Therapeutic Use of Adrenal Steroids Flashcards
What is the process of adrenal steroid production?
- Circadian stimulus + stress stimulates hypothalamus to produce CRH
- CRH stimulates the anterior pituitary gland to produce ACTH
- ACTH stimulates the adrenal gland to produce cortisol/other steroids
What are the 3 types of adrenal steroid produced and which adrenal gland regions are they produced in?
- Cortisol (zona fasciculata)
- Androgens, Oestrogens (zona reticularis)
- Aldosterone/mineralocorticoids (zona glomerulosa)
What effect does cortisol have on the hypothalamus and anterior pituitary?
Negative feedback effect
- Inhibits CRH release (hypoth.) and ACTH release (ant. pit.)
What stimulates aldosterone release?
- Angiotensinogen release released in the liver stimulates renin release in the kidneys. Angiotensin I release is stimulated and is converted to Angiotensin II by ACE. Angiotensin II has a positive effect on aldosterone release
- Hyperkalaemia (ald. excretes K+)
- Hyponatraemia (ald. retains Na+)
- Reduced renal blood flow
- B1-adrenoceptor stimulation
What are the principal physiological actions of the adrenal steroid steroids?
Cortisol - essential for life
Aldosterone - promotes Na+ retension and K+ excretion
Androgens/oestrogens - secondary sexual characteristics (less relevant here since the main producers of these are the gonads not the adrenals)
What are the two types of receptors for corticosteroids and what family of receptors are they members of?
- Glucocorticoid receptors (GR)
- Mineralocorticoid receptors (MR)
Part of the nuclear receptor super-family
What is the degree of distribution of GRs, what type of molecule are they selective for, and what is their affinity for cortisol?
- Wide distribution
- Selective for glucocorticoids
- Low affinity for cortisol
What is the degree of distribution of MRs, what type of molecule are they selective for, and what is their affinity for cortisol?
- Discrete distribution (kidney)
- Do NOT distinguish between aldosterone and cortisol (non-selective for the two)
- High affinity for cortisol
Which types, MR or GR, can cortisol and aldosterone bind to?
Cortisol - GR + MR
Aldosterone - MR only
What usually happens to prevent cortisol interfering too much with aldosterone binding to MRs and what happens when the body makes too much cortisol?
Cortisol inactivated by 11beta-hydroxysteroid dehydrogenase 2 (11betaHSD) so can’t bind to aldosterone receptors (MRs)
- With excess cortisol, these enzymes are overwhelmed and cortisol binds to MRs
- This is why you can regularly see hypokalaemia in Cushing’s syndrome due to overstimulation of MRs by the excess cortisol (excretion of K+, Na+ reabsorption)
What is the receptor selectivity of Hydrocortisone?
Glucocorticoid with mineralocorticoid activity at high doses(same overwhelming of 11betaHSD)
What is the receptor selectivity of Prednisolone?
Glucocorticoid with weak mineralocorticoid activity
What is the receptor selectivity of Dexamethasone?
Synthetic glucocorticoid with no mineralocorticoid activity
What is the receptor activity of Fludrocortisone?
Aldosterone analogue
- Used in long-term replacement therapy in cases of Addison’s disease
What is the administration route of corticosteroid drugs in long-term cases and which corticosteroid drugs are given this way?
Oral
- Hydrocortisone
- Prednisolone
- Dexamethasone
- Fludrocortisone
What is the administration route of corticosteroid drugs in acute cases (Addisonian Crisis) and which corticosteroid drugs are given this way?
Parenteral (IV or intramuscular)
- Hydrocortisone
- Dexamethasone
Corticosteroid drugs distribute themselves in the body by what process in the circulation?
Binding to plasma proteins
- Cortisol binding globulin (CBG)
- Albumin
Only the free hormone which is active
What are the durations of action of hydrocortisone, prednisolone, and dexamethasone?
Hydrocortisone - 8hrs
Prednisolone - 12hrs
Dexamethasone - 40hrs
Don’t need to remember specific hours just that they’re all different and it makes them useful in different clinical scenarios
What is Addison’s disease and which hormones need replacing?
Primary adrenocortical failure
- Lack cortisol and aldosterone
What drugs can be given to replace cortisol and aldosterone in cases of Addison’s disease?
- Hydrocortisone to replace cortisol
- Fludrocortisone to replace aldosterone
What is involved in secondary adrenocortical failure, what hormones are missing and what is different to Addison’s disease?
Secondary adrenocortical failure is failure of pituitary to produce ACTH
- only cortisol needing replaced
- different to Addison’s due to aldosterone being completely normal so only cortisol replacement required
What drugs are given to replace the hormones missing in secondary adrenocortical failure?
Hydrocortisone - replacement for cortisol
No need for aldosterone replacement
What is acute adrenocortical failure also known as?
Addisonian crisis
How do you go about treating acute adrenocortical failure (Addisonian crisis)?
- IV 0.9% NaCl to rehydrate patient (MOST IMPORTANT)
- High dose hydrocortisone (IV/IM infusion every 6h), gives mineralocorticoid effect at high dose (11betaHSD overwhelmed)
- 5% dextrose if hypoglycaemic
