ENDO; Lecture 6, 7 and 8 - Hyperadrenal disorders, Drugs used in treatment of hyperadrenal disorders and Hypoadrenal disorders

Question 1

What is the action of metyrapone?

Answer 1

Inhibits 11beta-hydroxylase; steroid synthesis in zona fasciculata and reticularis is arrested at 11-deoxycortisol level -> no negative feedback effect on hypothalamus/pit. gland

Question 2

What are the uses of metyrapone?

Answer 2

Cortisol synth blocked, ACTH secretion increased and plasma deoxycortisol increased; Control of Cushing’s syndrome before procedure (adjusting oral dose to cortisol levels in serum, improving patient’s symptoms and promotes better post-op recovery; control of Cushing’s symptoms after radiotherapy

Question 3

What are the unwanted actions of metyrapone?

Answer 3

Hypertension on long-term admin; hirsuitism (due to build up of precursors which are shuffled into the androgen arm of synthesis)

Question 4

What is the use of Ketoconazole?

Answer 4

Main use as anti-fungal agent, withdrawn due to risk of hepatotoxicity; at high conc, inhibits steroidogenesis; treatment and control of symptoms prior to surgery and are orally active

Question 5

What is the method of action of ketoconazole?

Answer 5

Blocks multiple steps inc. cortisol synthesis

Question 6

What are the unwanted actions of ketoconazole?

Answer 6

Liver damage -> possible fatal; monitor liver function weekly, clinically and biochemically

Question 7

What are the uses of spironolactone?

Answer 7

Primary hyperaldosteronism (conn’s syndrome)

Question 8

What is the mechanism of action of spironolactone?

Answer 8

Converted to several active metabolites inc. canrenone and competitive antagonist of MR; blocks Na reab and K excretion in kidney tubules

Question 9

What are the pharmacokinetics of spironolactone?

Answer 9

Orally active, highly protein bound and metabolised in liver

Question 10

What are the unwanted actions of spironolactone?

Answer 10

Menstrual irregularities (+progesterone receptor); gynaecomastia (androgen receptor antagonist)

Question 11

What is epleronone?

Answer 11

Mineralocorticoid receptor antagonist ithe similar affinity as spironolacton; less binding to androgen and progesterone receptors compared to spironolactone

Question 12

What are the key features and symptoms of Cushing’s syndrome?

Answer 12

Too much cortisol, centripetal obesity, moon face and buffalo hump, proximal myopathy, hypertension and hypokalaemia, red striae, thin skin, bruising, osteoporosis, diabetes

Question 13

What are the causes of Cushing’s syndrome?

Answer 13

Taking too many steroids, pit dependent Cushing’s disease, ectopic ACTH from lung cancer, adrenal adenoma secreting cortisol

Question 14

What investigations are carried out to determine cause of Cushing’s?

Answer 14

24h urine collection for urinary free cortisol, blood diurnal cortisol levels (need to check when asleep as that’s when they should be at the lowest), low dose dexamethasone (given every 6hrs reducing pit cortisol to 0 if normal but then if failure to suppress dexamethosone occurs then any cause of Cushing’s works)

Question 15

How do you treat Cushing’s (surgical and medical)?

Answer 15

Enzyme inhibitors, receptor blocking drugs, pit surgery (transphenoidal hypophysectomy), bilateral adrenalectomy, unilateral adrenalectomy for adrenal mass; metyrapone, ketoconazole

Question 16

What are phaeochromocytomas?

Answer 16

Tumours of adrenal medulla which secrete catecholamines (A or NA)

Question 17

What are the clinical features of phaeo?

Answer 17

Severe hypertension in young people which can cause MI or stroke, episodic severe hypertension after abdominal palpation, high adrenaline can cause ventricular fibrillation and death

Question 18

How do you manage phaeo?

Answer 18

Eventually need surgery, but patient needs careful prep as anaesthetic can precipitate a hypertensive crisis; alpha blockade (1st therapeutic), IV fluid as alpha blockade commences, beta blockade added to prevent tachycardia

Question 19

How do you diagnose Cushing’s?

Answer 19

Basal cortisol (9am) of 800 nM and at end of low dose dexamethasone suppression test: 680 nM

Question 20

What is Conn’s syndrome with biochemical symptoms?

Answer 20

Benign adrenal cortical tumour (zona glomerulosa), aldosterone in excess, hypertension, hypokalaemia

Question 21

How do you diagnose Conn’s syndrome?

Answer 21

Primary hyperaldosteronism -> RAS should be suppressed (excludes 2ry hyperaldosteronism)

Question 22

How do you treat Conn’s syndrome?

Answer 22

Aldosterone receptor antagonist -> spironolactone or surgery to remove adenome; if bilateral adrenal hyperplasia then stay on spironolactone

Question 23

What are some key facts of phaeochromocytoma?

Answer 23

10% extra-adrenal (symp chain), 10% malignant, 10% bilateral

Question 24

What are the pathways to make a mineralocorticoid, glucocorticoid and steroid hormones from cholesterol?

Answer 24

NB: main source of sex steroids is in the gonads

Question 25

What are the 2 general causes of adrenocortical failure?

Answer 25

Adrenal glands destroyed and enzymes in the steroid synthetic pathway not working

Question 26

What are the names of the causes of adrenocortical failure?

Answer 26

Tuberculous Addison’s disease (commonest worldwide), autoimmune Addison’s disease (UK commonest), congenital adrenal hyperplasia

Question 27

What are the consequences of adrenocortical failure?

Answer 27

Fall in BP, loss of salt in urine, increased plasma potassium, fall in glucose due to glucocorticoid deficiency, high ACTH resulting in increased pigmentation, eventual death due to severe hypotension

Question 28

What is POMC and where is it synthesised?

Answer 28

Pro-opio melanocortin and is synthesised in pit, broken down to ACTH and MSH (causes melanocytes to produce melanin which causes the increased pigmentation in Addison’s patients) and endorphins and enkephalins and other peptides

Question 29

What are the tests for Addison’s?

Answer 29

9am cortisol = low, ACTH = high -> short syn”ACTH”en test, give 250 micrograms syncathen IM and measure cortisol response

Question 30

What are a typical Addison’s patient’s cortisol before and after synacthen?

Answer 30

Cortisol 9am = 100 (270-900) -> after IM syncathen, cortisol at 9.30 = 150 (>600) -> very little rise in cortisol as adrenal glands are destroyed so cannot produce any more cortisol

Question 31

What is congenital adrenal hyperplasia?

Answer 31

Commonest caused by 21-hydroxylase deficiency -> complete/partial

Question 32

Which hormones will be absent and excess in complete 21-hydroxylase deficiency?

Answer 32

Aldosterone and cortisol totally absent; sex steroids and testosterone in excess -> presents usually by 1 week old

Question 33

At what age does complete 21-hydroxylase deficiency present?

Answer 33

Neonate with salt losing addisonian crisis -> in utero foetus gets steroids across placenta (but adrenal hyperplasia due to needing to produce more cortisol); girls may have ambiguous genitalia (increased testosterone causes virilisation)

Question 34

Which hormones are deficient and in excess in partial 21-hydroxylase deficiency?

Answer 34

Cortisol and aldosterone are deficient and sex steroids and testosterone are in excess but present at any age as they survive (not as neonate)

Question 35

What problem can adrenal testosterone cause in partial 21-hydroxylase deficiency?

Answer 35

In later life hirsuitism and virilisation in girls and precocious puberty in boys -> can still make enough cortisol and aldosterone to not present with Addisonian salt losing crisis

Question 36

What is an important fact about 11-deoxycorticosterone?

Answer 36

Behaves as aldosterone -> in excess it can cause hypertension and hypokalaemia

Question 37

Which hormones are deficient and in excess in 11-hydroxylase deficiency?

Answer 37

Deficient= cortisol and aldosterone; excess = sex steroids and testosterone and 11-deoxycorticosterone

Question 38

What are the problems in 11-hydroxylase deficiency?

Answer 38

Virilisation, hypertension and low K

Question 39

Which hormones are deficient and in excess in 17-hydroxylase deficiency?

Answer 39

Deficient = cortisol and sex steroids; excess = 11-deoxycorticosterone and aldosterone

Question 40

What problems are associated with 17-hydroxylase deficiency?

Answer 40

Hypertension, low K, sex steroid deficiency and glucocorticoid deficiency

Question 41

What is the simplified version of steroid synthesis beginning from cholesterol and finishing in aldosterone, cortisol and sex steroids?

Answer 41

x

Question 42

What are some symptoms of Addison’s disease?

Answer 42

Mucous membrane pigmentation, weak, loses weight, vitiligo, hypotension

Question 43

Why does adrenocortical failure lead to fall in BP, loss of salt in the urine and increased plasma potassium?

Answer 43

Loss of aldosterone -> hypotension and hyperkalaemia

Question 44

Why does adrenocortical failure lead to hypoglycaemia?

Answer 44

Due to the deficiency in glucocorticoids

Question 45

Why does adrenocortical failure lead to increased pigmentation?

Answer 45

Due to increase in ACTH levels as there isn’t any cortisol being released from the adrenals, so no negative feedback reducing ACTH release

Question 46

What are the symptoms of 21-hydroxylase deficiency?

Answer 46

Lethargy, hypotension, hyponatraemia, hyperkalaemia -> excess of sex steroids leading to hirsuitism (all precursors funneled into the sex steroid arm of steroid production)

Question 47

How do you differentiate between the different types of Cushing’s syndromes?

Answer 47