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

Question 3

What controls the production of aldosterone?

Answer 3

Angiotensin II

Question 4

What is the principle action of aldosterone?

Answer 4

Increases Na+ reabsorption

Increases K+ excretion

Question 5

State three differences between glucocorticoid receptors and mineralocorticoid receptors.

Answer 5

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 6

Describe how MRs are protected from cortisol stimulation.

Answer 6

There is an enzyme called 11-beta hydroxysteroid dehydrogenase-2, which converts cortisol to the inactive cortisone to prevent it from interacting with mineralocorticoid receptors. NOTE: 11-beta-HSD-1 converts cortisone back to cortisol

Question 7

Why do you get hypokalaemia in Cushing’s syndrome?

Answer 7

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

Question 8

Name three glucocorticoid drugs in order of decreasing mineralocorticoid activity.

Answer 8

Hydrocortisone (highest mineralocorticoid activity)
Prednisolone
Dexamethasone

Question 9

What does prednisolone tend to be used for?

Answer 9

Immunosuppression

Question 10

What does dexamethasone tend to be used for?

Answer 10

Acute anti-oedema

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

Question 11

Name an aldosterone analogue.

Answer 11

Fludrocortisone

Question 12

How are all these drugs administered?

Answer 12

Orally

Question 13

Describe the extent of plasma protein binding in each of these four drugs.

Answer 13

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 14

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

Answer 14

Hepatic metabolism

Excreted in the bile and urine

Question 15

Describe the half-lives of the four drugs.

Answer 15

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

Question 16

State five reasons for giving corticosteroid replacement therapy

Answer 16

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

Question 17

State two causes of primary adrenocortical failure.

Answer 17

Addison’s disease

Chronic adrenal insufficiency

Question 18

What is the usual treatment for primary adrenocortical failure?

Answer 18

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

Question 19

What is secondary adrenocortical failure?

Answer 19

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 20

Describe the treatment of secondary adrenocortical failure.

Answer 20

HYDROCORTISONE (titrate the dose to mimic normal physiology)

Question 21

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

Answer 21

IV saline (because they are suffering from a 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 22

What is the most common cause of congenital adrenal hyperplasia?

Answer 22

21-hydroxylase deficiency

Question 23

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

Answer 23

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 24

What are the consequences of CAH in childhood?

Answer 24

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

Question 25

How do you treat CAH?

Answer 25

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 26

How do you monitor CAH treatment?

Answer 26

Measure 17a-hydroxyprogesterone levels

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

Question 27

When would you change the dose of hydrocortisone in CAH?

Answer 27

If they are under any particular stress such as illness

Question 28

What is iatrogenic adrenocortical failure?

Answer 28

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