCS is absorbed percutaneously inIf a TCS is absorbed percutaneously in significant quantities, it can cause systemic adverse side effects similar tosystemic adverse side effects similar to systemically administered corticosteroids.

Adverse reactions (1/2)Adverse reactions (1/2)Can result from :

th d b tthe drug substance, orthe vehicle which can potentiate problems

• Metabolic toxicity:• Metabolic toxicity:– Iatrogenic Cushing’s syndrome– Hyperglycaemia, glycosuria, diabetesyp g y g y– Myopathy (negative nitrogen balance)– Osteoporosis (vertebral compression

fracture)fracture)– Retardation of growth (children)– Hypertension, edema, CCFyp , ,– Avascular necrosis of femur

Adverse reactions (2/2)• HPA axis suppression• Behavioral toxicity:

– Euphoria, psychomotor – reactions, suicidal tendency

O l t i it• Ocular toxicity:– steroid induced glaucoma,

posterior subcapsular cataract– posterior subcapsular cataract. • Others:

– SuperinfectionsSuperinfections– Delayed wound healing– Steroid arthropathyp y– Peptic ulcer– Live vaccines are dangerous

Risk factors for systemic d ffadverse effects

Y (i f t d hild )• Young age (infants and children)• Liver and renal disease• Amount of TCS appliedAmount of TCS applied• Extent of skin disease treated• Frequency of applicationq y pp• Length of treatment• Potency of drug

U f l i• Use of occlusionIt is not established whether catch up growth in

children will occur when TCS are discontinuedchildren will occur when TCS are discontinued.

Local side effects of TCSLocal side effects of TCS

• Epidermal Atrophy - wrinkled skin withEpidermal Atrophy wrinkled skin with prominent vasculature, pseudoscars, striae or purpurastriae or purpura

• Steroid dependence/reboundGl / t t• Glaucoma/cataracts

• Increased susceptibility to bacterial, fungal and viral infections

Topical SteroidsBenefits due to anti-inflammatory, immunosuppressive vasoconstrictor and

G d Sl

immunosuppressive, vasoconstrictor and anti-proliferative actions

Good response Slow responseAtopic eczema, Allergic contact dermatitis

Cystic acneAlopecia areataAllergic contact dermatitis,

Lichen simplex, Primary irritant dermatitis,

Alopecia areataDiscoid LEHypertrophied scars

Seborrheic dermatitis, Psoriasis of face, Varicose eczema

KeloidsLichen planusPsoriasis of palm soleVaricose eczema Psoriasis of palm, sole,

elbow & knee

Topical TreatmentsTopical Treatments

Wet dermatitis -Wet dermatitis wet treatment

dressings– dressings– light creams

D d titi

Fetal vaccinia

Dry dermatitis -dry treatment

i– ointments– petrolatum– oils Eczema vaccinatum

Topical steroids are combined pwith antimicrobial agents for

I ti• Impetigo• Furunculosis• Secondary infected dermatoses• Napkin rashNapkin rash• Otitis externa

I t t i i ti• Intertriginous eruptions

Guidelines for topical steroidsGuidelines for topical steroids

Penetration differs at different sites:• High: axilla, groin, face, scalp, scrotum• Medium: limbs, trunk• Low: palm, sole, elbow, knee

Occlusive dressing enhance absorption (10 fold)(10 fold)Absorption is greater in infants & ChildrenChildren

Guidelines for topical steroidsGuidelines for topical steroids

Absorption depends on nature of p plesion:

High: atopic & exfoliative dermatitisLow: hyperkeratinized & plaque forming lesions

More than 3 applications a day is notMore than 3 applications a day is not neededChoice of vehicle is importantC o ce o e c e s po ta t

Lotions & creams: for exudative lesionsSprays & gels: for hairy regionsOintments: for chronic scaly lesions

Therapeutic principlesTherapeutic principles

Dose selection by trial & error; Needs frequent y ; qevaluationSingle dose: No harmFew days therapy unlikely to be harmfulIncidence of side effects related to duration of ththerapyUse is only palliative (except replacement therapy)therapy)Inter-current illness: Dose is doubledAbrupt cessation of prolonged high dose leadsAbrupt cessation of prolonged high dose leads to adrenal insufficiency (contraindicated)

Dosage schedule

Goal of therapy: • To relieve pain or distressing symptom (e.g.,

rheumatoid arthritis): start with low dose• To treat life threatening condition (e g pemphigus):• To treat life threatening condition (e.g., pemphigus):

initial dose must be highPrevention of HPA axis suppression:Prevention of HPA axis suppression:• Single dose (morning)• Alternate dose therapy (short lived glucocorticoids)py ( g )• Pulse therapy (higher glucocorticoid therapy)

Steroid withdrawal

Longer the duration of therapy, slower the withdrawal

• Less than 1 week: withdrawal in few steps– Rapid withdrawal: 50% reduction of dose every day– Slow withdrawal: 2.5 – 5 mg prednisolone reduced

at an interval of 2 3 daysat an interval of 2-3 days• Longer period & high dose:

– Halve the dose weekly until 25 mg prednisolone or– Halve the dose weekly until 25 mg prednisolone or equivalent is reached

– Later reduce by about 1mg every 3-7 days.

HPA axis recovery may take months or up to 2 years

Contraindications

InfectionsHypertension with CCFPsychosisPsychosisPeptic ulcerDiabetes mellitusOsteoporosispGlaucomaPregnancy : (prednisolone preferred)Pregnancy : (prednisolone preferred)

Glucocorticoids antagonists• Mitotane: structure similar to DDT, used in

inoperable adrenal cancer• Metyrapone: inhibit 11 β-hydroxylase• Aminoglutethamide: inhibit conversion of

h l t l t l di l d l tcholesterol to pregnolone, medical adrenelectomy• Trilostane: inhibit conversion of pregnolone to

progesterone; used in Cushing’s syndromeprogesterone; used in Cushing s syndrome• Ketoconazole: anti-fungal, inhibit CYP450

enzymes, inhibit steroid synthesis in ad.cortex andenzymes, inhibit steroid synthesis in ad.cortex and testis; used in Cushing’s syndrome & Ca.prostate

• Mifepristone: glucocorticoid receptor antagonist; anti-progesterone, used in Cushing’s syndrome

Factors to consider when ibi t i l ti t idprescribing topical corticosteroids

1. Type of preparation (base and potency) –yp p p ( p y)Base can be ointment, cream, emulsion, gel or lotion

P l ifi d f I ( )Potency classified from group I (most potent) to VII (least potent)

2 Acute or chronic eczema2. Acute or chronic eczema3. Age of child4 Site to be treated4. Site to be treated5. Extent of eczema6 Method of application6. Method of application

TOPICAL IMMUNOSUPPRESANTSIMMUNOSUPPRESANTS

• Newest pharmacological class for ADNewest pharmacological class for AD • Introduced in this decade• Direct immunosuppressive action in• Direct immunosuppressive action in

diseases with immunologic basis– TACROLIMUSTACROLIMUS– PIMECROLIMUS– CYCLOSPORINECYCLOSPORINE

• All act through calcineurin inhibition• All act through calcineurin inhibition

Calcineurin inhibitorsCalcineurin inhibitorsTwo new agents: Tacrolimus (Protopic) 0.1% ointment g ( p )

Pimecrolimus (Elidel) 1.0% creamDerived from fungal polypeptides and Inhibit T-lymphocyte activation; Potent immunosuppressive iflymphocyte activation; Potent immunosuppressive if given systemicallyDemonstrated to be effective in childhood and adult ADDon’t cause atrophy of the skin or other steroid side effects Slow acting anti inflammatorySlow acting anti-inflammatoryCauses stinging and burn at initiation of therapy; slight increase in skin infections ? Long-term safety not known

Pimecrolimus is different from corticosteroids

Selective action on T cells and mast cells No effect on Langerhans’/dendritic cellsNo effect on Langerhans /dendritic cellsNo induction of skin atrophyMuch less permeation through skin

SummarySummaryHPA axis suppression does occur with ppthe use of topical corticosteroidsThe adrenal suppression is not limited to th t t l f t i lthe super potent class of topical corticosteroidsThe type of vehicle may contribute to theThe type of vehicle may contribute to the extent of absorption of the active chemical moietyyThe suppression appears, in most cases, to be reversible upon cessation of drug usage