Therapeutic Use of Adrenal Steroids

Question 1

What stimulates renin release?

Answer 1

• high K+
• low Na+
• decreased RBF
• beta-1 adrenoreceptor stimulation

Question 2

What stimulates Aldosterone secretion?

Answer 2

RAS -> angiotensin II

Question 3

What stimulates the release of Cortisol?

Answer 3

• ACTH

- (which itself is stimulated by stress and circadian stimuli)

Question 4

What is the principal physiological action of cortisol?

Answer 4

• essential for life
• if you lose this is adrenocortical failure, this is the tipping point to death
• stress hormone (relevant in intercurrent illness, e.g. pneumonia), essential hormone to help get you better

Question 5

What is the principal physiological action of aldosterone?

Answer 5

• promotes Na+ retention
• promotes loss of K+

=> water reabsorption, increased BP

Question 6

What is the principal physiological action of androgens/oestrogens?

Answer 6

• main source of these are gonads

- not clear if they have a major role

Question 7

Properties of Glucocorticoid receptors

Answer 7

• widely distributed
• selective for glucocorticoids
• low affinity for cortisol

Question 8

Properties of Mineralocorticoid receptors

Answer 8

• discrete distribution (Kidney)
• do NOT differentiate between aldosterone and cortisol
• high affinity for cortisol

Question 9

How are MRs protected from cortisol?

Answer 9

• 11-beta-hydroxysteroid dehydrogenase

- turns cortisol into the inactive cortisone

Question 10

Receptor selectivity of hydrocortisone?

Answer 10

Glucocorticoid with mineralocorticoid activity at high doses (if it overcomes 11-beta-hsd)

Question 11

Receptor selectivity of prednisolone?

Answer 11

Glucocorticoid with weak mineralocorticoid activity

Question 12

Receptor selectivity of dexamethasone?

Answer 12

Synthetic glucocorticoid with no mineralocorticoid activity

Question 13

Receptor selectivity of fludrocortisone?

Answer 13

• aldosterone analogue

- used as an aldosterone substitute

Question 14

What are the corticosteroid drugs you should know?

Answer 14

• hydrocortisone
• prednisolone
• dexamethasone
• fludrocortisone

Question 15

Pharmacokinetics: Which corticosteroids can be given orally?

Answer 15

• hydrocortisone
• prednisolone
• dexamethasone
• fludrocortisone

Question 16

Pharmacokinetics: Which corticosteroids are given parenterally?

Answer 16

• > i.v. or i.m.
• hydrocortisone
• dexamethasone

Question 17

Pharmacokinetics: How do corticosteroids distribute?

Answer 17

• binds to plasma proteins
• CBG or Albumin

-> as circulating cortisol does

Question 18

CBG

Answer 18

Cortisol Binding Globulin

Question 19

What is the duration of action of:

a) hydrocortisone
b) prednisolone
c) dexamethasone

Answer 19

a) ~8h
b) ~12h
c) ~40h

Question 20

How do you treat Addison’s disease long term?

Answer 20

• corticosteroid replacement therapy
• patients lack cortisol and aldosterone
• treat with hydrocortisone and fludrocortisone orally

Question 21

In what conditions can corticosteroid replacement therapy be used?

Answer 21

1. primary adrenocortical failure (Addison’s)
2. secondary adrenocortical failure (ACTH deficiency)
3. acute adrenocortical failure (Addisonian crisis)
4. congenital adrenal hyperplasia

Question 22

Primary adrenocortical failure

Answer 22

= Addison’s disease

Question 23

Secondary adrenocortical failure

Answer 23

= ACTH deficiency

Question 24

How do you treat secondary adrenocortical failure?

Answer 24

• patients lack cortisol but there is no problem with aldosterone
• treat with hydrocortisone

Question 25

Acute adrenocortical failure

Answer 25

= Addisonian crisis

Question 26

How do you treat an addisonian crisis?

Answer 26

- i.v. 0.9% NaCl to rehydrate patient - high dose of hydrocortisone (i.v. infusion or i.m.) every 6h, mineralocorticoid activity at high dose - 5% dextrose if hypoglycaemic

Question 27

Why does cortisol have mineralocorticoid activity at high levels?

Answer 27

- because at high levels 11-beta-hydroxysteroid dehydrogenase is overwhelmed.

Question 28

Which enzyme protects MRs from cortisol?

Answer 28

11-beta-hydroxysteroid-dehydrogenase

Question 29

What is CAH?

Answer 29

- congenital adrenal hyperplasia | - congenital lack of enzymes needed for adrenal steroid synthesis

Question 30

What fraction of CAH is due to 21-hydroxylase deficiency?

Answer 30

95%

Question 31

How do you treat CAH?

Answer 31

- Replace cortisol - Suppress ACTH and, thus, adrenal androgen production - Replace aldosterone in salt wasting forms.

Question 32

What extra caution should patients with adrenocortical failure take?

Answer 32

- Should carry a steroid alert card | - wear a MedicAlert bracelet/necklace

Question 33

When should you increase glucocorticoid dosage?

Answer 33

- in minor illness: 2x dose until you feel better - surgery: i.m. hydrocortisone with pre-med 6-8h intervals, oral once eating and drinking. - (anaesthetic is a stress to get over)

Question 34

Additional measurements in subjects with adrenocortical failure?

Answer 34

- Normal cortisol production ~ 20mg/day - In stress production -> 200-300 mg/day - Increase glucocorticoid dosage when patients are vulnerable to stress

Question 35

How do you monitor corticosteroid therapy in CAH?

Answer 35

- Monitor/optimise therapy by measuring - 17 OH progesterone - Clinical assessment - Cushingoid – GC dose too high - Hirsutism – GC dose too low (and hence ACTH has risen)

Question 36

Why is it so difficult to treat CAH?

Answer 36

- You have to find the right dose to find a good balance in-between Cushing's and too much androgen Production - diurnal rhythm - altering dose of cortisol when stressed or sick needed

Question 37

How would you mimic the diurnal rhythm of cortisol with meds?

Answer 37

morning: high dose midday: lower dose around 4: low dose