Therapeutic uses of adrenal steroids Flashcards
Name the 3 hormones that the different parts of the adrenal cortex produce
Zona Glomerulosa – Aldosterone
Zona Fasciculata – Cortisol
Zona Reticularis – Sex Steroids (androgens- which can be aromatised to oestrogen).
Describe the axis for cortisol production
Circadian stimuli and stress are the two inputs to the hypothalamus- triggering CRH release
CRH stimulates release of ACTH from the anterior pituitary
ACTH acts on the zone fasciculata- leading to cortisol synthesis and release.
Cortisol has negative feedback on the anterior pituitary and the hypothalamus
.
ACTH also stimulates androgen release from the zone reticularis.
Describe the axis for control of aldosterone production
Stimulated by activation of RAAS: Hyperkalaemia Hypokalaemia Reduced renal blood flow (haemorrhage) B1-adrenoreceptor stimulation
Renin will convert angiotensinogen to AI
ACE will convert AI- AII
AII (vasoconstrictor)- will also stimulate aldosterone release from the zona glomerulosa.
Aldosterone will lead to increase Na+ and water reabsorption in the kidney, and increase K+ excretion.
Describe the different physiological actions of the different adrenal steroids
Cortisol – essential for life- often kills you in adrenocrotical insufficiency- needed to fight infections etc
Aldosterone
Promotes Na+ retention and K+ loss
Androgens/oestrogens
?
Main source of these are gonads
Which family of receptors do the mineralocorticoid and glucocorticoid receptors belong to
The nuclear receptor super-family
binds to cytoplasmic receptor- dissociates from heat shock proteins to translocate to the nucleus
Describe the features of glucocorticoid receptors
Wide distribution
Selective for glucocorticoids
Low affinity for cortisol
Describe the features of mineralocorticoid receptors
Discrete distribution (kidney)
Do NOT distinguish between aldosterone and cortisol
High affinity for cortisol
How is the issue of cortisol having efficacy at the mineralocorticoid receptors (and thus behaving like aldosterone resolved).
The kidneys synthesise an enzyme called 11B-hydroxysteroid dehydrogenase 2 which inactivates cortisol to the inactive cortisone.
However, in Cushing’s we have supra-physiological concentrations of cortisol- so this system becomes saturated- allowing cortisol to exert mineralocorticoid effects.
This is why we see hypokalaemia in Cushing’s patients.
What is hydrocortisone
Hydrocortisone
Glucocorticoid with mineralocorticoid activity at high doses
What is prednisolone
Prednisolone
Glucocorticoid with weak mineralocorticoid activity
Used as an immunosuppressant- good at suppressing inflammation.
What is dexamethasone
Dexamethasone
Synthetic glucocorticoid with no mineralocorticoid activity
Acute anti-oedema
E.g. used clinically for things like brain metastases where there is a lot of oedema
What is fludrocortisone
Fludrocortisone Aldosterone analogue (aldosterone not effective when given orally). Used as an aldosterone substitute. § I.E. 21/11-hydroxylase deficiencies- or in Addison's
Describe the structure activity relationship of these different drugs.
Small changes in structure and synthesis pathways gives rise to different steroids with different properties.
How are these synthetic steroids administered
Oral
hydrocortisone, prednisolone, dexamethasone, fludrocortisone
How else can hydrocortisone and dexamethasone be administered
Parenteral (i.v. or i.m.)
This is important acutely- want to administer a large dose to a patient in casualty presenting with a salt-losing crisis and postural hypotension.
Summarise the distribution of these therapeutic steroids
Bind to plasma proteins (Cortisol Binding Globulin (CBG) and albumin) as circulating cortisol does
Describe the extent of plasma protein binding in each of these therapeutic steroids
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
Describe the metabolism and half-life of the therapeutic steroids
The steroids are metabolised mainly in the liver, the principal step being reduction of the A ring. Hydrocortisone and fludrocortisone have a plasma half life of ~ 1.5h but a duration of action of ~ 8h; the effects of prednisolone persist for longer (up to 12h) while dexamethasone is long acting (>36h) because metabolism is slow.
Excreted in the bile and urine
Describe the principles of treatment for primary adrenocrotical failure
Addison’s disease or chronic adrenal insufficiency
These patients are deficient in both cortisol and aldosterone. It is therefore necessary to replace BOTH hormones, i.e. use hydrocortisone and fludrocortisone (both given orally).
Describe corticosteroid replacement therapy for secondary adrenocrotical failure (ACTH deficiency)
May have had pituitary removed
Patients lack cortisol but aldosterone is normal
Treat with hydrocortisone- (titrate the dose to mimic normal physiology
Describe the management of acute adrenocortical failure (i.e and Addisonian crisis)
iv 0.9% sodium chloride to rehydrate patient
High dose hydrocortisone- to have both glucocorticoid and mineralocorticoid activity
i.v. infusion or i.m. every 6h, mineralocorticoid effect at high dose (11βHSD overwhelmed)
5% dextrose if hypoglycaemic
NOTE: don’t normally need dextrose because the hydrocortisone will increase blood glucose anyway
Describe congenital adrenal hyperplasia
congenital lack of enzymes
needed for adrenal steroid synthesis
* Approximately 95% of cases
lack 21-hydroxylase- therefore you cannot synthesise cortisol or aldosterone.
All the precursors are funnelled into androgen production- this leads to hirsutism and virilisation.
Which precursor can we measure to diagnose 21a-hydroxylase deficiency
In 21 hydroxylase deficiency,17α-
hydroxyprogesterone accumulates, as this is immediately before the enzyme ‘block’
What is the issue in patients with 21alpha-hydroxylase deficiency
In 21 hydroxylase deficiency
no cortisol production, so ACTH rises (no negative feedback)
High ACTH drives further adrenal androgen production
CAH caused by partial enzyme deficiency can result in virilisation and precocious puberty
What are the objectives of treatment in patients with congenital adrenal hyperplasia
Replace cortisol Suppress ACTH and, thus, adrenal androgen production Replace aldosterone in salt wasting forms.
Which drugs are used to treat congenital adrenal hyperplasia
Dexamethasone daily by mouth at night. Dexamethasone is a long-acting steroid and will therefore not only replace cortisol but also effectively suppress the morning rise in ACTH. Adrenal androgen production will therefore be suppressed. Alternatively hydrocortisone or prednisolone may be used (daily in 2/3 divided doses, higher dose at night) in doses which are sufficient to reduce ACTH secretion.
Fludrocortisone in salt wasting forms (by mouth, usually once daily in the morning)
Why is it hard to achieve all the treatment aims in congenital adrenal hyperplasia
High dose glucocorticoids may lower ACTH drive and hence reduce androgen output, but risk of developing iatrogenic
Cushing’s syndrome. A reduction in glucocorticoid dose will reduce the risk of iatrogenic Cushing’s, but ACTH will increase, producing more androgens.
The effectiveness of dexamethasone, hydrocortisone and prednisolone in suppressing androgen production may be monitored by measurement of 17α-hydroxyprogesterone.
Describe the body’s response to stress through cortisol
Normal subjects produce about 20mg/day cortisol but in severe stress production may rise to 200-300 mg/day.
Subjects with adrenocortical insufficiency are unable to produce cortisol in conditions of stress, e.g. in response to minor infections or surgery. It is therefore important to provide additional exogenous steroid (glucocorticoid) to protect them.
When should you increase glucocorticoid dosage
Minor illnesses: Double usual hydrocortisone dose.
Surgery: Administer hydrocortisone (100mg) intramuscularly with the pre-anaesthetic medication and repeat at 6-8 hourly intervals. Switch to oral regimen once eating and drinking).
Preparation for adrenalectomy or hypophysectomy: As for surgery above
What else can cause adrenal insufficiency
In addition to the causes detailed above, adrenal insufficiency may also be caused by long-term treatment with high doses of glucocorticoids in, for example, chronic inflammatory disease. These patients also require protection with exogenous glucocorticoids during surgery
Iatrogenic adrenocrotical 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 should you tell patients with adrenocortical failure
Patients on long-term corticosteroid treatment or replacement therapy are advised to carry a steroid alert card detailing their dosage and condition- so paramedics can respond appropriately in case of emergency.
Describe the different doses of exogenous steroids used for different conditions
Cortisol (approved drug name for hydrocortisone) is used clinically for replacement therapy (low dose). High doses eg for the treatment of inflammatory disease, are frequently associated with unwanted mineralocorticoid activity.
Synthetic steroid analogues which show more selectivity for the glucocorticoid receptor are frequently used in preference to control inflammation, to produce immunosuppression and in the treatment of neoplastic disease.
How would you assess whether a patient needs long term steroid replacement therapy
a. Insulin induced hypoglycaemia – get blood glucose to 2.2 and take a blood sample to check for rising cortisol. If the cortisol is low after test after 6 weeks, she still needs replacement therapy.
b. Hydrocortisone is expensive so most doctors prescribe prednisolone.
How would you reassure the patient that these steroids don’t puff you up
Anabolic steroids are the ones that make you bigger, not these types of steroids.
Summarise the investigations for congenital adrenal hyperplasia
a. Genetic testing for the gene that encodes 21-hydroxylase (if absent then confirmed).
b. Measure 17alpha-hydroxyprogesterone levels (should be high due to build up).
c. Short synacthen test – give ACTH and observe cortisol does not rise.
Summarise the treatment and advice for a patient with adrenocortical insufficiency
a. Yes – hydrocortisone – 20mg a day in 3 doses (10mg, 5mg, 5mg).
b. If she undergoes physiological stress (e.g. is ill), double the dose.
c. If she starts to vomit, come into A&E and say you take hydrocortisone and get IV steroids.
