Adrenocorticosteroids &

Adrenocortical antagonists

By

M.D. , Ph.D.Shahid Beheshti University of Medical Science

Adrenocorticosteroids Introduction Classification Mechanism of Action Glucocorticoids (Adverse) Effects Clinical Application Special Issues Contraindications Glucocorticoid Antagonists Drug Pictures

Introduction

Having important effects on intermediary metabolism and immune function (glucocorticoid).

Having principally salt-retaining activity (Mineralocorticoid).

Having androgenic or estrogenic activity.

Cortisol secretion follows a circadian rhythm that peak in the early morning & after meals

Cortisol

Aldosterone

Dehydroepiandrosterone sulfate (DHEAS)

Classification

Short- to medium-acting glucocorticoids

Intermediate-acting glucocorticoids

Long-acting glucocorticoids

Mineralocorticoids

Hydrocortisone (cortisol)Cortisone Prednisone Prednisolone Methylprednisolone

Triamcinolone

Betamethasone DexamethasoneFludrocortisone

Some commonly used natural and synthetic corticosteroids for general use.

    Activity  

  Agent Anti-Inflammatory Topical Salt-

RetainingOral Dose

(mg)

Short- to medium-acting glucocorticoids    

  Hydrocortisone (cortisol) 1 1 1 20

  Cortisone 0.8 0 0.8 25  Prednisone 4 0 0.3 5  Prednisolone 5 4 0.3 5  Methylprednisolone 5 5 0 4  Meprednisone2 5   0 4Intermediate-acting glucocorticoids    

  Triamcinolone 5 53 0 4

  Paramethasone2 10   0 2  Fluprednisolone2 15 7 0 1.5Long-acting glucocorticoids    

  Betamethasone 25-40 10 0 0.6

  Dexamethasone 30 10 0 0.75

Mineralocorticoids      Fludrocortisone 10 0 250 2

Glucocorticoids (Adverse) Effects Permissive effects:

The response of vascular and bronchial smooth muscle to catecholamines is diminished in the absence of cortisol.

The lipolytic response of fat cells to catecholamines is attenuated in the absence of glucocorticoids.

Metabolic effects Stimulate gluconeogenesis and glycogen synthesis in

the fasting state. Gluconeogenesis, muscle catabolism and lipolysis

contribute to an adequate glucose supply to the brain.

Glucocorticoids (Adverse) Effects cont,d

Anti-inflammatory & immunosuppressive effects: Decrease in lymphocytes, monocytes, eosinophils &

basophils. Inhibit the functions of macrophages. Reduce prostaglandin & leukotriene synthesis. Reduce expression of cyclooxygenase II. Cause vasoconstriction. Decrease capillary permeability. Inhibit complement effects. Reduce antibody production (large doses).

Glucocorticoids (Adverse) Effects cont,d

Catabolic effects: Decreased muscle mass Weakness Thinning of the skin. Osteoporosis. Reduce growth in children.

Glucocorticoids (Adverse) Effects cont,d

Other effects: Insomnia, euphoria, psychosis & depression. Increased intracranial pressure (pseudotumor

cerebri). Peptic ulcer, by suppressing the local immune

response against Helicobacter pylori. Increase in number of platelets & red blood cells.

Glucocorticoids (Adverse) Effects cont,d

Other effects Cont,d:

Antagonize the effect of vit. D on calcium absorption. Bacterial and mycotic infections, may be masked. Increased intraocular pressure (glaucoma). Severe proximal myopathy. Aseptic necrosis of the hip. Cataract.

Clinical Application of Glucocorticoids

Adrenocortical insufficiency. Congenital Adrenal Hyperplasia. Adrenocortical hyperfunction. For diagnostic purposes.

Almost any kind of inflammatory disease. Stimulation of lung maturation in the fetus.

Dexamethasone suppression test

Dexamethasone Suppression Test

Is used for the diagnosis of cushing's syndrome. Dexamethasone, is given at 11 pm:

Morning cortisol less than 3 mcg/dl => normal individual

Greater than 5 mcg/dl => cushing's syndrome The results are not reliable in the presence of

depression, anxiety, concurrent illness, and other stressful conditions.

Dexamethasone Suppression Test Cont,d

Large doses of dexamethasone helps to distinguish different types of Cushing's syndrome

High dose dexamethasone is given and the urine is assayed for cortisol or its metabolites (Liddle's test).

50% suppression in hormone level => Cushing's disease

No suppression in hormone level: ACTH is low => cortisol-producing adrenal tumor ACTH is high => ectopic ACTH-producing tumor.

Adrenocortical insufficiency

Chronic (addison's disease): Glucocorticoids that are long-acting and devoid of

salt-retaining activity should NOT be administered to these patients.

Acute: Treatment must be instituted immediately. Large amounts of parenteral hydrocortisone.

Congenital Adrenal Hyperplasia

Reduction in cortisol and increase in ACTH (hyperplastic gland).

The most common cause is 21β-hydroxylase deficiency.

Dexamethasone administration to the mother protectes fetuses at risk from genital abnormalities.

Negative feedback on ACTH

Congenital Adrenal Hyperplasia Cont,d

Defect in 11β-hydroxylase.

Hypertension with or without hypokalemic alkalosis.

Defect in 17 α-hydroxylase.

Hypogonadism

Hypertension and hypokalemia.

The affected newborn will be in acute adrenal crisis.

Treatment consists of correction of electrolytes and intravenous hydrocortisone in stress doses.

Adrenocortical hyperfunction Cushing's Syndrome:

The most common cause is an ACTH-secreting pituitary adenoma (Cushing's disease).

May also be due to tumors or nodular hyperplasia of the adrenal gland or ectopic production of ACTH.

Treatment is surgery followed by large doses of hydrocortisone.

Aldosteronism: Is due to adrenal adenoma, hyperplastic gland or

malignant tumor. Treatment (and diagnosis) is by spironolactone.

Special Issues In inflammation & allergy, use less frequent – higher

doses. In less than 2 weeks treatment, adverse effects are

unusual. Daily doses of 100 mg of hydrocortisone for longer than

2 weeks suppress adrenal gland. Chronic therapy with these drugs should be undertaken

with great care. If possible, the drug should be given as a single morning

dose.

Glucocorticoid therapy can reactivate dormant disease

Special Issues Cont,d

When large doses are required for prolonged periods, try alternate-day administration after control is achieved.

In prolonged treatment, at the time of severe stress the dose should be raised up to ten times for 72 hr.

In prolonged therapy, obtain a chest x-rays and a tuberculin test.

Therapy should not be decreased or stopped abruptly.

Patients treated with corticosteroids should be on high protein and potassium-enriched diets. It takes 2-12 months for the HPA axis to function

acceptably, and cortisol levels may not return to normal for another 6-9 months

Contraindications

Peptic ulcer Heart disease Hypertension Varicella Tuberculosis

Psychoses Diabetes Osteoporosis Glaucoma

Glucocorticoid Antagonists

Metyrapone: Inhibits 11-hydroxylation, interfering with cortisol and

corticosterone synthesis. It is the only adrenal-inhibiting medication that can be

administered to pregnant women with Cushing's syndrome. The adverse effects are salt - water retention and hirsutism.

Ketoconazole: Is a potent inhibitor of adrenal and gonadal steroid synthesis. These effects are seen only at high doses. Has been used for the treatment of Cushing's syndrome.

Glucocorticoid Antagonists Cont,d

Mifepristone (RU 486) Has strong antiprogestin activity. High doses exert antiglucocorticoid activity by

blocking the glucocorticoid receptor. Only for inoperable patients with ectopic ACTH

secretion or adrenal carcinoma who have failed to respond to other therapies.

Glucocorticoid Antagonists Cont,d

Aminoglutethimide: Blocks the conversion of cholesterol to pregnenolone and

reduces the synthesis of all hormonal steroids.

It is used with dexamethasone or hydrocortisone to reduce estrogen production in breast carcinoma.

Spironolactone: Reverses manifestations of primary aldosteronism

It is also an androgen antagonist so is used in treatment of hirsutism.

This effect is seen in 2 months and maximizes in 6 months.

Estradiol gel

Hydrocortisone

tetracosactide

triamcinolone oral paste

SummaryIn English

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