1. Adrenocorticosteroids

2. ADRENOCORTICOSTEROIDS

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

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

5. Interaction of a steroid with its receptor

6. Adrenocorticosteroids

7. Glucocorticosteroids

8. 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)

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

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

11. 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.

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

13. 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.

14. Synthetic Glucocorticoids
Drug Duration [hours] Anti-inflammatory Salt retaining Topical
(mainly glucocorticoids)
Cortisol
Prednisone
Triamcinolone
Dexamethasone
(mainly mineralocorticoids)
Aldosterone
Fludrocortisone

15. 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.

16. 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

17. 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

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