Cort icoste r oi d: topical and systemic

Aznan Lelo, Yunita Sari Pane

Dep. Farmakologi dan Terapeutik, Fakultas Kedokteran Universitas Sumatera Utara

8&11, 4 Februari 2009, KBK, FK USU, Medan Dermatitis

Atopic dermatitis Diapers dermatitis

Contact dermatitis Stasis dermatitis Symptoms of allergic drug reactions

ƒ Skin reactions (80%) ƒ Anaphylaxis (9 - 15%) ƒ Respiratory symptoms (6 - 9%) ƒ Drug fever (2 - 6%)

Stevens Johnson syndrome Eczema Treatment

ƒ Emollients: ointments > creams > lotions ƒ Topical corticosteroids ƒ Topical Immunomodulators (TIMs): safe for short-term or intermittent long-term • Pimecrolimus (Elidel) • Tacrolimus (Protopic) ƒ Systemic corticosteroids ƒ Oral Antihistamines • Sedating-AHis • Non-sedating-AHis ƒ Oral Leukotriene receptor antagonists • Monteleukast (Singulair) STEROID

ƒ Lipid characterized by a carbon skeleton with four fused rings. ƒ All steroids are derived from the acetyl CoA biosynthetic pathway. ƒ Systemic ƒ Topical Topical corticosteroids (TCS)

• First introduced in the 1950s and are currently the mainstay of prescription therapy for atopic dermatitis • Safe and effective when used as recommended • Weakest steroid that will keep the eczema undtlhldbdder control, should be used • Potent steroids should be used in short pulses, generally 2-3 weeks TCS = Topical corticosteroids

Drug Topical preparation Potency Beclomethasone 0.025 % cream Potent dipropionate Betamethasone benzoate 0.025 % cream, ointment Potent Betamethasone valerate 0.12 % cream, ointment Clobetasol propionate 0.05 % cream Potent Halcinonide 0.1 cream Potent Triamcinolone actonide 0.1 % ointment Potent Fluocinolone actonide 0.025% ointment Moderate Mometasone 0.1 % cream, ointment Moderate Fluticasone 0.05 % cream Moderate Hydrocortisone acetate 25%ointment2.5 % ointment Moderate Hydrocortisone acetate 0.1 – 1.0% ointment Mild Classification of TCS Anti- Anti- Class Potency Steroid inflam mitosi Diseases Disadvantage I Super- Betametason +++ +++ Liken simplex causes thin potent, dipropionat kronik skin, not safe fast 0,05 % Hyperkeratosis in kids short- acting eksema term use only Mycosis fungoides. LE, resist. eczema II Potent Triamsinolon +++ ++ Lichenified asetonid 0, 1% eczema, Betametasone psoriasis valerate Seboroika eksema III MdModera te Flume tason ++ + BdBody, still causes safer for pivalat 0,02 % extremities thinning over chronic long-term use IV Mild Hidrokortison 1 +-Face, flexures, Limited % children, aged effectiveness people Diprosone (Betamethasone Propionate) Approv ed in 2001

Betamethasone Class steroid Propionate 0.05% Diprosone Ointment, 0.05% a Class I steroid Diprosone Cream, 0. 05% a Class II steroid Diprosone Lotion, 0.05% a Class III steroid Mechanism of action of TCS 1. Antiinflammatory effects TCS affect inflammatory cells , chemical mediators and tissue responses which are all responsible for cutaneous inflammation 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 granulosum 3. Atrophogenic Effects TCS can promote atrophy of the dermis through inhibition of fibroblast proliferation, migration, chemotaxis and protein synthesis Topical Corticosteroids (TCS)

ƒ Antiinflammatory effects - TCS inhibit nuclear factor kappa B (NFkB), which upregulates cytokines. Inhibition done by increasing production of NFkB inhibitor (IkB) and directly binding & inactivating NFkB - Affects leukocytes, lymphocytes, monocytes, epidermal Langerhans’ cells - Inhibit phospholipase A2 and then inhibit PGs & LTs - Vasoconstrictive - Antipruritic - Mast cell sensitization & IgE induced mediator release inhibited ƒ Antiproliferative & Atrophogenic effects GLUCOCORTICOID (CORTISOL : HYDROCORTISONE)

MECHANISM OF ACTION

NlNuclear Cell membrane membrane

accceptor

Steroid + Steroid + Steroid receptor receptor complex complex

chromatin receptor GLUCOCORTICOID (CORTISOL : HYDROCORTISONE)

IMMUNOSUPPRESSIVE AND ANTI-INFLAMMATION EFFECT

ANTIGEN-ANTIBODY COMPLEX INHIBITED BY GLUCOCORTICOID PHOSPOLIPID

PHOSPOLIPASE A2 ARACHIDONIC ACID

LIPOXYGENASE CYCLOOXYGENASE

LEUKOTRIENE THROMBOXANES PROSTACYCLIN

PROSTAGLANDINS Systemic Effects of TCS

• If a TCS is absorbed percutaneously in significant quantities, it can cause systemic adverse side effects similar to systemically administered corticosteroids. Adverse reactions (1/2)

Can result from : the drug su bs tance, or the vehicle which can potentiate problems • Metabolic toxicity: – Iatrogenic Cushing’s syndrome – Hyper gyglycaemia, gyglycosuria, diabetes – Myopathy (negative nitrogen balance) – Osteoporosis (vertebral compression fracture) – Retardation of growth (children) – Hypertension, edema, CCF – Avascular necrosis of femur Adverse reactions (2/2) • HPA axis suppression • Behavioral toxicity: – Euphoria, psychomotor – reactions, suicidal tendency • OltiitOcular toxicity: – steroid induced glaucoma, – posterior subcapsular cataract. • Others: – Superinfections – Delayed wound healing – Steroid arthroppyathy – Peptic ulcer – Live vaccines are dangerous Risk factors for systemic adffdverse effects

• Young age (in fan ts and c hildren ) • Liver and renal disease • Amount of TCS applied • Extent of skin disease treated •Freqqyppuency of application • Length of treatment • Potency of drug • UfliUse of occlusion It is not established whether catch up growth in children will occur when TCS are discontinued. Local side effects of TCS

• Epidermal Atrophy - wrinkled skin with prominent vasculature, pseudoscars, striae or purpura • Steroid dependence/rebound • Glaucoma/ cat aract s • Increased susceptibility to bacterial, fungal and viral infections Topical Steroids Benefits due to anti-inflammatory, immunosuppressive, vasoconstrictor and anti-proliferative actions GdGood response Slow response Atopic eczema, Cystic acne Allergic contact dermatitis , Alopecia areata Lichen simplex, Discoid LE Primary irritant dermatitis, Hypertrophied scars Seborrheic dermatitis, Keloids Psoriasis of face, Lichen planus Varicose eczema Psoriasis of palm, sole , elbow & knee Topical Treatments

ƒ Wet dermatitis - wet treatment – dressings Fetal vaccinia – light creams ƒ Dry derma titis - dry treatment – ointments – petrolatum – oils Eczema vaccinatum Topical steroids are combined with antimicrobial agents for • ItiImpetigo • Furunculosis • Secondary infected dermatoses • Napkin rash • Otitis externa • ItIntert tiiriginous erupti ons Guidelines for topical steroids

ƒ Penetration differs at different sites: • High: axilla, groin, face, scalp, scrotum • Medium: limbs, trunk • Low: palm, sole, elbow, knee ƒ Occlusive dressing enhance absorption (10 fold) ƒ Absorption is greater in infants & Children Guidelines for topical steroids

ƒ Absorppption depends on nature of lesion: ƒ High: atopic & exfoliative dermatitis ƒ Low: hyperkeratinized & plaque forming lesions ƒ More than 3 applications a day is not needed ƒ CCoceohoice of v ehi cescle is im potatportant ƒ Lotions & creams: for exudative lesions ƒ Sprays & gels: for hairy regions ƒ Ointments: for chronic scaly lesions Therapeutic principles

ƒ Dose selection byy;q trial & error; Needs frequent evaluation ƒ Single dose: No harm ƒ Few days therapy unlikely to be harmful ƒ Incidence of side effects related to duration of therapy ƒ Use is only palliative (except replacement therapy) ƒ Inter-current illness: Dose is doubled ƒ Abrupt cessation of prolonged high dose leads to adrenal insufficiency (contraindicated) Dosage schedule

ƒ 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): initial dose must be high ƒ Prevention of HPA axis suppression: • Single dose (morning) • Alternate dose therapy ( short lived g lucocorticoids) • 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 days • Longer period & high dose: – 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

ƒ Infections ƒ Hypertension with CCF ƒ Psychosis ƒ Peptic ulcer ƒ Diabetes mellitus ƒ Osteoporosis ƒ Glaucoma ƒ Pregnancy : (prednisolone preferred) Glucocorticoids antagonists

• Mitotane: structure similar to DDT, used in inoperable adrenal cancer • Metyrapone: inhibit 11 β-hydroxylase • Aminoglutethamide: inhibit conversion of chlholes tero ltl to pregno lone, me dildical a drene lec tomy • Trilostane: inhibit conversion of pregnolone to progesterone; used in Cushing’ s syndrome • Ketoconazole: anti-fungal, inhibit CYP450 enzymes, 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 prescribing t opi cal corti cost eroid s 1. Type of pre paration (base and potenc y) – Base can be ointment, cream, emulsion, gel or lotion Potency cl ass ifie d from group I (most potent ) to VII (least potent) 2. Acute or chronic eczema 3. Age of child 4. Site to be treated 5. Extent of eczema 6. Method of application TOPICAL IMMUNOSUPPRESANTS • Newest pharmacological class for AD • Introduced in this decade • Direct immunosuppressive action in diseases with immunologic basis – TACROLIMUS – PIMECROLIMUS – CYCLOSPORINE

• All act through calcineurin inhibition Calcineurin inhibitors

ƒ Two new agents: Tacrolimus ((p)Protopic) 0.1% ointment Pimecrolimus (Elidel) 1.0% cream ƒ Derived from fungal polypeptides and Inhibit T- lymphocyte activation; Potent immunosuppressive if given systemically ƒ Demonstrated to be effective in childhood and adult AD ƒ Don’t cause atrophy of the skin or other steroid side effects ƒ Slow acting anti-inflammatory ƒ Causes stinging and burn at initiation of therapy; slight increase in skin infections ? Long-term safety not known Pimecrolimus is different from corticosteroids

ƒ Selective action on T cells and mast cells ƒ No effect on Langerhans’ /dendritic cells ƒ No induction of skin atrophy ƒ Much less permeation through skin Summary

ƒ HPA axis suppression does occur with the use of topical corticosteroids ƒ The adrenal suppression is not limited to the super po ttltent class of ftil topical corticosteroids ƒ The type of vehicle may contribute to the extent of absorption of the active chemical moiety ƒ The suppression appears, in most cases, to be reversible upon cessation of drug usage