Adrenal insufficiency with corticosteroids

Prednisone -corticosteroid -leukocytosis -nausea and vomiting indigestion -anorexia or increased appetite -CNS effects (depression, anxiety, euphoria, insomnia, psychosis, confusion) -fluid retention -hyperglycemia -osteoporosis -acne -adrenal insufficiency with prolonged use... 

Monitor patients with SIADH and teach patients with adrenal insufficiency that corticosteroids must be taken continuously (keep emergency doses in possession at all times). 

Close monitoring of 24-hour urinary free cortisol levels and serum cortisol levels are essential to identify adrenal insufficiency in patients with Cushing s syndrome. Steroid secretion should be monitored with all drug therapy and corticosteroid replacement given if needed. 

Corticosteroids are produced by the adrenal glands, and display two main types of biological activity. Glucocorticoids are concerned with the synthesis of carbohydrate from protein and the deposition of glycogen in the liver. They also play an important role in inflammatory processes. Mineralocorticoids are concerned with the control of electrolyte balance, promoting the retention of Na+ and CC, and the excretion of K+. Synthetic and semi-synthetic corticosteroid drugs are widely used in medicine. Glncocorticoids are primarily nsed for their antirhenmatic and anti-inflammatory activities, and mineralocorticoids are nsed to maintain electrolyte balance where there is adrenal insufficiency. 

Fludrocortisone acetate Synthetic corticosteroid with some glucocorticoid and potent mineralocorticoid activity Administered orally to treat primary adrenal insufficiency... 

IV.a.1.9. Adrenal suppression. It results from inhibition of pituitary ACTH secretion, and some suppression of the normal adrenal response to stress may persist for years after stopping therapy. Rapid withdrawal of corticosteroid therapy can therefore precipitate dangerous acute adrenal insufficiency ( Addisonian crisis , with hypotension, vomiting, coma and ultimately death), and for this reason steroid treatment should always be reduced gradually, sometimes over many months, according to the dose and duration of therapy. 

In patients with longstanding hypothyroidism and those with ischemic heart disease, rapid correction of hypothyroidism may precipitate angina, cardiac arrhythmias, or other adverse effects. For these patients, replacement therapy should be started at low initial doses, followed by slow titration to full replacement as tolerated over several months. If hypothyroidism and some degree of adrenal insufficiency coexist, an appropriate adjustment of the corticosteroid replacement must be initiated prior to thyroid hormone replacement therapy. This prevents acute adrenocortical insufficiency that could otherwise arise from a thyroid hormone-induced increase in the metabolic clearance rate of adrenocortical hormones. 

Thus, in patients with Addison s disease or other forms of adrenal insufficiency, continuing oral administration of cortisone acetate or fludrocortisone acetate enables salt balance to be restored. Other corticosteriods and analogues that have been used in the hormonal control of sodium levels include aldosterone and deoxycortone acetate. Individual corticosteroids vary in the extent to which they possess the various hormonal activities so that combination therapy is usually required if, for example, mineral balances are to be maintained when corticosteroids are administered for their anti-inflammatory, antirheumatic or anti-allergic properties. 

Corticosteroids have a range of activity. They have potent antiinflammatory and immunosuppressive activity. Many synthetic drugs are available as corticosteroids. In appropriate doses, these are used as replacement therapy in adrenal insufficiency. The topical application of corticosteroids is safer when compared with systemic use. Corticosteroids should be used in smaller doses for the shortest duration of time. A high dose may be used for life-threatening syndromes or diseases. A tapering pattern of withdrawal should be followed to avoid complications of sudden withdrawal. Systemic therapy is indicated in a variety of conditions. These are administered by intraarticular injections with aseptic conditions for rheumatoid arthritis and osteoarthritis. In skin diseases, such as eczema, contact dermatitis, and psoriasis, corticosteroids are used topically. In some cases, steroids are combined with antimicrobial substances such as neomycin. 

Secondary adrenal insufficiency most commonly results from exogenous corticosteroid use, leading to suppression of the hypothalamic-pituitary-adrenal axis and decreased release of ACTH, resulting in impaired androgen and cortisol production. Mirtazapine and progestins (e.g., medroxyprogesterone acetate, megestrol acetate) have also been reported to induce secondary adrenal insufficiency. Secondary disease typically presents with normal mineralocorticoid concentrations. 

Because most adrenal crises occur because of glucocorticoid dose reductions or lack of stress-related dose adjustments, patients receiving corticosteroid-replacement therapy should add 5 to 10 mg hydrocortisone (or equivalent) to their normal daily regimen shortly before strenuous activities such as exercise. During times of severe physical stress (e.g., febrile illnesses, after accidents), patients should be instructed to double their daily dose until recovery. Treatment of secondary adrenal insufficiency is identical to primary disease treatment with the exception that mineralocorticoid replacement is usually not necessary. 

These agents have use in diagnosis of adrenal disease and in controlling excessive production of corticosteroids, e.g. by corticotropin producing tumours of the pituitary (Cushing s syndrome) or by adrenocortical adenoma or carcinoma where the cause cannot be removed. They must be used with special care since they can precipitate acute adrenal insufficiency. Some members inhibit other steroid synthesis. 

The use of corticosteroids in the treatment of septic shock has been a topic of controversy for many years. A meta-analysis of early studies of steroids in sepsis demonstrated a lack of benefit and potential harm in sepsis and septic shock. There is a renewed interest in corticosteroid use because of the increased awareness of adrenocortical insufficiency in critically ill patients with septic shock. Relative adrenal insufficiency has been defined as a poor adrenal response [<250 nmol/L (9 mcg/dL) irrespective of the initial serum cortisol level] to a dose of synthetic adrenocorticotropic hormone (ACTH), indicating a low fnnctional reserve of the adrenal cortex. Although absolute insufficiency is rare, relative adrenocortical insufficiency in the presence of normal or high cortisol concentrations at baseline is present in 30% to 50% of patients with septic shock and is associated with a poor outcome. ... 

Recent data with moderate doses of corticosteroids (200 to 300 mg/day) infused over 5 to 7 days may reverse septic shock and dependency on vasopressor agents, particularly in patients with relative adrenal insufficiency. Data are still needed regarding optimal dosing and the effect on outcomes such as mortality. Initial uncontrolled studies with vasopressin suggest a potential role in the management of vasopressor-refractory septic shock patients, although further data are needed. 

The corticosteroids have been the subject of much controversy in the management of septic patients. Corticosteroids suppress the activation of polymorphonuclear leukocytes, complement activation, release of TNF, and activation of the coagulation system involved in the cascades of sepsis. A recent study demonstrated a decrease in mortality (absolute reduction of 10%) with lower doses of hydrocortisone and fludrocortisone in patients with adrenal insufficiency requiring high-dose or increasing vasopressor therapy within the first 8 hours of septic shock. There was no benefit for those patients without adrenal insufficiency. In summary, routine use of corticosteroids in patients with sepsis or septic shock is not recommended until further study. 

Mitotane (lysodren) is administered in initial daily oral doses of 2-6 g, usually given in 3 or 4 divided portions, but the maximal tolerated dose may vary from 2 to 16 g/day. Treatment should be continued for at least 3 months if beneficial effects are observed, therapy should be maintained indefinitely. Spironolactone should not be administered concomitantly, since it interferes with the adrenal suppression produced by mitotane. Treatment with mitotane is indicated for the palliation of inoperable adrenocortical carcinoma, producing symptomatic benefit in 30—50% of such patients. Although the administration of mitotane produces anorexia and nausea in 80% of patients, somnolence and lethargy in 34%, and dermatitis in 15—20%, these effects do not contraindicate the use of the drug at lower doses. Since this drug damages the adrenal cortex, administration of corticosteroids is indicated, particularly in patients with evidence of adrenal insufficiency, shock, or severe trauma. 

ELECTROLYTE AND WATER BALANCE Aldosterone is by far the most potent endogenous corticosteroid with respect to fluid and electrolyte balance. Thus, electrolyte balance is relatively normal in patients with adrenal insufficiency due to pituitary disease, despite the loss of glucocorticoid production by the inner cortical zones. Mineralocorticoids act on the distal tubules and collecting ducts of the kidney to enhance reabsorption of Na+ from the tubular fluid they also increase the urinary excretion of K and H . 

WITHDRAWAL OE THERAPY The most frequent problem in steroid withdrawal is flare-up of the underlying disease for which steroids were prescribed. There are several other complications associated with steroid withdrawal. The most severe complication of steroid cessation, acute adrenal insufficiency, results from overly rapid withdrawal of corticosteroids after prolonged therapy has suppressed the HPA axis. Treatment with supraphysiological doses of glucocorticoids for 2-4 weeks may cause some degree of HPA impairment. The therapeutic approach to acute adrenal... 

The immediate management of patients with acute adrenal insufficiency includes intravenous therapy with isotonic sodium chloride solution supplemented with 5% glucose and corticosteroids and appropriate therapy for precipitating causes such as infection, trauma, or hemorrhage. Because cardiovascular function often is reduced in the setting of adrenocortical insufficiency, the patient should be monitored for evidence of volume overload such as pulmonary edema. After an initial intravenous bolus of 100 mg, hydrocortisone (cortisol) should be given by continuous infusion at a rate of 50-100 mg every 8 hours. At this dose, which approximates the maximum daily rate of cortisol secretion in response to stress, hydrocortisone overwhelms the 11/1HSD2 barrier in mineralo-corticoid-responsive tissues and has sufficient mineralocorticoid activity to meet all requirements. As the patient stabilizes, the hydrocortisone dose may be decreased to 25 mg every 6-8 hours. Thereafter, patients are treated in the same fashion as those with chronic adrenal insufficiency see below). 

The adequacy of corticosteroid replacement therapy is judged by clinical criteria and biochemical measurements. The subjective well-being of the patient is an important clinical parameter in primary and secondary disease. In primary adrenal insufficiency, the disappearance of hyperpigmentation and the resolution of electrolyte abnormalities are valuable indicators of adequate replacement. Overtreatment may cause manifestations of Cushing s syndrome in children, linear growth may be decreased. Plasma ACTH levels may be used to monitor therapy in patients with primary adrenal insufficiency the early-morning ACTH level should not be suppressed, but should be less than 100 pg/mL (20 pmol/L). 

Adrenal disorders Glucocorticoids are essential to preserve life in patients with chronic adrenal cortical insufficiency (Addison s disea.se) and are necessary in acute adrenal insufficiency associated with life-threatening shock, infection, or trauma. Glucocorticoids are also used in certain types of congenital adrenal hyperplasia, in which synthesis of abnormal forms of corticosteroids are stimulated by ACTO. In these conditions, administration of a potent synthetic glucocorticoid suppresses ACTH secretion sufficiendy to reduce the synthesis of the abnormal steroids. 

In clinical chemistry, the variations of the Na concentration level in the extracellular fluid are interpreted as follows [3] (1) The level of Na" is elevated in dehydration (water deficit), central nervous system trauma or disease, and hyperadrenocorticism with hyperaldosteronism or corticosterone of corticosteroid excess. (2) A decrement of the Na level is observed in adrenal insufficiency, in renal insufficiency (especially with inadequate Na intake), in renal tubular acidosis as a physiological response to trauma and bums (Na shifts into cells), in unusual losses via the gastrointestinal tract as in acute or chronic diarrhea or intestinal obstruction or fistula, and in unusual sweating with inadequate sodium replacement. In some patients with edema associated with cardiac or renal disease, seram Na concentration is low, even though total body sodium content is greater than normal water retention (excess antidiuretic hormone, ADH) and abnormal distribution of sodium between intracellular and extracellular fluid contribute to this paradoxical situation. Hyperglycemia occasionally results in a shift of intracellular water to the extracellular... 

A rare form of adrenal insufficiency probably caused by an unresponsiveness to ACTH with cortisol deficiency and normal secretion of aldosterone, deoxycorticosterone and corticosterone probably as the result of a missing enzyme on the part of cortisol has been reported. The syndrome is inherited in some cases as an autosomal in others as an X-linked trait. It is associated with (1) undetectable levels of corticosteroids in plasma, (2) a failure to respond to ACTH infusion, (3) normal electrolytes with low salt diet [83]. 

Endocrine The effects of inhaled glucocorticoids on the hypothalamic-pituitary-adrenal axis in adults and children were reviewed in SEDA-31 (p. 305). In summary, at low doses inhaled glucocorticoids have little effect, but at high doses (2000 micrograms beclometasone equivalents) adrenal suppression can occur. In a French survey of 11 783 hospital specialists combined with a pharmacovigilance database, there were 46 cases of adrenal insufficiency attributable to inhaled corticosteroids at doses of over 500 micrograms beclometasone equivalents in children and over 1000 micrograms beclometasone equivalents in adults 12 cases were associated with concomitant use of enzyme inhibitors [10 ]. 

Lapi F, Kezouh A, Suissa S, Ernst P. The use of inhaled corticosteroids and the risk of adrenal insufficiency. Eur Respir J July 2013 42(l) 79-86. Ozkaya E, Nursoy MA, Uzuner S, Erenberk U, Cakir E. Osteocalcin, cortisol levels, and bone mineral density in prepubertal children with asthma treated with long-term fluticasone propionate. Horm Res Paediatr 2012 77(6) 351-7. 

Antibiotic therapy is generally only indicated for cases of secondary bacterial infection following primary viral pneumonia, especially in the case of late-onset pneumonia. Corticosteroids should not be used routinely, but may be considered for septic shock with demonstrable adrenal insufficiency. 

See also Withdrawal of corticosteroid pharmacotherapy, below) This occurs in patients who have recently received prolonged pharmacotherapy with a corticosteroid which inhibits h)rpothalamic production of the corticotropin releasing hormone and so results in secondary adrenal failure. It is treated by reinstituting therapy or as for acute insufficiency, as appropriate. To avoid an acute crisis on stopping, steroid therapy must be withdrawn gradually to allow the hypothalamus. 

---