Adrenocorticosteroids Flashcards
Triamcinolone
Synthetic Corticosteroids
Glucocorticoids have become important agents for use in the treatment of many inflammatory, immunologic, hematologic, and other disorders. This has stimulated the development of many synthetic steroids with anti-inflammatory and immunosuppressive activity:
Hydrocortisone, Prednisone, Methylprednisolone, Dexamethasone, Beclomethasone, and Triamcinolone
The synthetic glucocorticoids are rapidly and completely absorbed orally, have longer half-lives, reduced mineralocorticoid activity and selected compounds can also be given IV, IM, topically, intra-articularly and by aerosol.
Fludrocortisone
Physiologic effects of Mineralocorticoids
The most important mineralocorticoid in humans is aldosterone. Fludrocortisone, a synthetic corticosteroid, is the most commonly prescribed salt-retaining hormone.
Aldosterone and fludrocortisone promote the reabsorption of sodium from the distal part of the distal convoluted tubule and from the cortical collecting tubules, whilst also increasing the urinary excretion of K+ and H+. Excessive levels of aldosterone produced by tumors or overdosage with synthetic mineralocorticoids lead to hypokalemia, metabolic alkalosis, increased plasma volume, and hypertension.
Mineralocorticoids act by binding to the mineralocorticoid receptor in the cytoplasm of target cells. The major effect of activation of the receptor is increased expression of Na+/K+-ATPase and the epithelial sodium channel (ENaC).
Adrenocortical Insufficiency
Chronic (Addison’s Disease)
Chronic adrenocortical insufficiency is characterized by weakness, fatigue, weight loss, hypotension, hyperpigmentation, and inability to maintain the blood glucose level during fasting. In such individuals, minor noxious, traumatic, or infectious stimuli may produce acute adrenal insufficiency with circulatory shock and even death.
In primary adrenal insufficiency, hydrocortisone must be given daily, with increased amounts during periods of stress. Although hydrocortisone has some mineralocorticoid activity, this must be supplemented by an appropriate amount of a salt-retaining hormone such as fludrocortisone. Synthetic glucocorticoids that are long-acting and devoid of salt-retaining activity should not be administered to these patients.
Acute
When acute adrenocortical insufficiency is suspected, treatment must be instituted immediately. Therapy consists of large amounts of parenteral hydrocortisone in addition to correction of fluid and electrolyte abnormalities and treatment of precipitating factors.
High dose IV hydrocortisone is given until the patient is stable. The dose is then gradually reduced, achieving maintenance dose within a few days. The administration of a salt-retaining hormone is resumed when the total hydrocortisone dosage has been adequately reduced.
Adrenocortical Hypo- and Hyperfunction
Congenital Adrenal Hyperplasia
Caused by defects in cortisol synthesis, either in CRH production by the hypothalamus or in corticotropin production by the pituitary.
The most common congenital defect is a decrease or lack or 21-hydroxylase activity. This defect leads to a reduction in cortisol synthesis and a compensatory increase in ACTH release. The gland becomes hyperplastic and produces abnormally large amounts of precursors such as 17-hydroxyprogesterone that can be diverted to the androgen pathway, leading to virilization.
When first seen, the patient may be in acute adrenal crisis and should be treated as described above. Once the patient is stabilized, oral hydrocortisone, or prednisone is begun. Fludrocortisone should also be administered at this time.
Cushings Syndrome
Symptoms are associated with the chronic presence of excessive glucocorticoids. A rounded, plethoric face and trunk obesity are striking in appearance. The manifestations of protein loss are often found and include muscle wasting; thinning, purple striae, and easy bruising of the skin; poor wound healing; and osteoporosis. Other serious disturbances include mental disorders, hypertension, and diabetes. This disorder is treated by surgical removal of the tumor, or resection of one or both adrenals. These patients must receive large doses of cortisol during and after the surgical procedure. The dose must be reduced slowly to normal replacement levels, since rapid reduction in dose may produce withdrawal symptoms.
Aldosteronism
Primary aldosteronism usually results from excessive production by an adrenal adenoma. Symptoms results from renal loss of K+ (hypokalemia, alkalosis and elevation of serum Na+). Aldosteronism is treated with the aldosterone antagonist, spironolactone.
Dexamethasone
Use of Glucocorticoids for Diagnostic Purposes
It is sometimes necessary to suppress the production of ACTH to identify the source of a particular hormone or to establish whether its production is influenced by the secretion of ACTH. The dexamethasone suppression test is used for the diagnosis of Cushing’s syndrome and has also been used in the differential diagnosis of depressive psychiatric states.
Stimulation of Lung Maturation in the Fetus
Lung maturation in the fetus is regulated by the fetal secretion of cortisol. Treatment of the mother with large doses of glucocorticoids reduces the incidence of respiratory distress syndrome in infants delivered prematurely. When delivery is anticipated before 34 weeks of gestation, IM glucocortioids are administered (usually dexamethasone).
Adverse Effects of Glucocorticoids
The major undesirable effects of glucocorticoids are the result of their hormonal actions, which lead to a Cushing’s like syndrome. When glucocorticoids are used for short periods (< 2 weeks), it is unusual to see serious adverse effects even with moderately large doses.
Metabolic Effects
In the face, rounding, puffiness, fat deposition, and plethora usually appear (moon facies). Similarily, fat tends to be redistributed from the extremities to the trunk, the back of the neck, and the supraclavicular fossae. There is an increased growth of fine hair over the face, thighs and trunk. The continuing breakdown of protein and diversion of amino acids to glucose production increase the need for insulin and over time result in weight gain; visceral fat deposition; myopathy and muscle wasting; thinning of the skin, with striae and bruising; hyperglycemia; and eventually osteoporosis, diabetes, and aseptic necrosis of the hip.
Other Complications
Other serious adverse effects of glucocorticoids include peptic ulcers and their consequences. The clinical findings associated with certain disorders, particularly bacterial and mycotic infections, may be masked by the corticosteroids. Hypomania or acute psychosis may occur, particularly in patients receiving very large doses. Long- term therapy with intermediate- and long-acting steroids is associated with depression. Increased intraocular pressure is common and glaucoma may be induced. Benign intracranial hypertension also can occur.
Adrenal Suppression
When corticosteroids are administered for more than 2 weeks, adrenal suppression may occur. If treatment extends over weeks to months, the patients should be given appropriate supplementary therapy at times of minor stress such as accidental trauma or surgery.
If corticosteroid dosage is to be reduced, it should be tapered slowly. If therapy is to be stopped, the reduction process should be quite slow. It may take 2-12 months for the hypothalamic-pituitary-adrenal axis to function acceptably, and cortisol levels may not return to normal for another 6-9 months.
If the dosage is reduced too rapidly in patients receiving glucocorticoids for a certain disorder, the symptoms of the disorder may reappear or increase in intensity. However, patients without an underlying disorder also develop symptoms with rapid reductions in corticosteroid levels. These symptoms include anorexia, nausea or vomiting, weight loss, lethargy, headache, fever, joint or muscle pain, and postural hypotension. Although many of these symptoms may reflect true glucocorticoid deficiency, they may also occur in the presence of normal or even elevated plasma cortisol levels, suggesting glucocorticoid dependence.
Contraindications and Cautions with Glucocorticoids
Patients receiving glucocorticoids must be monitored carefully for the development of hyperglycemia, glycosuria, sodium retention with edema, or hypertension, hypokalemia, peptic ulcer, osteoporosis, and hidden infections.
The dosage should be kept as low as possible, and intermittent administration (eg, alternate-day) should be used with satisfactory therapeutic results can be obtained on this schedule. K+ loss and effects on bone can be prevented by giving the patient K+, Ca2+ and vitamin D supplements.
Glucocorticoids must be used with great caution in patients with peptic ulcer, heart disease or hypertension with heart failure, certain infectious illnesses such as varicella and tuberculosis, psychoses, diabetes, osteoporosis, or glaucoma.
Spironolactone
Mineralocorticoid Antagonists
Spironolactone
Spironolactone reverses many of the manifestations of aldosteronism. It has been useful in establishing the diagnosis in some patients and in ameliorating the signs and symptoms when surgical removal of an adenoma is delayed. Adverse effects include hyperkalemia, cardiac arrhythmia, menstrual abnormalities, gynecomastia, sedation, headache, GI disturbances, and skin rashes.
Aminogluthemide
Synthesis Inhibitors and Glucocorticoid Antagonists
Aminogluthemide
Aminogluthemide blocks the conversion of cholesterol to pregnenolone and causes a reduction in the synthesis of all hormonally active steroids. It can used in the treatment of adrenal cancer along with hydrocortisone or dexamethasone).
Ketoconazole
Synthesis Inhibitors and Glucocorticoid Antagonists
Ketoconazole
Ketoconazole, an antifungal imidazole derivative is a potent and rather non-selective inhibitor of adrenal and gonadal steroid synthesis. The sensitivity of the P450 enzymes to this compound in mammalian tissues is much lower than that needed to treat fungal infections, so that its inhibitory effects on steroid biosynthesis are seen only at high doses.
Ketoconazole has been used for the treatment of patients with Cushing’s syndrome due to several causes. It also has been used in the treatment of prostate cancer.
Metyrapone
Synthesis Inhibitors and Glucocorticoid Antagonists
Metyrapone
Metyrapone is a relatively selective inhibitor of steroid 11-hydroxylation, interfering with cortisol and corticosteroid synthesis. This agent has not been widely used for the treatment of Cushing’s syndrome, though it may be useful in the management of severe manifestations of cortisol excess while the cause of this condition is being determined or in conjunction with radiation or surgical treatment. Metyrapone is the only adrenal- inhibiting medication that can be administered to pregnant women with Cushing’s syndrome. The major adverse effects observed are salt and water retention and hirsutism resulting from diversion of the 11-deoxycortisol precursor to androgen synthesis.
Mifepristone
Synthesis Inhibitors and Glucocorticoid Antagonists
Mifepristone
Mifepristone is a pharmacologic antagonist at the steroid receptor. High doses of mifepristone exert antiglucocorticoid activity by blocking the glucocorticoid receptor. Mifepristone is only recommended for inoperable patients with ectopic ACTH secretion or adrenal carcinoma who have failed to respond to other therapeutic manipulations.
