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? How is this hormone produced?

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

What are the main two receptors targeted by corticosteroids? What is special about them?

Answer 6

Glucocorticoid receptors (GR) Mineralocorticoid receptors (MR) Members of the nuclear receptor super-family

Question 7

State three differences between glucocorticoid receptors and mineralocorticoid receptors.

Answer 7

1. GRs are widely distributed; MRs have a discrete distribution (kidney)
2. GRs are selective for glucocorticoids; MRs cannot distinguish between cortisol and aldosterone
3. 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

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 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 11-beta-HSD-2 system so the cortisol binds to the mineralocorticoid receptors and has mineralocorticoid effects.

Question 10

Name 3 corticosteroids 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- adldosterone analogue which is used as an aldosterone substitute

Question 14

How are all these drugs administered?

Answer 14

Orally

Question 15

Which two corticosteroids can be given parenterally?

Answer 15

Parenteral = IV or IM

hydrocortisone, dexamethasone

Question 16

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

Answer 16

They bind to plasma proteins – corticosteroid binding globulin + albumin

Extra:

• 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 17

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

Answer 17

• Hepatic metabolism
• Excreted in the bile and urine

Question 18

List the corticosteroids in order of increasing duration of action.

Answer 18

• Hydrocortisone (8 hr duration)
• Prednisolone (12 hour duration)
• Dexamethasone (40 hour duration)

Question 19

State five reasons for giving corticosteroid replacement therapy

Answer 19

1. Primary adrenocortical failure
2. Secondary adrenocortical failure
3. Acute adrenocortical failure
4. Congenital adrenal hyperplasia (CAH)
5. Iatrogenic adrenocortical failure

Question 20

State a cause of primary adrenocortical failure.

Answer 20

Addison’s disease

(+Chronic adrenal insufficiency)

Question 21

What is the usual treatment for primary adrenocortical failure?

Answer 21

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

• Hydrocortisone + Fludrocortisone are given by mouth

Question 22

What is secondary adrenocortical failure?

Answer 22

• ACTH deficiency
• 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) but there is a LACK of cortisol

Question 23

Describe the treatment of secondary adrenocortical failure.

Answer 23

HYDROCORTISONE (titrate the dose to mimic normal physiology) - lack of cortisol needs to be addressed

Question 24

What is another name for acute adrenocortical failure?

Answer 24

Addisonian crisis

Question 25

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

Answer 25

* **_IV saline - 0.9% sodium chloride to rehydrate_** patient and replace the salts (primary problem) * High dose **_hydrocortisone_** - IV or IM every 6 hours - *mineralocorticoid effect at high dose (11bHSD overwhelmed)* * 5% **_dextrose_** (if they are hypoglycaemic) NOTE: don’t normally need dextrose because the hydrocortisone will increase blood glucose anyway

Question 26

What is the most common cause of congenital adrenal hyperplasia?

Answer 26

21-hydroxylase deficiency- lack of enzymes for adrenal steroid synthesis

Question 27

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

Answer 27

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 28

What are the consequences of CAH in childhood?

Answer 28

CAH caused by partial enzyme deficiency --\> less production of vital hormones --\> build up of precursors (17alpha-hydroxyprogesterone, as this is just before the enzyme "block" --\> spills over to increased sex production ---\> **_Virilisation and Hirsutism_**

Question 29

What are the objectives of CAH therapy? What drugs are used?

Answer 29

1. Replace cortisol = high dose hydrocortisone (2-3/day) or dexamethasone (1/day) 2. Suppress ACTH and so adrenal androgen production 3. Replace aldosterone in salt wasting forms = fludrocortisone

Question 30

How do you monitor CAH?

Answer 30

Measure 17a-hydroxyprogesterone levels Monitor them clinically – are they complaining of hirsuitism/acne or cushingoid symptoms? * Cushingoid = GC dose too high * Hirsutism = GC dose too low (and hence ACTH has risen)

Question 31

When would you change the dose of hydrocortisone in subjects with adrenocortical failure?

Answer 31

1. If they are under any particular stress such as illness = "sick day rules" x2 normal dose 2. Surgery - hydrocortisone IM with pre-med at 6-8hr intervals (oral once eating and drinking) (normal cortisol production~20mg/day but in times of stress it rises to ~200-300mg/day)

Question 32

What is iatrogenic adrenocortical failure?

Answer 32

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

Question 33

What must patiens with adrenocortical failure have on them at all times?

Answer 33

A steroid alert card and wear a MedicAlert bracelet/necklace.