Therapeutic use of adrenal steroids

Question 1

What controls the production of aldosterone? Describe this controlling process

Answer 1

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

Question 2

State four triggers of renin release (and hence aldosterone release)

Answer 2

Hyperkalaemia
Hyponatraemia
Drop in renal blood flow
β1-adrenoceptor stimulation

Question 3

What is the principle action of aldosterone? Describe this mechanism

Answer 3

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.

Question 4

State three differences between glucocorticoid receptors and mineralocorticoid receptors

Answer 4

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

Question 5

Describe how MRs are protected from cortisol stimulation. What enzyme reverses this?

Answer 5

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

Question 6

Why do you get hypokalaemia in Cushing’s syndrome?

Answer 6

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

Question 7

Name three glucocorticoid drugs in order of decreasing mineralocorticoid activity.

Answer 7

Hydrocortisone (mineralocorticoid activity at high doses)

Prednisolone (weak mineralocorticoid activity)

Dexamethasone (no mineralocorticoid activity)

Question 8

Name an aldosterone analogue

Answer 8

Fludrocortisone

Question 9

What does prednisolone tend to be used for?

Answer 9

Immunosuppression

Question 10

What does dexamethasone tend to be used for clinically?

Answer 10

Acute anti-oedema

E.g. brain metastases where there is a lot of oedema

Question 11

How are the glucocorticoid drugs mentioned administered normally? How might they be administered in high doses, in emergencies?

Answer 11

Orally

Parenteral (i.v. or i.m.)
hydrocortisone, dexamethasone.

Question 12

How do these drugs travel in the blood? State the extent of binding for each.

Answer 12

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)

Question 13

Compare the half-lives of hydrocortisone, prednisolone and dexamethasone

Answer 13

Hydrocortisone: ~ 8h

Prednisolone: ~ 12h

Dexamethasone: ~ 40h

Question 14

State two causes of primary adrenocortical failure

Answer 14

1. Addison’s disease

2. Chronic adrenal insufficiency

Question 15

What is the usual treatment for primary adrenocortical failure?

Answer 15

Patients lack cortisol and aldosterone so treat with hydrocortisone and fludrocortisone orally

Question 16

Why is there no problem with aldosterone production in secondary adrenocortical failure?

Answer 16

The problem lies in the pituitary gland, not the adrenal gland (i.e. ACTH deficiency).
Aldosterone production isn’t dependent on ACTH

Question 17

Describe the treatment of secondary adrenocortical failure.

Answer 17

Treat with hydrocortisone

titrate dose to mimic normal physiology

Question 18

Describe the treatment for acute adrenocortical failure (Addisonian Crisis)?

Answer 18

1. iv saline (0.9% sodium chloride) to rehydrate patient and replenish salt
2. High dose hydrocortisone
   i. v. infusion or i.m. every 6h, (remember mineralocorticoid effect at high dose)
3. 5% dextrose if hypoglycaemic

Question 19

List the objectives of therapy for congenital adrenal hyperplasia

Answer 19

• Replace cortisol
• Suppress ACTH and, thus, adrenal androgen production
• Replace aldosterone in salt wasting forms

Question 20

Outline the treatment plan for congenital adrenal hyperplasia

Answer 20

• High dose hydrocortisone (2-3/day) pm or dexamethasone (1/day) pm
• Replace aldosterone with fludrocortisone

Question 21

How do you monitor a patient with CAH?

Answer 21

• Measure 17a-hydroxyprogesterone
• Monitor them clinically – are they complaining of hirsuitism/acne (GC dose too low) or cushingoid symptoms (GC dose too high)?

Question 22

State any additional measures in subjects with adrenocortical failure

Answer 22

• 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)

Question 23

What must you tell patients with adrenocortical failure?

Answer 23

They should carry a steroid alert card and wear a MedicAlert bracelet/necklace