CORTICOSTEROIDS

1.            Adrenocorticosteroids

a.         The adrenal cortex releases a large number of steroids into the circulation; some have minimal biologic activity and function primarily as precursors.

b.         The hormonal steroids may be classified as those having:

i.            important effects on intermediary metabolism (glucocorticoids).

ii.            principally salt-retaining activity (mineralocorticoids).

iii.            androgenic or estrogenic activity.

c.            Secretion of adrenocortical steroids is controlled by the pituitary release of ACTH.

d.         Both natural and synthetic corticosteroids are used for diagnosis and treatment of disorders of adrenal function.

e.         They are also used – more often and in much larger doses – for treatment of a variety of inflammatory and immunologic disorders.

f.          In humans, the major glucocorticoid is cortisol and the most important mineralocorticoid is aldosterone.

2.            Pharmacokinetics of Cortisol

a.            Synthesis:

i.          cortisol is synthesized from cholesterol by the cells of the zona fasciculata and zona reticularis and released into the circulation under influence of ACTH.

ii.          its immediate precursor is 17-OH-pregnenolone.

b.            Secretion rate:

i.          in the normal adult in the absence of stress, 10-20 mg of cortisol is secreted daily.

ii.          the rate of secretion changes in a circadian rhythm governed by irregular pulses of ACTH that peak in the early morning hours and after meals and that are also influenced by light.

c.            Transport in blood:

i.          in plasma, cortisol is bound to plsama proteins.

ii.            corticosteroid-binding globulin (CBG), an alpha-globulin synthesized by the liver, binds 75% of the circulating hormone under normal circumstances.

iii.         the remainder is free (20%) or loosely bound to albumin (5%) and is available to exert its effects on target cells.

d.            Variations in CBG:

i.          CBG is increased in pregnancy and with estrogen administration.

ii.          it is decreased by hypothyroidism, genetic defects in synthesis, and protein deficiency states.

e.         Half-life:

i.          the half-life of cortisol in the circulation is normally about 60-90 minutes.

ii.          half-life may be increased when hydrocortisone is administered in large amounts, or when stress, hypothyroidism or liver disease is present.

f.            Metabolism:

i.          only 1% of cortisol is excreted unchanged in the urine.

ii.          about 20 % of cortisol is converted to cortisone by 11-hydroxysteroid dehydrogenase in the kidney and other tissues with mineralocorticoid receptors before reaching the liver.

iii.         the rest are extensively metabolized in liver cytochrome P460 and excreted as glucuronides or sulfates.

3.            Physiologic effects of Glucocorticoids

a.         Cellular level:

i.          upon entering the tissues, glucocorticoids diffuses or are transported through cell membranes and bind to the cytoplasmic glucocorticoid receptor-heat-shock protein complex.

ii.          the heat shock protein is released and the hormone-receptor complex is then transported into the nucleus.

iii.         where it interacts with glucocorticoid response elements (GREs) on various genes and other regulatory proteins and stimulates or inhibits their expression.

b.            Metabolic effects:

i.            glucocorticoids stimulate and are required for gluconeogenesis in the fasted state and in diabetes.

ii.            glucocorticoids also increase amino acid uptake by the liver and kidney and increase the activity required for gluconeogenesis.

iii.         in the liver, glucocorticoids increase glycogen deposition by stimulating glycogen synthase.

iv.            glucocorticoids inhibit uptake of glucose by fat cells, leading to increased lipolysis; however the increased insulin secretion stimulates lipogenesis, leading to a net increase in fat deposition.

c.            Catabolic effects: they have catabolic effects in lymphoid, muscle, bone, skin and connective tissue.

d.            Immunosuppressive effects:

i.            glucocorticoids have profound effects on the concentration, distribution, and function of peripheral leukocytes.

ii.          after a single dose of a short-acting glucocorticoid, the concentration of neutrophils increases while the lymphocytes, monocytes, eosinophils, and basophils in the circulation decrease in number.

iii.         the increase in neutrophils is due both to the increased influx from the bone marrow and decreased migration from the blood vessels leading to a reduction in the number of cells at the site of inflammation.

iv.         the reduction in circulating lymphocytes, monocytes, eosinophils, and basophils is the result of their movement from the vascular bed to lymphoid tissue.

v.            glucocorticoids inhibit the function of leukocytes and tissue macrophages; the ability of these cells to respond to antigens and mitogens is reduced.

e.         Anti-inflammatory effects:

i.            glucocorticoids influence the inflammatory response by reducing the prostaglandin and leukotriene synthesis that results from the activation of phospholipase A₂.

ii.            glucocorticoids may reduce expression of cyclooxygenase, thus reducing the amount of enzymes available to produce prostaglandins.

iii.         direct vasoconstriction and decreased capillary permeability by blocking histamine release.

iv.         impair delayed hypersensitivity reactions.

f.          Other effects:

i.          large doses of glucocorticoids stimulate excessive production of acid and pepsin in the stomach and facilitate the development of peptic ulcer.

ii.            increase the number of platelets and red blood cells.

iii.            stimulate surfactant production in lung.

4.            Clinical Uses of Corticosteroids

a.         Adrenal Insufficiency:

i.            characterized by hyperpigmentation, weakness, fatigue, weight loss, hypotension, and inability to maintain blood glucose level during fasting.

ii.          therapy: 20-30 mg of cortisol given daily, with increased amounts during periods of stress.

b.            Adrenocortical hyperfunction: congenital adrenal hyperplasia

c.            Cushing’s syndrome:

i.          usually the result of bilateral adrenal hyperplasia secondary to a pituitary adenoma or tumors of adrenal gland.

ii.            rounded, plethoric face and trunk obesity.

iii.         muscle wasting, thinning of skin, easy bruisability, poor wound healing, and osteoporosis.

iv.         mental disorders, hypertension, and diabetes.

v.         treated by surgical removal of tumor; patients must receive large doses of cortisol during and following surgery.

d.            Dexamethasone suppression test:

i.          used for the diagnosis of Cushing’s syndrome and has also been used in the differential diagnosis of depressive psychiatric states.

ii.          1 mg of dexamethasone is given orally at 11 pm and a plasma sample is obtained in the morning.

iii.         in normal individuals, the cortisol concentration is usually less than 5 mg/dL, whereas in Cushing’s syndrome the level is usually greater than 10 mg/dL.

e.         Lung maturation in fetus:

i.          lung maturation in the fetus is regulated by the fetal secretion of cortisol.

ii.            treatment of the mother with large doses of glucocorticoid reduces the incidence of respiratory distress syndrome in infants delivered prematurely.

f.            Treatment of Inflammatory diseases:

5.         Side effects and Toxicity

a.         Benefits vs Toxicity:

i.          the benefits obtained from use of the glucocorticoids vary considerably.

ii.          they must be carefully weighed in each patient against the widespread effects on every part of the organism.

iii.         the major undesirable effects of the glucocorticoids are the result of their hormonal actions and lead to the clinical picture of iatrogenic Cushing’s syndrome.

b.            Metabolic effects:

i.            hyperglycemia

ii.            distribution of fat: moon face, ‘buffalo hump’ and truncal obesity.

iii.         growth retardation

iv.         acne, hirustism and menstrual disturbances

v.         delayed wound healing

vi.         skin thinning

vii.        Na / fluid retention

c.            Musculoskeletal system:

i.            osteoporosis (trabecular bone) – prevented by estrogen replacement therapy, bisphosphatonates (etidronate / alendronate), calcitriol, calcitonin.

ii.          aseptic necrosis of femoral head

iii.            myopathy (dexamethasone / triamcinolone)

d.         Immune system: increase in opportunistic infections – bacteria (TB), viral (Herpes and CMV), fungal (canadial, asperigilles and crytococcal), parasititc (toxoplasmosis).

e.         Eye:

i.            posterior subcapsular lens cataract

ii.            glaucoma

f.          GI system: development of peptic ulcers and their complications.

g.            Nervous system: euphoria, depression, psychosis.

h.         Other effects: nausea, dizziness, weight loss.

6.         Use of Corticosteroids in Treatment

a.            Considerations:

i.          since the corticosteroids are usually not curative, the pathologic process may progress while clinical manifestations are suppressed.

ii.            therefore, chronic therapy with these drugs should be undertaken with great care and only when the seriousness of the disorder warrants their use and less hazardous measures have been exhausted.

b.         General approach:

i.            attempts should be made to bring the disease process under control using short-acting glucocorticoids as well as all ancillary measures possible to keep the dose low.

ii.          where possible, alternate-day therapy should be utilized.

iii.         therapy should not be decreased or stopped abruptly.

iv.         when prolonged therapy is anticipated, it is advised to obtain chest firms and a tuberculin test.

v.         the presence of diabetes, peptic ulcer, osteoporosis, and psychological disturbances should be excluded, and cardiovascular function should be assessed.

c.            Supplementary measures:

i.          the diet should be rich in potassium and low in sodium to prevent electrolyte disturbances.

ii.          caloric management to prevent obesity.

iii.         high protein intake is required to compensate for loss due to increased breakdown of protein from gluconeogenesis.

iv.            antacids should be used three or four times daily in patients prone to epigastric distress.

d.            Withdrawing treatment:

i.          if corticoid dosage is to be reduced, it should be tapered slowly.

ii.          if therapy is to be stopped, the reduction process should be quite slow when the dose reaches replacement levels.

iii.         it will take 2-3 months for the pituitary to become responsive, and cortisol levels may not return to normal for another 6-9 months.

iv.         results of rapid withdrawal: anorexia, nausea, vomiting, weight loss, lethargy, headache, fever, joint or muscle pain, postural hypotension.

e.            Dosage:

i.          in determining the dosage regimens to be used, the physician must consider the seriousness of the disease, the amount of drug likely to be required to obtain the desired effect, and the duration of therapy.

ii.          the lowest possible dosage for the needed effect should be determined by gradually lowering the dose until an increase in signs or symptoms is noted.

iii.         when it is necessary to maintain a continuously elevated plasma corticosteroid levels in order to suppress ACTH, a slowly absorbed parenteral preparation or small doses at frequent intervals are required.

iv.         when selecting a drug for use in large doses, a shorter-acting synthetic steroid with little mineralocorticoid effect is advisable.

f.            Alternate-day treatment:

i.          when large doses are required for prolonged periods of time, alternate-day administration of the compound may be tried after control is achieved.

ii.          when used in this manner, very large amounts can sometimes be administered with less marked adverse effects because there is a recovery period between each dose.

iii.         the transition to an alternate-day schedule can be made after the disease process is under control.

g.         Special dosage forms to reduce systemic side effects:

i.          topical: ointments, creams, lotions

ii.            ophthalmic forms

iii.         enemas for ulerative colitis

iv.            inhalation for asthma

v.         nasal sprays for allergic rhinitis

vi.         intra-articular injection for joint disease