8 - Therapeutic use of adrenal steroids Flashcards
Name the three parts of the adrenal cortex and the steroids that each produces.
Zona Glomerulosa – Aldosterone
Zona Fasciculata – Cortisol
Zona Reticularis – Sex Steroids
What hormone controls the production of adrenal sex steroids?
ACTH
NOTE: important when considering congenital adrenal hyperplasia
What controls the production of aldosterone?
Angiotensin II
Briefly summarise the control of aldosterone release
- 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
State four triggers of aldosterone release.
- Hyperkalaemia
- Hyponatraemia
- Drop in renal blood flow
- Beta-1 stimulation
What is the principle action of aldosterone?
Increases Na+ reabsorption
Increases K+ excretion
State three differences between glucocorticoid receptors and mineralocorticoid receptors.
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
Describe how MRs are protected from cortisol stimulation.
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
Why do you get hypokalaemia in Cushing’s syndrome?
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.
Name three glucocorticoid drugs in order of decreasing mineralocorticoid activity.
Hydrocortisone (highest mineralocorticoid activity)
Prednisolone
Dexamethasone
What does prednisolone tend to be used for?
Immunosuppression
What does dexamethasone tend to be used for?
Acute anti-oedema
E.g. used clinically for things like brain metastases where there is a lot of oedema
Name an aldosterone analogue.
Fludrocortisone
The drugs that act as glucocorticoid substitutes (hydrocortisone, prednisone and dexamethasone) and fludrocortisone (aldosterone analogue) are administered in what way?
orally
in some acute situations, they may have to be given IV or IM
Describe the extent of plasma protein binding in each of these four drugs (hydrocortisone, prednisone, dexamethasone and fludrocortisone)
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
Where are the corticosteroid drugs metabolised and how are they excreted?
Hepatic metabolism
Excreted in the bile and urine
Describe the half-lives of the four drugs.
hydrocortisone, prednisone, dexamethasone and fludrocortisone
In order of increasing half-life (shortest half-life first):
• Hydrocortisone + Fludrocortisone (1 hr duration)
• Prednisolone (12 hour duration)
• Dexamethasone (40 hour duration)
State five reasons for giving corticosteroid replacement therapy.
Primary adrenocortical failure Secondary adrenocortical failure Acute adrenocortical failure Congenital adrenal hyperplasia Iatrogenic adrenocortical failure
State two causes of primary adrenocortical failure
Addison’s disease
Chronic adrenal insufficiency
What is the usual treatment for primary adrenocortical failure?
There is a lack of cortisol and aldosterone so you must replace both
Hydrocortisone
Fludrocortisone
What is secondary adrenocortical failure (in reference to treatment)?
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
Describe the treatment of secondary adrenocortical failure.
HYDROCORTISONE (titrate the dose to mimic normal physiology)
What is the treatment for acute adrenocortical failure (Addisonian Crisis)?
- 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
What is the most common cause of congenital adrenal hyperplasia?
21-hydroxylase deficiency
Describe the ACTH levels in CAH and explain the effect this has on steroid synthesis.
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
What are the consequences of CAH in childhood?
CAH caused by partial enzyme deficiency can result in virilisation and precocious puberty
How do you treat CAH?
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
How do you monitor CAH?
Measure 17a-hydroxyprogesterone levels
Monitor them clinically – are they complaining of hirsuitism/acne or cushingoid symptoms?
When would you change the dose of hydrocortisone in CAH?
If they are under any particular stress such as illness or during surgery to mimic the normal physiology of cortisol
NOT SURE IF THIS WAS IN THE SLIDES
What is iatrogenic adrenocortical failure? What is it caused by?
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
