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
What controls the production of aldosterone? How is this hormone produced?
Angiotensin II
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
What are the main two receptors targeted by corticosteroids? What is special about them?
Glucocorticoid receptors (GR) Mineralocorticoid receptors (MR) Members of the nuclear receptor super-family
State three differences between glucocorticoid receptors and mineralocorticoid receptors.
- GRs are widely distributed; MRs have a discrete distribution (kidney)
- 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.
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
Why do you get hypokalaemia in Cushing’s syndrome?
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.
Name 3 corticosteroids 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- adldosterone analogue which is used as an aldosterone substitute
How are all these drugs administered?
Orally
Which two corticosteroids can be given parenterally?
Parenteral = IV or IM
hydrocortisone, dexamethasone
Describe the extent of plasma protein binding in each of these four drugs.
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
Where are the corticosteroid drugs metabolised and how are they excreted?
- Hepatic metabolism
- Excreted in the bile and urine
List the corticosteroids in order of increasing duration of action.
- Hydrocortisone (8 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 (CAH)
- Iatrogenic adrenocortical failure
State a cause 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 are given by mouth
What is secondary adrenocortical failure?
- 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
Describe the treatment of secondary adrenocortical failure.
HYDROCORTISONE (titrate the dose to mimic normal physiology) - lack of cortisol needs to be addressed
What is another name for acute adrenocortical failure?
Addisonian crisis
What is the treatment for acute adrenocortical failure (Addisonian Crisis)?
- 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
What is the most common cause of congenital adrenal hyperplasia?
21-hydroxylase deficiency- lack of enzymes for adrenal steroid synthesis
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 –> 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
What are the objectives of CAH therapy? What drugs are used?
- Replace cortisol = high dose hydrocortisone (2-3/day) or dexamethasone (1/day)
- Suppress ACTH and so adrenal androgen production
- Replace aldosterone in salt wasting forms = fludrocortisone
How do you monitor CAH?
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)
When would you change the dose of hydrocortisone in subjects with adrenocortical failure?
- If they are under any particular stress such as illness = “sick day rules” x2 normal dose
- 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)
What is iatrogenic adrenocortical failure?
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
What must patiens with adrenocortical failure have on them at all times?
A steroid alert card and wear a MedicAlert bracelet/necklace.
