Adrenocortical hormones. Classification of Adrenocortical Hormones 1.Glucocorticoids 2.Mineralocorticoids 3.Sex hormones.

Adrenocortical hormones

Classification of Adrenocortical Hormones

1. Glucocorticoids2. Mineralocorticoids3. Sex hormones

1. Glucocorticoid

1. Short acting: hydrocortisone, Prednisone (8-12 hours)

2. Intermediate-acting: triamcinolone (12-36 hours)3. Long acting: dexamethasone (48 hours)

Pharmacokinetics:• Well absorbed after oral administration.• 75% of corticosteroids are bound to plasma globulins

(CBG). CBG is increased by estrogen and decreased in liver cirrhosis.

• Metabolism is by the liver and excretion is by the kidney.

Mechanism of action:• Corticosteroids transported to the nucleus, where it

interacts with many DNA receptors (genes) and affect their function.

Pharmacological effects:1. On metabolism:

A. Carbohydrate metabolism: hyperglycemia (↓ peripheral glucose utilization).

B. Protein metabolism: Catabolic effect → ↓ muscle mass and thin limbs.

C. Fat metabolism: ↑ lipolysis with redistribution of fat.

2. Na+ & water retention and hypokalemia.

3. Anti-inflammatory and anti-immunological effects:– Inhibit antigen-antibody reaction.– Inhibit lymphocyte and macrophage activity and

function.– Stabilize lysosomal membrane.– ↓ release of inflammatory mediators and cytokine

production by inflammatory cells.– Inhibit phospholipase A2 enzyme so reduce

synthesis of PGs & LTs. – ↓ capillary permeability.

4. CVS: Hypertension due to Na+ & water retention.5. Hematological effects:

1. ↑ RBCs and ↓ lymphocytes and eosinophils.2. ↑ coagulation factors and blood cholesterol.

6. On growth:1. Growth retardation, which is not prevented by

growth hormone.7. On bone:

1. ↓ bone matrix and ↑ Ca2+ excretion (osteoporosis).

8. Inhibit hypothalamo-pituitary-adrenal axis.

Doses:• Short-term therapy: duration of

therapy is < 2 weeks.• Long term therapy: duration of

therapy is > 3 weeks.• Alternate day therapy: double

the dose and give it every other day.

Therapeutic uses:1. As replacement therapy in adrenocortical insufficiency:

A. Acute adrencortical insufficiency (acute addisonian crisis

B. Chronic adrenocortical insufficiency (Addison’s disease).

2. Adrenocortical hyperplasia due to elevated ACTH:A. Congenital adrenal hyperplasia:B. Cushing syndrome: due to pituitary adenoma, adrenal

tumors.

3. Stimulation of lung maturation in the fetus

4. Anti-inflammatory: e.g. vasculitis, rheumatic fever, arthritis, bronchial asthma, etc.

5. Allergic diseases: e.g. anaphylactic shock, urticaria and bronchial asthma.

6. Autoimmune disease: e.g. SLE 13. Shock and hypotension14. Organ transplantation: as immunosuppressive to

prevent graft rejection.15. Cerebral edema: dexamethasone is used after brain

surgery to minimize edema.16. Acute hypercalcemia: to enhance Ca2+ excretion.

Side effects:1. Acute adrenal insufficiency (acute addisonian crisis):– It occurs after sudden withdrawal of corticosteroids

after prolonged administration.– Prevention: Gradual withdrawal of corticosteroids.

2. Iatrogenic Cushing syndrome: – Occurs if high doses used or it is used for > 2 -3

weeks. It is characterized by moon face, buffalo hump, weak muscles, osteoporosis, hypertension, DM, edema, etc.

3. Immune suppression leading to:– Flaring of infections (especially viral and TB). – Decrease wound healing

4. Peptic ulcer– Due to prolonged PGs suppression.

5. Rise of IOP (Glaucoma).6. Hyperglycemia.7. Hypercoagulability leading to thromboembolism8. Osteoporosis.9. Retardation of growth in children.10. Pregnancy: congenital cleft palate.

6. Local side effects:• Skin atrophy & hypopigmentation on prolonged

use.• Repeated administration in joints may produce

joint destruction & infection

Contraindications:

1. Presence of infections: especially viral infection and TB:

because corticosteroids can inhibit immune functions.

N.B. Uses of corticosteroids in presence of T.B:

• TB meningitis: to prevent adhesions.

• TB of the suprarenal gland: to correct hypofunction.

• Miliary TB: to ↓ TB toxemia.

2. Peptic ulcer: they ↓ synthesis of PGE2 and I2 that protect

the stomach.3. Hypertension & heart failure: they cause salt and water

retention.4. DM (except fluorinated corticosteroids e.g.

dexamethasone and betamethasone because they have anti-inflammatory with less hyperglycemic effects).

5. Mental disorders e.g. psychosis or depression.6. In early pregnancy: may cause cleft palate.

Drug interactions:1. With NSAIDs: ↑ incidence of peptic ulcer and

decreases its healing2. With insulin: It has anti-insulin effect

(hyperglycemia)3. With anticoagulant drugs: it decreases their effect.4. With loop diuretics: it aggravate hypokalemia.

Mineralocorticoids1. Natural mineralocorticoids: • Aldosterone• It binds to specific intracellular receptors in the distal

convoluting tubules to inhibit Na+ excretion and stimulates K+ and H+ excretion.

2. Synthetic mineralocorticoidsA. Deoxycorticosterone acetate(DOCA)• It has mainly mineralocorticoid effect.B. Fludrocortisone• It has both glucocorticoid and mineralocorticoid

effect.

Adverse effects

• Hypernatremia• Hypervolemia• Hypokalemic alkalosis (weakness, paralytic ileus and

tetany)• Hypertension

Therapeutic uses

• Acute adrenal insufficiency• Chronic adrenal insufficiency (Addison's disease)

Hyperaldosteronism

• Treatment of hyperaldosteronism:1. Primary hyperaldosteronism: by surgical removal

of tumor.2. Secondary hyperaldosteronism: Aldosterone

antagonists: spironolactone.

Adrenocortical hormone antagonistsA. Glucocorticoid inhibitors:

1. Aminoglutethimide:• Inhibit steroid hormone synthesis .• Used in adrenocortical malignancies and cancer

breast. In postmenopausal or Ovariectomized women with metastatic breast cancer (to eliminate adrenal estrogen production

2. Metyrapone:• It inhibits enzyme necessary for synthesis of

glucocorticoids. • Used to measure the capacity of the anterior

pituitary to secrete ACTH.

3. Ketoconazole:• It is antifungal drug with slight inhibition of

mineralocorticoids synthesis.• Used in Cushing’s syndrome

4. Mifepristone • Blockade cytoplasmic glucocorticoid receptor• Inoperable patients with ectopic ACTH

secretions or adrenal carcinoma (it is also an antiprogestin)

B. Aldosterone receptors inhibitors:Spironolacone • Blockade of cytoplasmic mineralocorticoid

receptor• (used in hyperaldosteronism)

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