Steroid

Dr Noor Wijayahadi

The anterior pituitary : thyroid stimulating hormone (TSH) adenocorticotrope hormone (ACTH) growth hormone (GH) follicle stimulating hormone (FSH) luteinizing hormone (LH) prolactin (PRL). Specific releasing hormones from the hypothalamus regulate the release posterior pituitary: Antidiuretic hormone (ADH) or vasopressin directly released in the bloodstream by neurons originating from the supraoptic nucleus

(1)A disorder at the level of the hypothalamus (e.g. a tumor): the releasing hormones are not secreted or cannot reach the endocrine cells in the anterior pituitary. (2)A disorder in the vascularisation of the pituitary caused by an infarction or trauma. (3)A disorder at the level of the endocrine cells of the pituitary mostly as a result of benign tumors. Substitution of all target hormones (thyroxine, glucocorticoids, growth hormone, androgens and estrogens) is necessary, when there is complete hypofunction.

1. ACTH dependent Cushing's syndrome is a secondary hyperfunction of the zona fasciculata in the adrenal cortex. ACTH oversecretion is mostly due to a pituitary adenoma (1, Cushing's disease), 2. or rarely due to ectopic ACTH production (2). 3. At the level of the adrenal cortex cell increased ACTH levels induce excessive cortisol synthesis and secretion (3). ACTH independent Cushing's syndrome is caused by cortisol overproduction by the adrenal (due to an adenoma or carcinoma). High glucocorticoid levels in the blood cause similar symptoms as discussed with Cushing's disease. Drugs that inhibit glucocorticoid synthesis are used to treat this disease, in the period prior to final treatment by surgical removal of the tumors that cause Cushing's syndrome.

 Synthesis of cortisol is the main function of the adrenal cortex cell in the zona fasciculata. LDL particles containing cholesterol are endocytosed. Then, cholesterol is transferred to the mitochondrion, where it is converted into pregnenolone. Pregnenolone is taken to the endoplasmic reticulum and converted, step-bystep to deoxycortisol. The latter is converted to cortisol, again in the mitochondrion. Finally, cortisol is secreted from the cortex cell. ACTH regulates the process of cortisol production

1. Cushing's disease is due to an ACTH-secreting pituitary adenoma. 2. ACTH-dependent Cushing's syndrome can also be caused by an ectopic ACTH producing tumor. Excessive secreted amounts of corticotropin-releasing hormone by an ectopic tumor is a rare cause of Cushing's syndrome. The excess of ACTH results in overproduction of glucocorticoids and to a much lesser extent of mineralocorticoids and androgens.A pituitary adenoma can be removed by transsphenoidal microsurgery. Preoperative pharmacological treatment is focused on the inhibition of glucocorticoid synthesis in the adrenals.

Ketoconazole

 Metyrapone is a specific inhibitor of the enzyme 11b-hydroxylase, which is responsible for the conversion of 11deoxycortisol into cortisol in the adrenal gland. Prior to surgery, metyrapone can be applied as an inhibitor of cortisol synthesis in the treatment of Cushing's disease or of Cushing's

Some Therapeutic Indications for the Use of Glucocorticoids in Nonadrenal Disorders. Allergic reactions Collagenvascular disorders Eye diseases Gastrointestinal diseases Angioneurotic edema, asthma, bee stings, contact dermatitis, drug reactions, allergic rhinitis, serum sickness, urticaria Giant cell arteritis, lupus erythematosus, mixed connective tissue syndromes, polymyositis, polymyalgia rheumatica, rheumatoid arthritis, temporal arteritis Acute uveitis, allergic conjunctivitis, choroiditis, optic neuritis Inflammatory bowel disease, nontropical sprue, subacute hepatic necrosis

Hematologic disorders
Systemic inflammation

Acquired hemolytic anemia, acute allergic purpura, leukemia, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, multiple myeloma
Acute respiratory distress syndrome; (sustained therapy with moderate dosage accelerates recovery and decreases mortality)

Infections
Inflammatory conditions of bones and joints

Gram-negative septicemia; (occasionally helpful to suppress excessive inflammation)

Arthritis, bursitis, tenosynovitis

Neurologic disorders

Cerebral edema (large doses of dexamethasone are given to patients following brain surgery to minimize cerebral edema in the postoperative period), multiple sclerosis

Organ transplants Pulmonary diseases Renal disorders Skin diseases

Prevention and treatment of rejection (immunosuppression) Aspiration pneumonia, bronchial asthma, prevention of infant respiratory distress syndrome, sarcoidosis Nephrotic syndrome Atopic dermatitis, dermatoses, lichen simplex chronicus (localized neurodermatitis), mycosis fungoides, pemphigus, seborrheic dermatitis, xerosis

Thyroid diseases

Malignant exophthalmos, subacute thyroiditis

Miscellaneous Hypercalcemia, mountain sickness

Some Commonly Used Natural and Synthetic Corticosteroids for General Use

Agent

Anti-inflam

Topi Saltcal Retain ing

Equi Oral Dose (mg)

Forms Available

Short- to mediumacting glucocorticoids Hydrocortisone (cortisol) Cortisone Prednisone Prednisolone 1 0.8 4 5 1 0 0 4 1 0.8 0.3 0.3 20 25 5 5 Oral, injectable, topical Oral, injectable, topical Oral Oral, injectable, topical

Methylprednisolo 5 ne
Meprednisone2 5

0
0

4
4

Oral, injectable, topical

Oral, injectable

Intermediateacting glucocorticoids Triamcinolone Paramethasone2 Fluprednisolone Long-acting glucocorticoids Betamethasone 2540 10 0 0.6 Oral, injectable, topical 5 10 15 7 53 0 0 0 4 2 1.5 Oral, injectable, topical Oral, injectable Oral

Dexamethasone
Mineralocorticoid Fludrocortisone Desoxycorticost erone acetate

30

10

0.75

Oral, injectable, topical

10 0

10 0

250 20

Oral, injectable, topical Injectable, pellets

 The cause of primary adrenal insufficiency, better known as Addison's disease, lies at the level of the adrenal gland itself. Addison's disease is caused by destruction of the adrenal cortex. This is mostly due to autoimmune destruction. Tuberculosis or adrenal haemorrhage can also destroy the adrenal cortex. Adrenal insufficiency involves both the zona fasciculata (glucocorticoids) and the zona glomerulosa (mineralocorticoids). Symptoms that can occur, are hypotension, loss of appetite, hypovolemia, and low blood glucose levels. In addition, hyponatriemia and hyperkalemia are due to hypoaldosteronism. Both glucocorticoids and mineralocorticoids are needed to control the symptoms.

 Secondary adrenal insufficiency describes the situation in which a shortage of ACTH impairs normal function of the cells in the zona fasciculata. The other cells of the cortex, in the zona reticularis and zona glomerulosa, are not affected by this disorder. The hormones produced in these zones (aldosterone in the zona glomerulosa, sex steroids in the zona reticularis) are only controlled by a limited extent by ACTH. As a result of deficient ACTH levels, cortisol levels drop. This is accompanied by symptoms like gastrointestinal complaints, hypotension, low blood glucose levels and weakness. Administration of glucocorticoids relieves the symptoms.

 Mineralocorticoids play an important role in water and salt balance control. They stimulate retention of sodium ions against the loss of potassium ions in urine. Mineralocorticoids bind to a mineralocorticoid-receptor in the nucleus. This complex can interact with a specific binding site on the DNA, resulting in transcription of genes. Fludrocortison is the only mineralocorticoid with clinical application. In Addison's the dose of fludrocortisone is between 0.05-0.2 mg daily in combination with 20 mg hydrocortisone.

 Control of the circulatory volume is regulated to a large extent by the reninangiotensin system. The kidney releases renin upon decreasing plasma sodium levels and decreasing circulatory volume. Renin converts angiotensinogen from the liver to angiotensin I. Angioconverting enzyme from the lungs converts angiotensin I into angiotensin II. The latter stimulates the cells in the zona glomerulosa to synthesise and secrete aldosterone. This hormone forces the tubular cells in the kidney to reabsorb sodium ions, and as a result, water.

 A tumor (2) of the zona glomerulosa can be the cause of hyperaldosteronism. Rarely, an overactivated angiotensin receptor (1) can result in primary hyperaldosteronism. Secondary hyperaldosteronism is due to increased levels of angiotensin II or renin (3), which cause increased aldosterone secretion (like in liver cirrhosis and cardiac failure). In hyperaldosteronism, the kidneys retain sodium ions and potassium ions are lost in urine. In primary hyperaldosteronism, symptoms as hypertension and hypokalemia are common. Spironolactone, a receptor-antagonist of aldosterone, is the main drug to treat primary hyperaldosteronism.

 Spironolactone is a specific antagonist of the mineralocorticoid receptor in the distal tubules of the kidney. Spironolactone counteracts the actions of aldosterone and thus has a natriuretic and potassium-sparing effect. It is the drug of choice in the treatment of hyperaldosteronism (100-150 mg divided over different doses daily).

 When the sympathetic nervous system is activated, the brain stimulates the adrenal medulla. The cells in the medulla immediately secrete adrenaline (80%) and noradrenaline (20%). These hormones stimulate adrenergic receptors throughout the whole body. Adrenaline mobilises glucose, fatty acids and energy, and increases heart rate and force of muscle contraction.

 Pheochromocytoma is a tumor from the adrenal medulla (1) that produces large amounts of adrenaline (and/or noradrenaline). Rarely, a similar condition can also be caused by tumors in other catecholaminergic tissues (paragangliomas, 2). A pheochromocytoma mimicks the condition of chronic sympathetic activation. So, upon excessive secretion of catecholamines from a pheochromocytoma, a patient develops tachycardia, sweating, hypertension, headache and paleness. The patients are treated with a- and b-blocking agents. After adequate blocking by these drugs, the definite treatment of pheochromocytoma is by surgical adrenalectomy.

Glucocorticoids for Oral & Parenteral Use Betamethasone (Celestone) Oral: 0.6 mg tablets; 0.6 mg/5 mL syrup Betamethasone sodium phosphate (Celestone Phosphate) Parenteral: 4 mg/mL for IV, IM, intralesional, or intra-articular injection Cortisone (generic, Cortone Acetate) Oral: 5, 10, 25 mg tablets Parenteral: 50 mg/mL solution Dexamethasone (generic, Decadron, others) Oral: 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6 mg tablets; 0.5 mg/5 mL elixir; 0.5 mg/5 mL, 0.5 mg/0.5 mL solution Dexamethasone acetate (generic, Decadron-LA, others) Parenteral: 8 mg/mL suspension for IM, intralesional, or intra-articular injection; 16 mg/mL suspension for intralesional injection Dexamethasone sodium phosphate (generic, Decadron Phosphate, others) Parenteral: 4, 10, 20 mg/mL for IV, IM, intralesional, or intra-articular injection; 24 mg/mL for IV use only Hydrocortisone [cortisol] (generic, Cortef) Oral: 5, 10, 20 mg tablets Hydrocortisone acetate (generic) Parenteral: 25, 50 mg/mL suspension for intralesional, soft tissue, or intra-articular injection Hydrocortisone cypionate (Cortef) Oral: 10 mg/5 mL suspension Hydrocortisone sodium phosphate (Hydrocortone) Parenteral: 50 mg/mL for IV, IM, or SC injection Hydrocortisone sodium succinate (generic, Solu- Cortef) Parenteral: 100, 250, 500, 1000 mg/vial for IV, IM injection

 Methylprednisolone (generic, Medrol) Oral: 2, 4, 8, 16, 24, 32 mg tablets Methylprednisolone acetate (generic, Depo- Medrol) Parenteral: 20, 40, 80 mg/mL for IM, intralesional, or intra-articular inj Methylprednisolone sodium succinate (generic, Solu-Medrol) Parenteral: 40, 125, 500, 1000, 2000 mg/vial for injection Prednisolone (generic, Delta-Cortef, Prelone) Oral: 5 mg tablets; 5, 15 mg/5 mL syrup Prednisolone acetate (generic) Parenteral: 25, 50 mg/mL for soft tissue or intra-articular injection Prednisolone sodium phosphate (Hydeltrasol, others) Oral: 5 mg/5 mL solution Parenteral: 20 mg/mL for IV, IM, intra-articular, or intralesional injection Prednisolone tebutate (generic) Oral: 5 mg/5 mL liquid Parenteral: 20 mg/mL for intra-articular or intralesional injection Prednisone (generic, Meticorten) Oral: 1, 2.5, 5, 10, 20, 50 mg tablets; 1, 5 mg/mL solution and syrup

 Triamcinolone (generic, Aristocort, Kenacort) Oral: 4, 8 mg tablets; 4 mg/5 mL syrup Triamcinolone acetonide (generic, Kenalog) Parenteral: 3, 10, 40 mg/mL for IM, intra-articular, or intralesional inj Triamcinolone diacetate (generic) Parenteral: 25, 40 mg/mL for IM, intra-articular, or intralesional injection Triamcinolone hexacetonide (Aristospan) Parenteral: 5, 20 mg/mL for intra-articular, intralesional, or sublesional Mineralocorticoids Fludrocortisone acetate (generic, Florinef Ace- tate) Oral: 0.1 mg tablets Adrenal Steroid Inhibitors Aminoglutethimide (Cytadren) Oral: 250 mg tablets Ketoconazole (generic, Nizoral) Oral: 200 mg tablets (unlabeled use) Mitotane (Lysodren) Oral: 500 mg tablets