8 - Therapeutic use of adrenal steroids

Question 1

Name the three parts of the adrenal cortex and the steroids that each produces.

Answer 1

Zona Glomerulosa – Aldosterone
Zona Fasciculata – Cortisol
Zona Reticularis – Sex Steroids

Question 2

What hormone controls the production of adrenal sex steroids?

Answer 2

ACTH

NOTE: important when considering congenital adrenal hyperplasia

Question 3

What controls the production of aldosterone?

Answer 3

Angiotensin II

Question 4

Briefly summarise the control of aldosterone release

Answer 4

• aldosterone release is simulated by the renin-angiotensin system
• renin from the juxtaglomerular cells in the kidney convertes angitensinogen into ATI and then ACE convertes it to ATII
• ATII stimulates the release of aldosterone from the adrenal cortex

Question 5

State four triggers of aldosterone release.

Answer 5

• Hyperkalaemia
• Hyponatraemia
• Drop in renal blood flow
• Beta-1 stimulation

Question 6

What is the principle action of aldosterone?

Answer 6

Increases Na+ reabsorption

Increases K+ excretion

Question 7

State three differences between glucocorticoid receptors and mineralocorticoid receptors.

Answer 7

GRs are widely distributed; MRs have a discrete distribution

GRs are selective for glucocorticoids; MRs cannot distinguish between cortisol and aldosterone

GRs have a low affinity for cortisol; MRs have a high affinity for cortisol

Question 8

Describe how MRs are protected from cortisol stimulation.

Answer 8

The enzyme 11β-hydroxysteroid dehydrogenase-2, which converts cortisol to the inactive cortisone to prevent it from interacting with mineralocorticoid receptors.
NOTE: 11β-HSD-1 converts cortisone back to cortisol

Question 9

Why do you get hypokalaemia in Cushing’s syndrome?

Answer 9

In Cushing’s syndrome there is so much cortisol that it overloads the 11β-HSD-2 system so the cortisol binds to the mineralocorticoid receptors and has mineralocorticoid effects.

Question 10

Name three glucocorticoid drugs in order of decreasing mineralocorticoid activity.

Answer 10

Hydrocortisone (highest mineralocorticoid activity)
Prednisolone
Dexamethasone

Question 11

What does prednisolone tend to be used for?

Answer 11

Immunosuppression

Question 12

What does dexamethasone tend to be used for?

Answer 12

Acute anti-oedema

E.g. used clinically for things like brain metastases where there is a lot of oedema

Question 13

Name an aldosterone analogue.

Answer 13

Fludrocortisone

Question 14

The drugs that act as glucocorticoid substitutes (hydrocortisone, prednisone and dexamethasone) and fludrocortisone (aldosterone analogue) are administered in what way?

Answer 14

orally

in some acute situations, they may have to be given IV or IM

Question 15

Describe the extent of plasma protein binding in each of these four drugs (hydrocortisone, prednisone, dexamethasone and fludrocortisone)

Answer 15

They bind to plasma proteins – corticosteroid binding globulin + albumin

• Hydrocortisone is extremely plasma protein bound – 90-95%
• Prednisolone is less bound
• Dexamethasone and fludrocortisone are even less bound
• Fludrocortisone only binds to albumin

Question 16

Where are the corticosteroid drugs metabolised and how are they excreted?

Answer 16

Hepatic metabolism

Excreted in the bile and urine

Question 17

Describe the half-lives of the four drugs.

hydrocortisone, prednisone, dexamethasone and fludrocortisone

Answer 17

In order of increasing half-life (shortest half-life first):
• Hydrocortisone + Fludrocortisone (1 hr duration)
• Prednisolone (12 hour duration)
• Dexamethasone (40 hour duration)

Question 18

State five reasons for giving corticosteroid replacement therapy.

Answer 18

Primary adrenocortical failure 
Secondary adrenocortical failure 
Acute adrenocortical failure 
Congenital adrenal hyperplasia
Iatrogenic adrenocortical failure

Question 19

State two causes of primary adrenocortical failure

Answer 19

Addison’s disease

Chronic adrenal insufficiency

Question 20

What is the usual treatment for primary adrenocortical failure?

Answer 20

There is a lack of cortisol and aldosterone so you must replace both
Hydrocortisone
Fludrocortisone

Question 21

What is secondary adrenocortical failure (in reference to treatment)?

Answer 21

The adrenal gland itself is fine but there is a problem with the pituitary gland (ACTH deficiency)
There is NORMAL aldosterone production (because aldosterone isn’t dependent on ACTH)
So only cortisol needs to be replaced

Question 22

Describe the treatment of secondary adrenocortical failure.

Answer 22

HYDROCORTISONE (titrate the dose to mimic normal physiology)

Question 23

What is the treatment for acute adrenocortical failure (Addisonian Crisis)?

Answer 23

• IV saline (salt losing crisis)
• High dose hydrocortisone
• Dextrose (if they are hypoglycaemic)
  NOTE: don’t normally need dextrose because the hydrocortisone will increase blood glucose anyway

Question 24

What is the most common cause of congenital adrenal hyperplasia?

Answer 24

21-hydroxylase deficiency

Question 25

Describe the ACTH levels in CAH and explain the effect this has on steroid synthesis.

Answer 25

High ACTH – because no cortisol is being produced so there is no negative feedback on the hypothalamo-pituitary axis
High ACTH means that the sex steroid synthesis pathway is turned on – there is an increase in adrenal sex steroids

Question 26

What are the consequences of CAH in childhood?

Answer 26

CAH caused by partial enzyme deficiency can result in virilisation and precocious puberty

Question 27

How do you treat CAH?

Answer 27

Replace cortisol with high dose hydrocortisone (2-3/day) or dexamethasone (1/day)
Replace aldosterone with fludrocortisone
This is to replace cortisol and to suppress the ACTH axis to reduce adrenal sex steroid production

Question 28

How do you monitor CAH?

Answer 28

Measure 17a-hydroxyprogesterone levels

Monitor them clinically – are they complaining of hirsuitism/acne or cushingoid symptoms?

Question 29

When would you change the dose of hydrocortisone in CAH?

Answer 29

If they are under any particular stress such as illness or during surgery to mimic the normal physiology of cortisol

Question 30

NOT SURE IF THIS WAS IN THE SLIDES

What is iatrogenic adrenocortical failure? What is it caused by?

Answer 30

Long-term, high dose glucocorticoid therapy can suppress the HPA axis and hence suppress adrenal function so that they no longer produce cortisol by themselves
They need to keep a steroid dependence bracelet