Therapeutic Use of Adrenal Steroids Flashcards
17.10.2019
What stimulates renin release?
- high K+
- low Na+
- decreased RBF
- beta-1 adrenoreceptor stimulation
What stimulates Aldosterone secretion?
RAS -> angiotensin II
What stimulates the release of Cortisol?
- ACTH
- (which itself is stimulated by stress and circadian stimuli)
What is the principal physiological action of cortisol?
- essential for life
- if you lose this is adrenocortical failure, this is the tipping point to death
- stress hormone (relevant in intercurrent illness, e.g. pneumonia), essential hormone to help get you better
What is the principal physiological action of aldosterone?
- promotes Na+ retention
- promotes loss of K+
=> water reabsorption, increased BP
What is the principal physiological action of androgens/oestrogens?
- main source of these are gonads
- not clear if they have a major role
Properties of Glucocorticoid receptors
- widely distributed
- selective for glucocorticoids
- low affinity for cortisol
Properties of Mineralocorticoid receptors
- discrete distribution (Kidney)
- do NOT differentiate between aldosterone and cortisol
- high affinity for cortisol
How are MRs protected from cortisol?
- 11-beta-hydroxysteroid dehydrogenase
- turns cortisol into the inactive cortisone
Receptor selectivity of hydrocortisone?
Glucocorticoid with mineralocorticoid activity at high doses (if it overcomes 11-beta-hsd)
Receptor selectivity of prednisolone?
Glucocorticoid with weak mineralocorticoid activity
Receptor selectivity of dexamethasone?
Synthetic glucocorticoid with no mineralocorticoid activity
Receptor selectivity of fludrocortisone?
- aldosterone analogue
- used as an aldosterone substitute
What are the corticosteroid drugs you should know?
- hydrocortisone
- prednisolone
- dexamethasone
- fludrocortisone
Pharmacokinetics: Which corticosteroids can be given orally?
- hydrocortisone
- prednisolone
- dexamethasone
- fludrocortisone
Pharmacokinetics: Which corticosteroids are given parenterally?
- > i.v. or i.m.
- hydrocortisone
- dexamethasone
Pharmacokinetics: How do corticosteroids distribute?
- binds to plasma proteins
- CBG or Albumin
-> as circulating cortisol does
CBG
Cortisol Binding Globulin
What is the duration of action of:
a) hydrocortisone
b) prednisolone
c) dexamethasone
a) ~8h
b) ~12h
c) ~40h
How do you treat Addison’s disease long term?
- corticosteroid replacement therapy
- patients lack cortisol and aldosterone
- treat with hydrocortisone and fludrocortisone orally
In what conditions can corticosteroid replacement therapy be used?
- primary adrenocortical failure (Addison’s)
- secondary adrenocortical failure (ACTH deficiency)
- acute adrenocortical failure (Addisonian crisis)
- congenital adrenal hyperplasia
Primary adrenocortical failure
= Addison’s disease
Secondary adrenocortical failure
= ACTH deficiency
How do you treat secondary adrenocortical failure?
- patients lack cortisol but there is no problem with aldosterone
- treat with hydrocortisone
Acute adrenocortical failure
= Addisonian crisis
How do you treat an addisonian crisis?
- i.v. 0.9% NaCl to rehydrate patient
- high dose of hydrocortisone (i.v. infusion or i.m.) every 6h, mineralocorticoid activity at high dose
- 5% dextrose if hypoglycaemic
Why does cortisol have mineralocorticoid activity at high levels?
- because at high levels 11-beta-hydroxysteroid dehydrogenase is overwhelmed.
Which enzyme protects MRs from cortisol?
11-beta-hydroxysteroid-dehydrogenase
What is CAH?
- congenital adrenal hyperplasia
- congenital lack of enzymes needed for adrenal steroid synthesis
What fraction of CAH is due to 21-hydroxylase deficiency?
95%
How do you treat CAH?
- Replace cortisol
- Suppress ACTH and, thus, adrenal androgen production
- Replace aldosterone in salt wasting forms.
What extra caution should patients with adrenocortical failure take?
- Should carry a steroid alert card
- wear a MedicAlert bracelet/necklace
When should you increase glucocorticoid dosage?
- in minor illness: 2x dose until you feel better
- surgery: i.m. hydrocortisone with pre-med 6-8h intervals, oral once eating and drinking.
- (anaesthetic is a stress to get over)
Additional measurements in subjects with adrenocortical failure?
- Normal cortisol production ~ 20mg/day
- In stress production -> 200-300 mg/day
- Increase glucocorticoid dosage when patients are vulnerable to stress
How do you monitor corticosteroid therapy in CAH?
- Monitor/optimise therapy by measuring
- 17 OH progesterone
- Clinical assessment
- Cushingoid – GC dose too high
- Hirsutism – GC dose too low
(and hence ACTH has risen)
Why is it so difficult to treat CAH?
- You have to find the right dose to find a good balance in-between Cushing’s and too much androgen Production
- diurnal rhythm
- altering dose of cortisol when stressed or sick needed
How would you mimic the diurnal rhythm of cortisol with meds?
morning: high dose
midday: lower dose
around 4: low dose
