Lísek, 2003 Corticosteroids Slíva, M.D.

Lísek, 2003 ADRENOCORTICOSTEROIDS GLUCOCORTICOIDS MINERALOCORTICOIDS SEXUAL HORMONS Lísek, 2003

ADRENOCORTICOSTEROIDS Hypothalamus Adenohypophysis Suprarenal cortex trauma emotion diurnal rhythm corticosteroids ACTH CRF negative feedback Lísek, 2003

A. Clinical uses Substitutional therapy suprarenal insuficiency Non-endocrine diseases arthritis vascular disorders eye diseases gastrointestinal diseases blood disorders sarcoidosis immunosuppression infections (suppression of inflammation) mountain sickness nervous system disorders (MS) diseases of skin, kidney etc. Lísek, 2003

Daily production of corticosteroids: Lísek, 2003

1. Corticosteroids bind to glucocorticoid or mineralocorticoid receptors, the steroid-receptor complex then regulates gene transcription. 2. Example for anti-inflammatory properties: glucocorticoids increase lipocortin transcription lipocortin inhibits phospholipase A decreased arachadonic acid and eicosanoids B. Mechanism of action: Lísek, 2003

Mechanism of action:

Lísek, 2003 C. Effects of glucocorticoids  liver deposits of glykogen  gluconeogenesis  catabolism of proteins  catabolism of bones  inflammatory response  immune response Lísek, 2003

Fluoride CH3-methyl group (  antiinflam. úč.) (  retence sodíku) D. Structure-activity relationship: - required for activity: ketone at position 3 & double bounds at 4-5 Smaller modifications in the basic corticosteroid structure alter: sodium-retaining potency antiinflammatory potency drug half-life transcortin binding Lísek, 2003

E. Therapeutic potential of various corticosteroids (in comparisson to hydrocortisone): Lísek, 2003

Glucocorticoid potencies : very high high very low dexamethasone prednisolon fludrocortisone triamcinolone methylprednisolone betamethasone Mineralocorticoid potencies: very high low very low fludrocortisoneprednisolonedexamethasone methylprednisolonebetamethasone triamcinolone Lísek, 2003 E. Therapeutic potential of various corticosteroids (in comparisson to hydrocortisone):

Lísek, 2003 F. Pharmacokinetics 1. Routes of administration: - oral (systemic, long-term treatment - i.m., i.v. (emergency) - topical (eyes, skin, HEENT) - intra-articular injection - inhalation - nosespray systemic local Lísek, 2003

2. Metabolism of corticosteroids (liver): - reduction of double bound at 4-5 position yield to inactive forms - conjugation of inactive metabolism - excretion Liver disease affects steroid metabolis: prednisone (inactive) prednisolone (active) Lísek, 2003 F. Pharmacokinetics

Lísek, Half-lives of various corticosteroids : Lísek, 2003 F. Pharmacokinetics

Lísek, 2003 G. Adverse effects & toxicity: 1. General considerations: - route of administration - systemic x local - dose - length of therapy 2. Short-term systemic therapy: - no ADRs Lísek, 2003

3. Long-term systemic administration: - Cushingoid features (fat redistribution) - Sodium retetion (edema, hypertension, heart failure) - Potassium loss (muscle weakness) - Glucose intolerance - Weight gain - Loss of skin collagen => skin atrophy, stria - Osteoporosis - Peptic ulcer - HPA axis suppression - CNS effects (psychosis, insomnia, nervousness, euphoria depression) - Susceptibility to infection - triamcinolone – weight loss and sedatione - Masking of symptoms of other diseases Lísek, 2003 G. Adverse effects & toxicity:

Lísek, Local use: - inhaled steroids - candidal infection, dysphonia - nasal steroids – irritation, headache, nosebleed, dry nose - topical - epidermal atrophy, steroidal acne akné, teleangiectasis, hypertrichosis, pigmentation disorders, dermatitis perioralis, granuloma gluteale infantum Lísek, 2003 G. Adverse effects & toxicity:

Lísek, Minimizing side effects: - Smallest possible dose - Shortest possible duration - Local application - Alternate day therapy - Descendent therapy during withdrawal - Encapsulation into liposomes Lísek, 2003 G. Adverse effects & toxicity:

Lísek, 2003 H. Corticosteroid withdrawal: 1. General consideration - dose - duration - half-life 2. Withdrawal - administration of short or intermediating-acting steroids - gradually taper dose Lísek, 2003

3. Withdrawal symptoms: - acute adrenal insufficiency - dependence - exacerbation of underlying disease - re-bound phenomenon Lísek, 2003 H. Corticosteroid withdrawal:

Lísek, 2003 I. Drug interactions: Drugs that decrease steroid effectiveness: inductors of liver enzymes cholestyramine Drugs that increase steroid effectiveness: ATB - erythromycin oral contraceptives ketoconazole Lísek, 2003

Drugs affected by steroid administration: anticoagulants (dosage increase needed) antihypertensives (dosage increase needed) hypoglycemics (dosage increase needed) sympathomimetics (dosage decrease needed) Lísek, 2003 I. Drug interactions: