20 cortisoladrenal-4pp (1)
DESCRIPTION
cortisol adrenal pharmTRANSCRIPT
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Adrenal Corticosteroids
Outline• Stress response & the adrenal cortex
• Hypothalamic & anterior pituitary stimulation of cortisol synthesis
• Biological role of cortisol
• Pharmacological uses of glucocorticoids
• Cortisol excess
• Cortisol deficiency
• Tests for hypothalamic-pituitary function
DHEA
Affects kidneys to regulate salt metabolism
↑ catabolic rxns, ↑ metabolic fuels,↑ blood glucose
Source of androgens
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Aldosterone Cortisol
DHEA
Biological Actions of Cortisol
What are the effects of excess cortisol?
• Cushing’s syndrome
Glucocorticoid Excess: Cushing’s syndrome
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What are the effects of insufficient cortisol?• Addison’s disease
– Cortisol is required for survival– Carbohydrate imbalance– Tiredness (low blood glucose)– Low blood pressure– ↑ skin pigmentation – (JFK had Addison’s)
• Congenital adrenogenital syndrome
X X
Congenital Adrenogenital Syndrome: deficiency in 21-β-hydroxylase
↑ Androgens
When are glucocorticoids used therapeutically?
Minimize suppression of pituitary & adrenal cortex by administration of glucocorticoid in morning after normal peak of release
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Fig. 28.4 The long negative feedback loop is more important than the short loop (dashed lines). Adrenocorticotrophic hormone (ACTH, corticotrophin) has only a minimal effect on mineralocorticoid production. Drugs are shown in yellow boxes. ADH, antidiuretic hormone (vasopressin); CRF, corticotrophin-releasing factor.
Regulation of synthesis and secretion of adrenal corticosteroids.
Tests of hypothalamic-pituitary-adrenocortical function:
To test for causes of adrenal excess (Cushings’ Syndrome)
Dexamethasone suppression test:
• Administer low dose of dexamethasone (potent glucocorticoid)
• Test for suppression in ACTH and suppression of cortisol secretion due to long feedback inhibition of the hypothalamus & pituitary
DHEA
Dexamethasone suppression test:
Dexamethasone1
ACTH2
Cortisol3
Stimulation of Long Feedback Loop with Dexamethasone
1) Control
2) Pretreat with Dexamethasone
Normal: Dexamethasone causes ↓ ACTH and ↓ cortisol due to negative feedback.
If cortisol doesn’t decrease, may indicate Cushings syndrome, suggesting that there is an ectopic source of ACTH or cortisol (eg: adrenal adenoma) that is not inhibited by the dexamethasone
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Tests of hypothalamic-pituitary-adrenocortical function:
To test for causes of adrenal insufficiency
1) Administer ACTH:
• Does [cortisol] increase?
2) Metyrapone enhancement test:
• Block synthesis of cortisol in the adrenal cortex with metyrapone
• Test for ↑ [ACTH] and ↑ [11-deoxycortisol] due to decreasing long feedback inhibition of the hypothalamus & pituitary
X X cortisol
Metyrapone blocks 11-β-hydroxylase & decreases cortisol synthesis
28.5
11-deoxycortisol
ACTH
Decrease in Long Feedback Loop Inhibition by Metyrapone
Normal: Metyrapone causes ↓ cortisol, ↑ ACTH, ↑ 11-deoxycortisol due to lack of negative feedback.
If ACTH and 11-deoxycortisol don’t increase, may indicate deficiency of hypothalamic-pituitary regulation.
Summary• Cortisol released in response to stress• CRH (hypothalamus) stimulates ACTH secretion (anterior
pituitary), which stimulates cortisol synthesis (adrenal cortex)• Cortisol causes catabolic reactions: increases blood glucose• Cortisol is slow acting (via transcriptional regulation)• Glucocorticoids use therapeutically to decrease inflammation
& immune suppression• Feedback inhibition causes suppression of adrenal; very slow
to recover• Cortisol excess: Cushing’s syndrome• Cortisol deficiency: Addison’s syndrome• Dexamethasone suppression test & metyrapone
enhancement test used to test long feedback inhibition loop