Therapeutic use of adrenal steroids Flashcards
Corticosteroid receptors
- Glucocorticoid receptors
- Mineralocorticoid receptors
Glucocorticoid receptor features
‘cortisol receptors’
- wide distribution
- selective for glucocorticoids
- low cortisol affinity
Mineralocorticoid receptor features
‘aldosterone receptors’
- discrete distribution (concentrated in kidney and sweat glands)
- does not distinguish between aldosterone and cortisol (problem as cortisol can stimulate the receptor)
- high cortisol affinity
Protection of mineralocorticoid receptors from cortisol
- 11-beta hydroxysteroid dehydrogenase 2 converts cortisol to cortisone which is inactive (inactivates cortisol) and cannot stimulate the mineralocorticoid receptors
- However, when cortisol is present in high concentrations, it gains access to receptors and exerts mineralocorticoid activity
Hydrocortisone (corticosteroid)
- Glucocorticoid with mineralocorticoid activity at high doses
- Oral or parenteral (i.v. or i.m.) administration
- Plasma half life of ~1.5 hour duration but ~8 hour action duration
- Binds to specific carrier protein in blood plasma (CBG=Corticosteroid Binding Globulin) and albumin->~90-95% protein bound in blood with free steroid penetrating body compartments
Prednisolone (corticosteroid)
- Glucocorticoid with weak mineralocorticoid activity
- Oral or parenteral (i.v. or i.m.) administration
- ~12 hour action duration
- Binds to plasma protein
Dexamethasone (corticosteroid)
- Synthetic glucocorticoid with no mineralocorticoid activity
- Oral or parenteral (i.v. or i.m.) administration
- ~40 hour action duration (long acting as slow metabolism)
- Will weakly bind to albumin only
Fludrocortisone (corticosteroid)
- Aldosterone analogue
- Used as an aldosterone substitute
- Oral administration
- Will weakly bind to albumin only
- Plasma half life of ~1.5 hour duration
Congenital adrenal hyperplasia
- Congenital lack of enzymes in adrenal cortex needed for adrenal steroid synthesis
- ~95% of cases lack 21-hydroxylase leading to 17alpha-hydroxyprogesterone accumulation
- 21-hydroxylase deficiency results in no cortisol production, reducing the negative feedback inhibition so ACTH rises (high ACTH drives further adrenal androgen production) and aldosterone deficiency
Primary adrenocortical failure
ADDISON’S DISEASE
-Patients lack cortisol and aldosterone so replacement of both hormones needed
Management: hydrocortisone (replacement cortisol) and fludrocortisone (replacement aldosterone) by mouth
Secondary adrenocortical failure
ACTH DEFICIENCY
-Patients lack cortisol but aldosterone is normal
Management: hydrocortisone (replacement cortisol)
Acute adrenocortical failure
Management:
ADDISONIAN CRISIS (EMERGENCY TREATMENT REQUIRED)
Management:
-IV normal saline (0.9% sodium chloride solution for rehydration and to improve BP)
-High dose hydrocortisone (i.v. infusion or i.m. every 6 hours, mineralocorticoid receptor activation at high dose)
-5% dextrose if hypoglycaemic
Increasing glucocorticoid dosage
- minor illness (double the normal hydrocortisone dose)
- surgery (hydrocortisone intramuscular with pre-anaesthetic medication at 6-8 hour intervals. Given orally once patient is eating and drinking)
- preparation for adrenalectomy or hypophysectomy (as for surgery above)
Patients with adrenocortical failure
For patients on long-term corticosteroid treatment/replacement therapy
- carry a steroid alert card (describes medication, dose, frequency and for which condition they are used)
- wear a MedicAlert bracelet/necklace
Principal physiological actions of adrenal steroids
- Cortisol-> essential for life
- Aldosterone-> promotes sodium retention and potassium loss
- Androgens/oestrogens
Management of congenital adrenal hyperplasia
- Dexamethasone (1 per day at night) or hydrocortisone (2-3 per day) to replace cortisol
- Fludrocortisone (replace aldosterone in salt wasting forms)
- Monitor therapy measuring 17alpha-hydroxyprogesterone levels and clinical assessment of patient for cushingoid (glucocorticoid dose too high) or hirsutism (glucocorticoid dose too low so ACTH has risen)
Objectives of corticosteroid replacement therapy in congenital adrenal hyperplasia
TREATMENT AIMS ARE THREEFOLD
- Replace cortisol
- Suppress ACTH and thus, adrenal androgen production
- Replace aldosterone in salt wasting forms
Too high glucocorticoid dose
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Too low glucocorticoid dose
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