Download Glucocorticoids

Adrenocorticosteroids
ADRENOCORTICOSTEROIDS
Hypothalamic-pituitary-adrenal axis
‫בקרת משק המים והמלח‬
CRF
‫מטבוליזם נורמלי ותגובה לסטרס‬
Adrenaline
Noradrenaline
Adrenocorticosteroids
Adrenal
Adrenal corticosteroids
corticosteroids and
and inhibitors
inhibitors
Agonists
Agonists
Glucocorticoids
Glucocorticoids
Antagonists
Antagonists
Mineralocorticoids
Mineralocorticoids
Long acting
Intermediate acting
Short acting
Receptor
Receptor antagonists
antagonists
Synthesis
Synthesis inhibitors
inhibitors
Interaction of a steroid with its receptor
Adrenocorticosteroids
Glucocorticosteroids
Glucocorticoids
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)
Growth inhibition in children
Immune system
Neutrophils↑, other leukocytes↓ → Immune suppression (especially in
lymphocytic disorders)
Inhibition of inflammation
Glucocorticoids
Renal function
Cortisol: excretion of water loads
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
• Good oral availability
• Cleared by the liver
• Poor transdermal availability, but absorbed across inflamed
skin
• Salt retention activity = hypertension
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Cushing disease:
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
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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
• Hypercalcemia
• 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
A. Aldosterone:
Regulaed 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)
• Ketoconazole: inhibition of P450