Adrenal Disorders Flashcards
What are the clinical features of Cushing’s
Excess cortisol (zona fasciculata)
Thin skin Hypertension and hypokalaemia Easy bruising, striae Moon face Proximal myopathy Immunosuppression Centripetal obesity Osteoporosis, diabetes
What are the causes of cushing’s
Excessive steroid use
Pituitary dependent Cushing’s disease
Ectopic ACTH from lung cancer
Adrenal adenoma secreting cortisol
What are the investigations done to determine the cause of Cushing’s syndrome
24hr urine collection for urinary free cortisol
Blood diurnal cortisol levels
Low dose dexamethasone suppression test
When are cortisol levels highest and lowest
Highest at 9am and lowest at midnight if asleep
Describe the low dose dexamethasone suppression test
Dexamethasone - artificial steroid
0.5mg 6 hourly for 48 hours
Normal people will suppress cortisol to 0 and those with Cushing’s will fail to do so
What are the diagnostic cutoffs for Cushing’s diagnosis
Basal cortisol of 800nM (9am)
End of low does dexamethasone suppression test of 690nM
How is Cushing’s treated pharmaceutically
Enzyme inhibitors of steroid biosynthesis
Metyrapone and ketoconazole
What is the mechanism of action for metyrapone
Inhibition of 11beta-hydrolyxase, arresting steroid synthesis in the zone fasciculata (and reticularis) at the 11-doexycortisol stage
What does 11b-hydroxylase do
Catalyses conversion of 11-deoxycorticosterone to corticosterone
Catalyses conversion off 11-deoxycortisol to cortisol
What are the biochemical effects of metyrapone
Cortisol synthesis decreases
ACTH secretion increases
Plasma deoxycortisol increases
What are the uses of metyrapone
Control of Cushing’s prior to surgery
Control of Cushing’s symptoms after radiotherapy (which is slow)
Describe the use of metyrapone for controlling Cushing’s before surgery
Improves patients symptoms and promotes better post-op recovery (better wound healing, less infection)
Adjust the oral dose according to cortisol, aiming for mean serum cortisol 150-300 nmol/L
What are the unwanted actions of metyrapone
Deoxycortisone accumulates in the glomerulosa, having aldosterone-like activity
Leads to salt retention and therefore hypertension
Hirutism
What is the mechanism of action for ketoconazole
Blocks production of glucocorticoids, mineralocorticoids and sex steroids by inhibiting cytochrome P450
High conc. - inhibits steroidogenesis
What are the uses of ketoconazole
Treatment and control of Cushing’s symptoms prior to surgery
Orally active
(Antifungal agent (withdrawn due to hepatotoxicity))
What are the unwanted actions of ketoconazole and how are they controlled
Liver damage - monitor the liver function weekly. clinically and biochemically
What are the non pharmaceutical methods of treating Cushing’s
Depends on cause
Pituitary surgery (trans-sphenoidal hypophysectomy)
Bilateral adrenalectomy
Unilateral adrenalectomy for adrenal mass
What are the causes of Conn’s syndrome
Benign adrenal cortical tumour (zona glomerulosa)
Aldosterone in excess
Hypertension and hypokalaemia
How is Conn’s syndrome diagnosed
Primary hyperaldosteronism
Renin-angiotensin system suppressed (except secondary hyperaldosteronism)
How is Conn’s syndrome treated pharmaceutically
Receptor blocking drugs (MR antagonist)
Spironolactone and epleronone
What are the uses of spironolactone
Primary hyperaldosteronism (Conn’s)
How does spironolactone work
Converted to several active metabolites, including canrenone, a competitive antagonist of the mineralocorticoid receptors
Blocks sodium resorption and potassium excretion in the kidney tubules = potassium sparing diuretic
What are the unwanted actions of spiromolactone
Menstrual irregularities (stimulates progesterone receptor) Gynaecomastia (inhibits the androgen receptor)
Describe epleronone
Drug used to treat Conn’s
Mineralocorticoid receptor antagonist
Similar affinity to the MR compared to spironolactone
Less binding to androgen and progesterone receptors compared to spironolactone, so better tolerated
