Therapeutic use of adrenal steroids Flashcards
What controls the production of aldosterone? Describe this controlling process
Renin-angiotensin-aldosterone system
- Renin (from the kidney) converts angiotensinogen (produced by the liver) to angiotensin I
- Angiotensin I is converted by ACE (which is found in high concentration in the lung endothelium) to Angiotensin II
- Angiotensin II (vasoconstrictor) stimulates the production of aldosterone
State four triggers of renin release (and hence aldosterone release)
Hyperkalaemia
Hyponatraemia
Drop in renal blood flow
β1-adrenoceptor stimulation
What is the principle action of aldosterone? Describe this mechanism
Increases Na+ reabsorption
Increases K+ excretion
=> increased water reabsorption
Aldosterone binds to intracellular receptors and translocates to the nucleus and causes changes in transcription leading to the synthesis of ion channels and pumps.
State three differences between glucocorticoid receptors and mineralocorticoid receptors
GR:
- Wide distribution
- Selective for glucocorticoids
- Low affinity for cortisol
MR:
- Discrete distribution (kidney)
- Do NOT distinguish between aldosterone and cortisol
- High affinity for cortisol
Describe how MRs are protected from cortisol stimulation. What enzyme reverses this?
11-beta hydroxysteroid dehydrogenase-2 converts cortisol to the inactive cortisone to prevent it from interacting with mineralocorticoid receptors.
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 and so the cortisol binds to the mineralocorticoid receptors and has mineralocorticoid (aldosterone-like) effects
Name three glucocorticoid drugs in order of decreasing mineralocorticoid activity.
Hydrocortisone (mineralocorticoid activity at high doses)
Prednisolone (weak mineralocorticoid activity)
Dexamethasone (no mineralocorticoid activity)
Name an aldosterone analogue
Fludrocortisone
What does prednisolone tend to be used for?
Immunosuppression
What does dexamethasone tend to be used for clinically?
Acute anti-oedema
E.g. brain metastases where there is a lot of oedema
How are the glucocorticoid drugs mentioned administered normally? How might they be administered in high doses, in emergencies?
Orally
Parenteral (i.v. or i.m.)
hydrocortisone, dexamethasone.
How do these drugs travel in the blood? State the extent of binding for each.
Bound to plasma proteins - Cortisol Binding Globulin (CBG) and albumin
Hydrocortisone: extremely plasma protein bound (90-95%)
Prednisolone: less bound
Dexamethasone and Fludrocortisone: even less bound
(fludrocortisone only binds to albumin)
Compare the half-lives of hydrocortisone, prednisolone and dexamethasone
Hydrocortisone: ~ 8h
Prednisolone: ~ 12h
Dexamethasone: ~ 40h
State two causes of primary adrenocortical failure
- Addison’s disease
2. Chronic adrenal insufficiency
What is the usual treatment for primary adrenocortical failure?
Patients lack cortisol and aldosterone so treat with hydrocortisone and fludrocortisone orally
Why is there no problem with aldosterone production in secondary adrenocortical failure?
The problem lies in the pituitary gland, not the adrenal gland (i.e. ACTH deficiency).
Aldosterone production isn’t dependent on ACTH
Describe the treatment of secondary adrenocortical failure.
Treat with hydrocortisone
titrate dose to mimic normal physiology
Describe the treatment for acute adrenocortical failure (Addisonian Crisis)?
- iv saline (0.9% sodium chloride) to rehydrate patient and replenish salt
- High dose hydrocortisone
i. v. infusion or i.m. every 6h, (remember mineralocorticoid effect at high dose) - 5% dextrose if hypoglycaemic
List the objectives of therapy for congenital adrenal hyperplasia
- Replace cortisol
- Suppress ACTH and, thus, adrenal androgen production
- Replace aldosterone in salt wasting forms
Outline the treatment plan for congenital adrenal hyperplasia
- High dose hydrocortisone (2-3/day) pm or dexamethasone (1/day) pm
- Replace aldosterone with fludrocortisone
How do you monitor a patient with CAH?
- Measure 17a-hydroxyprogesterone
- Monitor them clinically – are they complaining of hirsuitism/acne (GC dose too low) or cushingoid symptoms (GC dose too high)?
State any additional measures 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 e.g. In minor illness, prior to surgery (hydrocortisone, i.m., with pre-med and at 6-8 hour intervals, oral once eating and drinking)
What must you tell patients with adrenocortical failure?
They should carry a steroid alert card and wear a MedicAlert bracelet/necklace
