Adrenocorticosteroids

What are the two types of glucocorticoid toxicity?

1.Toxicity due to withdrawal of steroid therapy. 2.Toxicity due to continued use of supraphysiological doses.

90% of plasma cortisol associated with Corticosteroid Binding Globulin (CBG) with the remainder free or bound to albumin/. But synthetic steroids?

90% of plasma cortisol associated with Corticosteroid Binding Globulin (CBG) with the remainder free or bound to albumin. In contrast, synthetic steroids are mostly bound to albumin.

Since Glucocorticois can bind to mineralcorticoid receptors how is this prevent?

A mineralocorticoid effect is avoided in some tissues by expression of 11b-hydroxysteroid dehydrogenase type 2, which converts cortisol to cortisone (cortisone has minimal affinity for aldosterone receptors).

What disease has hyposecretion?

Addison's Disease — Hyposecretion

Alterations in the steroid molecule affect its...?

Alterations in the steroid molecule affect its affinity for the glucocorticoid and mineralocorticoid receptors, protein-binding affinity, side chain stability, rate of elimination and metabolic products.

What disease has hypersecretion?

Cushing's Syndrome — Hypersecretion

What are the effects of corticosteroids on monocytes and macrophages

Decreased Production of proinflammatory cytokines (IL-1, IL-6, TNF-a) Chemotaxis response Differentiation into macrophages

GR and MR bind cortisol with equal affinity. Cortisol mineralocorticoid effects are avoided...?

GR and MR bind cortisol with equal affinity. Cortisol mineralocorticoid effects are avoided through conversion to cortisone by 11ß-hydroxysteroid dehydrogenase

Acute adrenal insufficiency treatment?

Glucose, electrolyte replacement, IV hydrocortisone, eventual maintenance with hydrocortisone and fludrocortisone.

What are two examples of short acting corticosteroids?

Hydrocortisone (cortisol) Cortisone

Primary adrenal insufficiency (Addison's disease) treatment?

Insufficient cortisol and aldosterone production. Treat with hydrocortisone and fludrocortisone.

What is the net effect of corticosteroids?

Net Effect Immunosuppression Anti-inflammatory (frequently palliative, rather than curative) decreased Pain decreased Tissue destruction

When is pharmacological doses required?

Pharmacological Doses •Supraphysiological doses •Numerous applications (see later slides)

What is the cause of toxicity of withdrawal?

Potential iatrogenic acute adrenal insufficiency due to suppression of the HPA axis.

Secondary adrenal insufficiency treatment?

Secondary adrenal insufficiency - Affects only cortisol production. Treat with hydrocortisone.

Tapering Dose

Tapering Dose after a therapeutic response is achieved •gradual reduction in dose over weeks or 2-3 months •prevents flare of inflammatory process •erratic dosing hazardous

Congenital adrenal hyperplasia - Treat

Treat with hydrocortisone and fludrocortisone (if necessary). In utero administration of dexamethasone to the mother suppresses excessive androgen production and prevents female virilization. (Usually, key enzymes in cortisol synthesis are lacking, resulting in low negative feedback on CRH and ATCH production, causing high androgen production; see last slide)

Localized Delivery

When possible, nonsystemic GC therapy should be used to deliver higher local concentrations while minimizing systemic exposure

What is FLudrocortisone?

a potent steroid with both glucocorticoid and mineralocorticoid activity. Used for the treatment of adrenocortical insufficiency associated with mineralocorticoid deficiency. Low enough doses are given to maintain potent salt-retaining activity without having anti-inflammatory or antigrowth effects.

What are two examples of long acting corticosteroid?

betmethasone and dexamethasone

What does cortisol decrease production of ?

cortico releasing hormone in the hypothalmuls and adrenocorticotropic hormone in the anterior pituitary

What does the hormone bind to ?

corticosteroid binding globulin

What are the effects of corticosteroids on Mast cells and baso phil?

decrease histamine release

What are the effects of corticosteroids on Lympocytes?

decreased T cell response to antigens, mitogens Proliferation (IL-1 and 2) Proinflammatory Cytokine Gene Expression (ILs-1, 2, 3, 6, TNF-a, INF-g) Little direct effect on antibody formation Net Effect

What is the only mineralcorticoid we need to know?

fludrocortisone

Cushing's syndrome

if adrenal gland or pituitary adenoma is removed, the patient is given high IV doses of hydrocortisone on the day of surgery, followed by reduction to normal replacement levels. If adrenalectomy is performed, long-term maintenance is similar to that for adrenal insufficiency.

Prodrugs exist in some cases - for example

prednisone is rapidly converted to the active product prednisolone in the liver (Note: prednisone may be poorly activated in patients with severe liver disease).

What are the three ways to reduce toxicity?

tapering dose, alternate day therapy, or localized delivery

•In humans, the major glucocorticoid is _______ and the major mineralocorticoid is _________

•In humans, the major glucocorticoid is cortisol and the major mineralocorticoid is aldosterone.

When is replacement therapy required?

•Primary adrenal insufficiency (Addison's disease) •Secondary adrenal insufficiency (Iatrogenic suppression of HPA axis) •Acute adrenal insufficiency •Congenital adrenal hyperplasia •After removal of adrenal glands or pituitary adenoma (Cushing's syndrome)

Alternate Day Therapy

•reduces side effects in patients receiving long-term therapy (metabolism/infection/growth) •can prevent adrenal-pituitary suppression — allows recovery of ACTH release