STEROID THERAPY AND DRUGS USED IN ADRENAL DYSFUNCTION

Question 1

What are ADRENOCORTICAL STEROIDS?
And examples

Answer 1

Adrenocorticoids are made up of:
1. Corticosteroids (glucocorticoids and mineralocorticoids)
2. Androgens

Main glucocorticoid is cortisol and main mineralocorticoid is aldosterone.

Synthetic glucocorticoids include bethamethasone, triamcinolone, prednisolone, dexamethasone, paramethasone, methylprednisolone, decorticosterone acetate.

Synthetic mineralocorticoids include fludrocortisone, deoxycorticosterone.

Question 2

Cortisol (hydrocortisone).

Answer 2

Major glucocorticoid
Synthesised in the zona fasciculata.
C-21 steroid.
Secretion follows a diurnal rhythm being maximal around 8am.
Secretion is regulated by ACTH and also influenced by stress.
10-20mg secreted daily.
More than 90% protein bound mainly to CBG and albumin.
T1/2 is 60-90 minutes.
Metabolism is in the liver by glucoronidation or sulfation to form water soluble metabolites which are excreted in the urine.

Question 3

Cortisol Mechanism of action

Answer 3

Binding of cortisol to receptor.
Dissociation of receptor from associated proteins.
Interaction with coactivators to induce trasncription of GRE in the regulatory region of the gene.
New protein synthesis.
Glucocorticois can also interact with GRE to inhibit transcription of some genes like POMC, COX-2, NOS2 genes.
Second mechanism of action is by direct interaction to cell membrane receptors to produce quicker responses.

Question 4

Physiological effects of glucocorticoids

Answer 4

Effects on carbohydrate and protein metabolism.
Increased production of glucose from amino acids and glycerol.
Increased storage of glucose as glycogen.
Diminished glucose utilization in the peripheral tissues.
Increased lipolysis to provide amino acids and glycerol for gluconeogenesis.
Increased protein breakdown.
Net effect is increased blood glucose levels

Effects on lipid metabolism:
Fat redistribution.
Lipolytic effects of agents like growth hormone, beta antagonists are facilitated.
Net effect is increased free fatty acids.

Effects on electrolyte and water balance (mineralocorticoids):
Enhancement of distal tubular reabsorption of Na+.
Increased urinary excretion of K+ and H+.
ECF volume expansion.

Effects on blood
Polycythemia in cushing’s syndrome and anemia in adrenal insufficiency.
Lymphocytopenia and leukocytosis.
Decreased number of eosinophils, monocytes and basophils.

CVS effects
Hypertension can be consequent upon primary hyperaldosteronism.
Enhancement of vascular reactivity to other vasoactive agents.

Antiinflammatory and immunosuppressive effects (glucocorticoids).
Decreased release of vasoactive and chemoattractive factors.
Decreased migration of leucocytes to areas of injury.
Secretion of lipolytic and proteolytic enzymes are reduced.
Decresaed production of IL-1, IL-6, TNF-alpha, GM-CSF, IFN-γ.

CNS effects:
Elevated mood.
Euphoria.
Insomnia.
Restlessness.
Increased motor activity.
Psychosis.

Other effects:
Suppression of TSH, LH, ACTH release.
Important effects on fetal lung development.
Normal functioning of skeletal muscles.

Question 5

Pharmacokinetics

Answer 5

Absorption is good from all sites with significant absorption leading to systemic effects a potential effect of application with occlusive dressing.
High protein binding in the order of 90%.
Binding is by CBG and albumin.
Steroids compete for binding sites on CBG which has a higher affinity for corticosteroids than for mineralocorticoids.
Serum levels of CBG and cortisol increase markedly during pregnancy ?significance.
The drugs are reduced and subsequently conjugated with glucuronide or sulfate to yield metabolites which are excreted in the urine.

Question 6

Principles of therapeutic use of glucocorticoids

Answer 6

The advantage of use must outweigh the risks.
Appropriate dose to achieve a predetermined effect and should be adjusted periodically based on response or development of toxicities.
A single dose even if large is usually safe.
Administration for a short period (up to one week) is usually safe.
The agents are only palliative except in specific replacement settings.

Question 7

Uses of glucocorticoids

Answer 7

Replacement therapy in adrenal insufficiency which may be primary or secondary.
Rheumatic disorders.
Diseases of the kidneys.
Allergic disorders.
Skin disorders.
Bronchial asthma.
GIT diseases.
Eye problems.
Malignancies.
Cerebral edema.
Organ transplantation.

Question 8

Discuss Adrenal insufficiency

Answer 8

Adrenal insufficiency can be acute, chronic or a result of congenital adrenal hyperplasia.
Result from inadequate secretion of cortisol and or aldosterone.
Potentially fatal.
Commonly due to abrupt withdrawal of chronic glucocorticoid therapy.
Primary adrenocortical failure is called Addison’s disease.
Causes of Addison’s disease include autoimmune, TB, HIV/AIDS, metastatic carcinomas, bilateral adrenalectomy, lymphoma, intraadrenal hemorrhage, amyloidosis, haemochromatosis, CAH, drugs.

Question 9

Clinical presentation of adrenal insufficiency are predictable from the physiological effects of the adrenocortical hormones. Symptoms due to mineralocorticoid insufficiency include:

Answer 9

Hypotension
Shock
Hyponatremia
Hyperkalemia.
Sypmtoms due to glucocorticoid insufficiency include:
Weight loss
Malaise
Weakness
Anorexia
Hypoglycemia
others

Question 10

ACTH excess can cause what?

Answer 10

ACTH excess will cause hyperpigmentation while deficiency of adrenal androgens will cause decreased body hair and loss of libido.
Treatment of acute adrenal insufficiency
Administration of normal saline.
Administration of cortisol, 100mg bolus followed by continous infusion at a rate of 50-100mg 8 hrly.
Treatment of precipitating cause.