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

State four triggers of aldosterone release

Answer 4

Hyperkalaemia
Hyponatraemia
Drop in renal blood flow
Beta-1 stimulation

Question 5

What is the principle action of aldosterone?

Answer 5

Increases Na+ reabsorption

Increases K+ excretion

Question 6

State three differences between glucocorticoid receptors and mineralocorticoid receptors.

Answer 6

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 7

Describe how MRs are protected from cortisol stimulation.

Answer 7

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 8

Why do you get hypokalaemia in Cushing’s syndrome?

Answer 8

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 9

Name three glucocorticoid drugs in order of decreasing mineralocorticoid activity.

Answer 9

Hydrocortisone (highest mineralocorticoid activity)
Prednisolone
Dexamethasone

Question 10

What does prednisolone tend to be used for?

Answer 10

Immunosuppression

Question 11

What does dexamethasone tend to be used for?

Answer 11

Acute anti-oedema

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

Question 12

Name an aldosterone analogue.

Answer 12

Fludrocortisone

Question 13

How are all these drugs administered?

Answer 13

Orally

Question 14

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

Answer 14

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 15

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

Answer 15

Hepatic metabolism

Excreted in the bile and urine

Question 16

Describe the half-lives of the four drugs.

Answer 16

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

Question 17

State five reasons for giving corticosteroid replacement therapy

Answer 17

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

Question 18

State two causes of primary adrenocortical failure.

Answer 18

Addison’s disease

Chronic adrenal insufficiency

Question 19

What is the usual treatment for primary adrenocortical failure?

Answer 19

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

Question 20

What is secondary adrenocortical failure?

Answer 20

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 21

Describe the treatment of secondary adrenocortical failure.

Answer 21

HYDROCORTISONE (titrate the dose to mimic normal physiology)

Question 22

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

Answer 22

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 23

What is the most common cause of congenital adrenal hyperplasia?

Answer 23

21-hydroxylase deficiency

Question 24

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

Answer 24

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 25

What are the consequences of CAH in childhood?

Answer 25

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

Question 26

How do you treat CAH?

Answer 26

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 27

How do you monitor CAH?

Answer 27

Measure 17a-hydroxyprogesterone levels | Monitor them clinically – are they complaining of hirsuitism/acne or cushingoid symptoms?

Question 28

When would you change the dose of hydrocortisone in CAH?

Answer 28

If they are under any particular stress such as illness

Question 29

What is iatrogenic adrenocortical failure?

Answer 29

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