Adrenocorticosteroids

ADRENOCORTICOSTEROIDS

Hypothalamic-pituitary-adrenal axis בקרת משק המים והמלח CRF מטבוליזם נורמלי ותגובה לסטרס Adrenaline Noradrenaline

Adrenocorticosteroids Adrenal corticosteroids and inhibitors Agonists Antagonists Glucocorticoids Mineralocorticoids Receptor antagonists Synthesis inhibitors Long acting (Dexamethasone/Betamethasone) Intermediate acting (Prednisone) Short acting (Hydrocortisone)

Interaction of a steroid with its receptor

Adrenocorticosteroids

Glucocorticosteroids

Glucocorticoids- side effects Metabolic effects Stimulate gluconeogenesis  Blood sugar, insulin secretion Lipolysis + Lipogenesis  Fat deposition [“moon face”, “buffalo hump”] Catabolic effects catabolism of muscle protein, connective tissue, fat, skin Bone (osteoporosis) – Supplement Vitamin D+ Calcium Growth inhibition in children- In asthma? Immune system Neutrophils↑, other leukocytes↓ → Immune suppression (especially in lymphocytic disorders)

Glucocorticoids Renal function Cortisol CNS In large doses: behavioral disturbances Gastrointestinal system Stimulation of gastric acid secretion → Peptic ulcers

Important Glucocorticoids CORTISOL [hydrocortisone] Regulated by ACTH. Secretion varies during the day (circadian rhythm), Peak in the morning:

Important Glucocorticoids CORTISOL [hydrocortisone] Synthetized from 17-OH-pregnenolone 95% is bound in the plasma by corticosteroid-binding globulin As a drug: Short action (anaphylaxis) Good oral availability Cleared by the liver Poor transdermal availability, but absorbed across inflamed skin (atopic dermatitis) Salt retention activity = hypertension Cushing syndrome: Hyper activity of the Hypothalamus-Pituitary-Adrenal Increased Cortisol levels– all the above effects Diagnosis: low dose dexamethasone suppression test Treatment: anti-steroids (synthesis + receptor), surgery.

Cushing’s symptoms (or Glucocorticoid side effects) Lipodystrophy Buffalo hump Moon face Hirsutism, weight gain, muscle degradation, acne, thinning of the skin

Synthetic Glucocorticoids Mechanism identical to cortisol. Prednisone, dexamethasone, triamcinolone Longer duration of action Reduced salt-retaining effect Better topical activity In asthma: beclomethasone, budesonide: good surface activity on mucous membranes, systemic effects avoided due to very short half-lives.

Synthetic Glucocorticoids Drug Duration [hours] Anti-inflammatory Salt retaining Topical (mainly glucocorticoids) Cortisol 8-12 1 1 - Prednisone 12-24 4 0.3 + Triamcinolone 15-24 5 0 +++ Dexamethasone 24-36 30 0 +++++ (mainly mineralocorticoids) Aldosterone 1-2 0.3 3000 - Fludrocortisone 8-12 10 125-250 -

Glucocorticoids CLINICAL USES Adrenal disorders: Addison’s disease: adrenocortical insufficiency Acute adrenal insufficiency (in shock, trauma etc.) Congenital adrenal hyperplasia Non-adrenal disorders Inflammation Immune disorders Leukemias Neurologic disorders Chemotherapy-induced vomiting ADVERSE EFFECTS Life threatening adrenal suppression Metabolic effects: growth inhibition, diabetes, muscle wasting, osteoporosis Immune effects: infections Psychosis To avoid: local application, alternate-day therapy. Slow withdrawal to allow recovery of normal adrenal function.

Mineralocorticoids- Analouges Aldosterone: Regulated by ACTH and the renin angiotensin system. Very important for regulation of blood volume and blood pressure B. Others: Fludrocortisone: Long duration, replacement therapy for adrenalectomy

Adrenocorticosteroids CORTICOSTEROID ANTAGONISTS Receptor antagonists: spironolactone, mifepristone Synthesis inhibitors: Aminogluthetimide: suppression of adrenal estrogen production Metyrapone: inhibition of cortisol synthesis (but not precursors)- Treatment for cushing! Ketoconazole: inhibition of P450

Drug list: Hydrocortisone Prednisone Dexamethasone Budesonide - Asthma Spironolactone – Diuresis/heart failure Ketoconazole – Also antifungal