Half-Life, Potency, and Duration of Action

The important differences among the systemically used glucocorticoid compounds are duration of action, relative glucocorticoid potency, and relative mineralocorticoid potency1,2 (Table 5-1). The commonly used glucocorticoids are classified as short-acting, intermediate-acting, and long-acting on the basis of the duration of adrenocorticotropic hormone (ACTH) suppression after a single dose, equivalent in antiinflammatory activity to 50 mg of prednisone⁵ (see Table 5-1). The relative potencies of the glucocorticoids correlate with their affinities for the glucocorticoid receptor.⁶ The observed potency of a glucocorticoid, however, is determined not only by the intrinsic biological potency but also by the duration of action.^6,7 The relative potency of two glucocorticoids varies as a function of the time interval between the administration of the two steroids and the determination of the potency. In particular, failure to consider the duration of action may lead to a marked underestimation of the potency of dexamethasone.⁷

Little correlation exists between the circulating half-life (T_1/2) of a glucocorticoid and its potency. The T_1/2 of cortisol in the circulation is 80 to 115 minutes.¹ The T_1/2 values of other commonly used agents are as follows: cortisone, 0.5 hour; prednisone, 3.4 to 3.8 hours; prednisolone, 2.1 to 3.5 hours; methylprednisolone, 1.3 to 3.1 hours; and dexamethasone, 1.8 to 4.7 hours.^1,7,8 Although prednisolone and dexamethasone have comparable T_1/2 values, dexamethasone is clearly more potent. Similarly, little correlation is found between the T_1/2 of a glucocorticoid and its duration of action. The many actions of glucocorticoids do not have an equal duration.

The duration of action is a function of the dose. For example, the duration of ACTH suppression produced by an individual glucocorticoid is dose related.⁵ The duration of ACTH suppression is not simply a function of the level of antiinflammatory activity, because variations in the duration of ACTH suppression are achieved by doses of glucocorticoids with comparable antiinflammatory activity.

In short, the slight differences in the T_1/2 values of the glucocorticoids contrast with their marked differences in potency and duration of ACTH suppression. Thus the potency and the duration of action of a glucocorticoid are not determined solely by its presence in the circulation; this is consistent with the mechanism of action of steroid hormones. Steroid molecules bind to a specific intracellular receptor protein, the glucocorticoid receptor. The steroid-receptor complex modifies the process of transcription by which RNA is transcribed from the DNA template, among other mechanisms of action (see later discussion). This process alters the rate of synthesis of specific proteins. The steroid thereby modifies the phenotypic expression of the genetic information. Thus a glucocorticoid continues to act inside the cell after it has disappeared from the circulation. Moreover, the events initiated by a glucocorticoid may continue to occur, or a product of these events (such as a specific protein) may be present, after the disappearance of the glucocorticoid from the circulation.

Bioavailability, Absorption, and Biotransformation

Normally the plasma cortisol level is much lower after oral administration of cortisone than after an equal dose of cortisol.⁹ Although oral cortisone may be adequate replacement therapy in chronic adrenal insufficiency, the oral form of this agent should not be used when pharmacologic effects are sought. Comparable plasma prednisolone levels are achieved in normal persons after equivalent oral doses of prednisone and prednisolone.^8,10 After the administration of either of these substances, a wide variation is found in individual prednisolone concentrations, which may reflect variability in absorption.⁸

In contrast to the marked increase in the plasma cortisol level that follows the intramuscular injection of hydrocortisone, the plasma cortisol level increases little or not at all after an intramuscular injection of cortisone acetate. When given intramuscularly, cortisone acetate does not provide an adequate plasma cortisol level and offers no advantage over hydrocortisone delivered by the same route. The explanation for the failure of intramuscular cortisone acetate to provide adequate plasma cortisol levels is not known. It may reflect poor absorption from the site of injection. Intramuscular cortisone acetate, which reaches the liver through the systemic circulation, also may be metabolically inactivated before it can be converted to cortisol in the liver, in contrast to oral cortisone acetate, which reaches the liver through the portal circulation.

Plasma Transport Proteins

In normal people, circadian fluctuations occur in the capacity of corticosteroid-binding globulin (transcortin) to bind cortisol and prednisolone. Patients who have received prednisone for a prolonged period have no diurnal variation in the binding capacity of corticosteroid-binding globulin for cortisol or prednisolone, and both capacities are reduced in comparison with normal persons. Thus, long-term glucocorticoid therapy not only changes the endogenous secretion of steroids but also affects the transport of some glucocorticoids in the circulation. This may explain why the disappearance of prednisolone from the circulation is more rapid in those persons who have previously received glucocorticoids.

Effects of Other Medications on Glucocorticoids

The metabolism of glucocorticoids is accelerated by substances that induce hepatic microsomal enzyme activity, such as phenytoin, barbiturates, and rifampicin. The administration of these medications can increase the corticosteroid requirements of patients with adrenal insufficiency or lead to deterioration in the condition of patients whose underlying disorders are well controlled by glucocorticoid therapy. These substances should be avoided if possible in patients receiving corticosteroids. Diazepam does not alter the metabolism of glucocorticoids and is preferable to barbiturates in this setting. If drugs that induce hepatic microsomal enzyme activity must be used in patients taking corticosteroids, an increase in the required dose of corticosteroids should be anticipated.

Conversely, ketoconazole increases the bioavailability of large doses of prednisolone (0.8 mg/kg) because of inhibition of hepatic microsomal enzyme activity.²⁴ Oral contraceptive use decreases the clearance of prednisone and increases its bioavailability.²⁵

The bioavailability of prednisone is decreased by antacids in doses comparable to those used clinically.²⁶ The bioavailability of prednisolone is not impaired by sucralfate, H₂-receptor blockade, or cholestyramine.

Effects of Glucocorticoids on Other Medications

The concurrent administration of a glucocorticoid and a salicylate may reduce the serum salicylate level. Conversely, reduction of the glucocorticoid dose during the administration of a fixed dose of salicylate may produce a higher and possibly toxic serum salicylate level. This interaction may reflect the induction of salicylate metabolism by glucocorticoids.²⁷

Glucocorticoids may increase the required dose of insulin or other agents used to treat hyperglycemia, blood-pressure medications, or glaucoma medications. They also may alter the required dose of sedative-hypnotic or antidepressant therapy. Digitalis toxicity can result from hypokalemia caused by glucocorticoids, as from hypokalemia of any cause. Glucocorticoids can reverse the neuromuscular blockade induced by pancuronium.

Duration of Therapy

The anticipated duration of glucocorticoid therapy is a critical consideration. The use of glucocorticoids for 1 to 3 weeks for a condition such as poison ivy or allergic rhinitis is unlikely to be associated with serious side effects in the absence of a contraindication. An exception to this rule is a corticosteroid-induced psychosis, which may occur after only a few days of high-dose glucocorticoid therapy, even in patients with no previous history of psychiatric disease.31,32 The risk of most complications is related to the dose and duration of therapy.^33–36 Consequently, one should prescribe the smallest possible dose for the shortest possible period. If hypoalbuminemia is present, the dose should be reduced. If long-term treatment is indicated, the use of alternate-day glucocorticoid therapy should be considered (see later).

Local Use

Local corticosteroid preparations should be used whenever possible because they produce fewer side effects than do systemically administered agents. Examples include topical therapy in dermatologic disorders such as bullous pemphigoid, corticosteroid aerosols in bronchial asthma and allergic rhinitis, and corticosteroid enemas in ulcerative proctitis.30,37,38 Inhaled glucocorticoids have a markedly better safety profile than do orally administered agents.³⁹ Nevertheless, adrenal suppression and other complications may develop from topical, inhaled, and regional administration of glucocorticoids. The risk factors for the development of these side effects from topical steroids for dermatologic indications include application to a large surface area of skin, application for a prolonged period, use of occlusive dressings, and use of a highly potent (class I) glucocorticoid. In sufficient doses, inhaled glucocorticoids produce an acute but apparently temporary decrease in growth velocity in children, cause osteoporosis, and may increase the risk of cataracts, glaucoma, skin atrophy, and ecchymoses.³⁹ The development of adrenal suppression from inhaled steroids is related to dose, duration of therapy, and use of a potent agent (e.g., fluticasone).⁴⁰ The intraarticular injection of corticosteroids may be of value in carefully selected patients if strict aseptic techniques are used and if frequent injections are avoided.

Selecting A Systemic Preparation

Agents with no mineralocorticoid activity should be used when a glucocorticoid is prescribed for pharmacologic purposes. If the dosage is to be tapered over a few days, a long-acting agent should be avoided. For alternate-day therapy, one should use a short-acting agent that generally does not cause sodium retention (e.g., prednisone, prednisolone, or methylprednisolone). The use of supplemental medications to minimize the systemic corticosteroid dose and to reduce the side effects of systemic glucocorticoids should always be considered. In asthma, for example, treatment should include inhaled glucocorticoids and bronchodilators such as β-adrenergic agonists and theophylline.

Antiinflammatory and Immunosuppressive Effects

Among their many actions, endogenous glucocorticoids protect the organism from damage caused by its own defense reactions and the products of these reactions during stress. They do this by confining inflammatory responses to the area of injury. Consequently, the use of glucocorticoids as antiinflammatory and immunosuppressive agents represents an application of the physiologic effects of glucocorticoids to the treatment of disease (see Chapter 3).

Chronic inflammation is characterized by the increased expression of multiple inflammatory genes that are regulated by transcription factors such as nuclear factor (NF)-κB and activator protein-1 (AP-1).41–45 These transcription factors bind to and activate coactivator molecules, which acetylate core histone proteins, causing the DNA to unwind, thereby switching on gene transcription, a process called chromatin remodeling.^44,45 Glucocorticoids switch off multiple inflammatory genes (including those related to synthesis of cytokines, chemokines, adhesion molecules, inflammatory enzymes, receptors, and other proteins) that are activated during the chronic inflammatory process.^41–45 They do so principally by reversing histone acetylation of activated inflammatory genes through binding of glucocorticoid receptors to coactivators (which have been activated by transcription factors such as NF-κB and AP-1) and recruitment of histone deacetylase-2 to the activated transcription site.^44,45 In high concentrations, glucocorticoids increase the synthesis of antiinflammatory proteins, notably annexin-1 (also called lipocortin-1), an inhibitor of phospholipase A2 (see following); inhibit transcription of genes linked to proteins related to the pathogenesis of glucocorticoid side effects; and have postgenomic effects.^44,45

Side Effects

The side effects of glucocorticoids include the diverse manifestations of Cushing’s syndrome and HPA suppression36,53 (Table 5-3) Exogenous Cushing’s syndrome differs from endogenous Cushing’s syndrome in several respects. Hypertension, acne, menstrual disturbances, male erectile dysfunction, hirsutism or virilism, striae, purpura, and plethora are more common in endogenous Cushing’s syndrome. Benign intracranial hypertension, glaucoma, posterior subcapsular cataract, pancreatitis, and avascular necrosis of bone are virtually unique to exogenous Cushing’s syndrome. Obesity, psychiatric symptoms, and poor wound healing have nearly equal frequency in endogenous and exogenous Cushing’s syndrome.^53,54 These differences may be explained as follows. When Cushing’s syndrome is caused by exogenous glucocorticoids, ACTH secretion is suppressed; in spontaneous, ACTH-dependent Cushing’s syndrome, the elevated ACTH output causes bilateral adrenal hyperplasia. In the former circumstance, the secretion of adrenocortical androgens and mineralocorticoids is not increased. Conversely, when ACTH output is elevated, the secretion of adrenal androgens and mineralocorticoids may be increased.¹ The augmented secretion of adrenal androgens may account for the higher prevalence of virilism, acne, and menstrual irregularity in the endogenous form of Cushing’s syndrome, and the enhanced production of mineralocorticoids may explain the higher prevalence of hypertension.¹ Some of the complications that are virtually unique to exogenous Cushing’s syndrome arise after the prolonged use of large doses of glucocorticoids. Examples are benign intracranial hypertension, posterior subcapsular cataract, and avascular necrosis of bone.¹

Glucocorticoids appear to increase the risk of peptic ulcer disease and also gastrointestinal hemorrhage.⁵⁵ The magnitude of the association between glucocorticoid therapy and these complications is small and is related to the total dose and duration of therapy.^55,56 The risk of peptic ulcer disease and related gastrointestinal problems is increased by the concurrent use of glucocorticoids and nonsteroidal antiinflammatory drugs.^57,58

Glucocorticoid therapy, especially daily therapy, may suppress the immune response to skin tests for tuberculosis. When possible, a tuberculin skin test should be performed before the initiation of glucocorticoid therapy, with the intention to treat with isoniazid if the skin test meets the criteria of the American Thoracic Society.⁵⁹

Some patients respond to (and experience side effects of) glucocorticoids more readily than others at comparable doses. Increased responsiveness to glucocorticoids may be a consequence of hypoalbuminemia, the nephrotic syndrome, impaired renal function, age, drug interactions, and variations in the severity of the underlying disease (see earlier). Impaired renal function may contribute to a decrease in the clearance of prednisolone and an increase in the prevalence of cushingoid features.⁶⁰ In patients who experience side effects, the metabolic clearance rate of prednisolone and the volume of distribution are lower^10,61 and the T_1/2 is longer than in those who do not.⁶¹ Patients who have a cushingoid habitus while taking prednisolone have higher endogenous plasma cortisol levels than do those without this complication, perhaps because of resistance of the HPA axis to suppression by exogenous glucocorticoids.⁶² Alterations in bioavailability probably do not account for variations in the therapeutic response to glucocorticoids.

Variations in the effectiveness of corticosteroids may be the result of altered cellular responsiveness to the drugs.63–66 In patients with primary open-angle glaucoma, exogenous glucocorticoids produce a more pronounced increase of intraocular pressure⁶³; a greater suppression of the 8:00 am plasma cortisol level when dexamethasone, 0.25 mg, is administered the previous evening at 11:00 pm;⁶⁵ and greater suppression of phytohemagglutinin-induced lymphocyte transformation^64,66 than in normal persons. Primary open-angle glaucoma is relatively common. These findings suggest that a distinct subpopulation of patients is hyperresponsive to glucocorticoids and that this sensitivity is genetically determined.

Prevention of Side Effects

The issues of concern to physicians and patients with respect to glucocorticoid therapy are not only HPA suppression but also long-term complications such as glucocorticoid-induced osteoporosis and Pneumocystis carinii pneumonia. The risk of most complications can be reduced by the use of the lowest possible dose of a glucocorticoid for the shortest possible period, by the use of regional or topical rather than systemic steroids, and by the use of alternate-day steroid therapy. In addition, pharmacologic interventions to prevent specific complications such as bone disease and P. carinii pneumonia are now widely used.

Osteoporosis

Patients who receive long-term glucocorticoid therapy develop low bone-mineral density. Fractures occur in as many as 30% to 50% of patients chronically receiving systemic glucocorticoid therapy.⁶⁷ The prevalence of vertebral fractures in asthmatic patients on glucocorticoid therapy for at least a year is 11%.⁶⁸ Patients with rheumatoid arthritis who are treated with glucocorticoids have an increased incidence of fractures of the hip, ribs, spine, leg, ankle, and foot.⁶⁸ Skeletal wasting occurs most rapidly during the first 6 to 12 months of therapy, presumably due to excessive bone resorption. This is followed by a slower progressive phase related to impaired bone formation.⁶⁷ Trabecular bone is affected more than cortical bone. Fractures occur at higher levels of bone-mineral density than in postmenopausal osteoporosis.⁶⁷ The effects on the skeleton are related to the cumulative dose and duration of treatment.⁶⁸ Alternate-day glucocorticoid therapy does not reduce the risk of osteopenia. Inhaled steroids are associated with bone loss.³⁹

Glucocorticoids have both direct and indirect effects on the skeleton.⁶⁷ They impair the replication, differentiation, and function of osteoblasts and also induce the apoptosis of mature osteoblasts and osteocytes. These effects result in suppression of bone formation. Glucocorticoids promote the formation of osteoclasts with a prolonged life span, which results in enhanced and prolonged bone resorption. Glucocorticoids also affect bone cells by their effects on growth factors present in the bone microenvironment.⁶⁷ In particular, glucocorticoids suppress transcription of the insulin-like growth factor 1 (IGF-1) gene.⁶⁷ The indirect effects of glucocorticoids on bone metabolism include inhibition of intestinal calcium absorption (by antagonizing the actions of vitamin D and decreasing the expression of specific calcium channels in the duodenum) and inhibition of renal tubular calcium absorption.⁶⁷ These changes may lead to secondary hyperparathyroidism in at least some patients. Glucocorticoids reduce sex steroid–hormone production, probably by inhibition of gonadotropin release as the most important mechanism. Reduced sex steroid–hormone production also may result from reduced ACTH secretion from the pituitary, with consequent diminution of adrenal androgen production. Importantly, some of the disorders for which glucocorticoids are given may themselves cause osteoporosis.⁶⁷

The evaluation of the patient should emphasize risk factors for osteoporosis, including inadequate dietary calcium and vitamin D intake, alcohol consumption, smoking, menopause, and hypogonadism in males. Attention also should be devoted to the possibility of thyrotoxicosis, overtreatment with thyroid hormone medication, renal osteodystrophy, multiple myeloma, osteomalacia, or primary hyperparathyroidism. In selected patients, laboratory studies should be ordered for evaluation of these disorders. Serial assessment of bone-mineral density by using dual energy x-ray absorptiometry, especially in the lateral projection of the spine, is the best way to assess the effects of glucocorticoids on bone.

All patients treated with glucocorticoids systemically should receive calcium and vitamin D supplementation to correct any nutritional deficiency. Calcium therapy alone is associated with rapid rates of spinal bone loss and offers only partial protection from this loss. No evidence suggests that the combination of calcium and vitamin D prevents bone loss due to glucocorticoids.⁶⁹ Bisphosphonates (such as etidronate, alendronate, and risedronate) are effective as antiresorptive agents in the prevention of bone loss and fractures resulting from glucocorticoid therapy.^67,70 These agents are the treatment of choice for the prevention and treatment of glucocorticoid-induced osteoporosis.

Daily subcutaneous injections of teriparatide (human parathyroid hormone 1-34) stimulate bone formation and dramatically increase bone mass in the spines of women with glucocorticoid-induced osteoporosis.⁷¹ In glucocorticoid-treated patients with osteoporosis at high risk for fracture, bone-mineral density increases more in patients treated with teriparatide than in those treated with alendronate.⁷² Also, fewer new vertebral fractures occur in those on teriparatide than in those on alendronate.⁷² Teriparatide, an expensive agent that requires daily subcutaneous injections, should be considered for selected patients who are at high risk for fracture by virtue of low bone-mineral density and long-term glucocorticoid therapy.^70,72

Women with a premature menopause should receive hormone-replacement therapy unless contraindicated. In postmenopausal women, alternatives to hormone-replacement therapy such as those just indicated should be used. Hypogonadotropic men should receive testosterone therapy unless contraindicated. Patients should be educated about the risks and the consequences of osteoporosis and the factors in their own lives that may contribute thereto. Because steroids also affect muscle mass and function, the patient should be advised about exercises to maintain muscle strength and about the need for adequate protein intake.

Pneumocystis Carinii Pneumonia

Glucocorticoids predispose patients to many different infections. In the past, prophylaxis against infections for patients treated with glucocorticoids was limited to patients receiving transplantation of organs, who also receive other forms of immunosuppression. Currently, prophylaxis is often used for patients with other disorders who are treated with glucocorticoids, particularly for P. carinii pneumonia.73,74

In a series of 116 patients without acquired immunodeficiency syndrome (AIDS) who experienced a first episode of P. carinii pneumonia between 1985 and 1991, 105 (90.5%) had received glucocorticoids within 1 month before the diagnosis of P. carinii pneumonia was established.⁷³ The median daily dose was equivalent to 30 mg of prednisone; 25% of the patients had received as little as 16 mg/day. The median duration of glucocorticoid therapy was 12 weeks before the development of the pneumonia. In 25% of the patients, P. carinii pneumonia developed after 8 weeks or less of glucocorticoid therapy. However, the attack rate in patients with primary or metastatic central nervous system tumors who receive glucocorticoid therapy is about 1.3% and may be lower in other conditions.⁷⁴ Prophylactic therapy also may produce side effects.

Many physicians recommend prophylaxis (e.g., trimethoprim-sulfamethoxazole, one double-strength tablet per day) for patients with impaired immunocompetence conferred by chemotherapy, transplantation, or an inflammatory disease who have received prednisone, 20 mg or more per day, for more than 1 month. Controlled studies with such prophylaxis in steroid-treated patients are not available. Physicians at the Mayo Clinic detected no cases of P. carinii pneumonia in patients who received adequate chemoprophylaxis, when not contraindicated, in recipients of bone marrow or organ transplantation from 1989 to 1995.⁷³

Withdrawal from Glucocorticoids

The symptoms associated with glucocorticoid withdrawal include anorexia, myalgia, nausea, emesis, lethargy, headache, fever, desquamation, arthralgia, weight loss, and postural hypotension. Many of these symptoms can occur with normal plasma glucocorticoid levels and in patients with normal responsiveness to conventional tests of HPA function.75,76 These patients may have abnormal responses to a low-dose ACTH test with 1 µg of α1-24 ACTH rather than the conventional 250-µg dose.^77,78 Because glucocorticoids inhibit PG production and because many of the features of the glucocorticoid withdrawal syndrome can be produced by PGs such as PGE₂ and PGI₂, this syndrome may be caused by a sudden increase in PG production after the withdrawal of exogenous corticosteroids. In addition, increased circulating interleukin 6 (IL-6) levels may mediate the signs and symptoms of glucocorticoid deficiency.⁷⁹ The glucocorticoid withdrawal syndrome may contribute to psychological dependence on glucocorticoid treatment and to difficulties in discontinuing such therapy.

Development of Hypothalamo-Pituitary-Adrenal Suppression

Adrenal suppression (i.e., abnormal adrenocortical function as a consequence of glucocorticoid therapy) occurs without hypotension. Secondary adrenal insufficiency caused by glucocorticoid therapy is a clinical entity in which hypotension is always present.³⁵ Adrenal suppression is much more common than adrenal insufficiency and may indicate susceptibility to overt adrenal insufficiency, especially under stressful circumstances such as general anesthesia and surgery.

Few well-documented cases of acute adrenocortical insufficiency after prolonged glucocorticoid therapy have been reported, and none after ACTH therapy.¹ After ACTH and glucocorticoids were introduced into clinical practice in the late 1940s, patients were reported in whom shock was attributed to adrenocortical insufficiency caused by these agents, but biochemical evidence of adrenocortical insufficiency was not available to substantiate the diagnosis.¹ Prolonged hypotension or an apparent response of hypotension to intravenous hydrocortisone is not a reliable means of assessing adrenocortical function; one must demonstrate simultaneously that the plasma cortisol level is lower than the values found in normal persons experiencing a comparable degree of stress. When measurement of plasma cortisol levels became available in the early 1960s, three cases were described that met these criteria. The paucity of reports may relate to acute adrenocortical insufficiency after glucocorticoid therapy being uncommon in properly treated patients and physicians being reluctant to report such events.

The minimal duration of glucocorticoid therapy that can produce HPA suppression must be determined from studies of adrenocortical weight and adrenocortical responsiveness to provocative tests.1,2 Any patient who has received a glucocorticoid in a dose equivalent to 20 to 30 mg/day of prednisone for more than 5 days should be suspected of having HPA suppression.^1,2 If the dose is closer to, but still above, the physiologic range, 1 month is probably the minimal interval.^1,2

The stress of general anesthesia and surgery is not hazardous to patients who have received only replacement doses (≤25 mg of hydrocortisone, 5 mg of prednisone, 4 mg of triamcinolone, or 0.75 mg of dexamethasone), as long as the corticosteroid is given early in the day. If doses of this size are given late in the day, suppression may occur because of inhibition of the diurnal surge of ACTH release.

Assessment of Hypothalamo-Pituitary-Adrenal Function

When HPA suppression is suspected, it may be helpful to assess the integrity of the HPA system. A test of HPA reserve is required only when the result will modify therapy. In practice, this applies to patients who may need an increase in the glucocorticoid dosage to cover a stressful event (such as general anesthesia and surgery) and to patients in whom discontinuation of glucocorticoid therapy is contemplated. In the latter group, a test of the HPA axis is indicated only when the glucocorticoid dosage has been reduced to replacement levels (for example, prednisone, 5 mg/day, or an equivalent dose of another glucocorticoid). In stable patients receiving prolonged glucocorticoid therapy, frequent tests of HPA reserve function are not indicated. For example, it is not necessary to test before each reduction in dose during tapering of the steroid regimen. The responsiveness of the HPA system may change as glucocorticoid therapy continues, and repeated testing is costly.

The short ACTH test is a valuable guide to the presence or absence of HPA suppression in glucocorticoid-treated patients (Table 5-4). Although this test assesses directly only the adrenocortical response to ACTH, it is usually an effective measure of the integrity of the entire HPA axis. Because hypothalamo-pituitary function returns before adrenocortical function during recovery from HPA suppression, a normal adrenocortical response to ACTH in this setting implies that hypothalamo-pituitary function also is normal. This rationale is supported by clinical studies. Thus the maximal response of the plasma cortisol level to ACTH corresponds to the maximal plasma cortisol level observed during the induction of general anesthesia and surgery in patients who have received glucocorticoid therapy.^1,2 A normal response to ACTH before surgery is not likely to be followed by impaired secretion of cortisol during anesthesia and surgery in glucocorticoid-treated patients. An abnormal response to ACTH is a necessary but not a sufficient condition for the occurrence of adrenal insufficiency in a steroid-treated patient who undergoes surgery, because some patients with an abnormal response to ACTH tolerate surgery without steroid treatment.⁸⁰ Furthermore, hypotension in the operative or postoperative period in a patient who has been treated previously with glucocorticoid therapy is often due to another cause, such as volume depletion or a reaction to anesthetic medication, and may respond to treatment of the other factor. The serum total cortisol response to ACTH may be abnormal in critically ill patients with hypoalbuminemia and reduced levels of corticosteroid-binding globulin, in whom the serum free (bioactive) cortisol levels are normal.^81,82 Thus the abnormal circulating cortisol response to ACTH may reflect decreased circulating binding proteins rather than adrenocortical insufficiency.

Other tests of HPA function generally are not indicated. The low-dose (1-µg) short ACTH test is more sensitive than the conventional ACTH test in patients treated with glucocorticoids.77,83 The conventional dose of ACTH used in the short ACTH test (and other ACTH tests) produces circulating ACTH levels that are well above the physiologic range. These supraphysiologic levels may result in a normal plasma cortisol level in patients with partial adrenocortical insufficiency. Nevertheless, the low-dose short ACTH test has not yet replaced the conventional-dose short ACTH test in clinical practice. The lower limit of the normal range for the low-dose ACTH test has not been defined.⁷⁸ No commercial preparations of ACTH are available for use in the low-dose short ACTH test. The injection for the low-dose short ACTH test must be prepared by dilution, a source of inconvenience and potential error. Insulin-induced hypoglycemia may be dangerous (especially in patients with cardiac or neurologic disease), and the symptoms may be uncomfortable, but it is the only test of the entire HPA axis and is preferred by some. This procedure is more time-consuming and expensive than the ACTH test, because more cortisol values must be obtained. The measurement of plasma cortisol levels before and after the administration of corticotropin-releasing hormone also has been proposed.⁸⁴ This test also is longer and more expensive than the ACTH test and has not been compared with a physiologic stress such as anesthesia and surgery; it offers no advantage over the short ACTH test.³⁵

Adrenocorticotropic Hormone and the Hypothalamo-Pituitary-Adrenal System

Pharmacologic doses of ACTH produce elevated cortisol secretory rates and increased plasma cortisol levels. The elevated plasma cortisol levels might be expected to suppress ACTH secretion, but no evidence indicates that ACTH therapy causes significant hypothalamo-pituitary suppression in patients.¹ The failure of ACTH therapy to suppress hypothalamo-pituitary function is not explained by the dose of ACTH used, the frequency of injection, the time of administration, or the plasma cortisol pattern after ACTH administration. Alternatively, the hyperplastic and overactive adrenal cortex that results from ACTH therapy may compensate for hypothalamo-pituitary suppression. Although the threshold adrenocortical sensitivity to ACTH is not changed in patients who have received daily ACTH therapy, adrenocortical responsiveness to ACTH in the physiologic range may be enhanced. The normal response of the plasma cortisol level in patients treated with ACTH also may be preserved, at least in part, because ACTH treatment reduces the rate of endogenous ACTH secretion but not the total amount secreted, whereas glucocorticoids reduce both the rate of secretion and the total amount secreted.⁸⁵

Recovery from Hypothalamo-Pituitary-Adrenal Suppression

During recovery from HPA suppression, hypothalamo-pituitary function returns before adrenocortical function.1,2,86 Twelve months must elapse after the discontinuation of large glucocorticoid doses given for a prolonged period before HPA function, including responsiveness to stress, returns to normal.^1,2,86 In contrast, recovery from HPA suppression induced by a brief course of glucocorticoids (i.e., prednisone, 25 mg, twice daily for 5 days) occurs within 5 days.⁸⁷ Patients with mild suppression of the HPA axis (i.e., normal basal plasma and urine corticosteroid levels but impaired responses to ACTH and insulin-induced hypoglycemia) resume normal HPA function more rapidly than do those with severe depression of the HPA axis (i.e., low basal plasma and urine corticosteroid levels and impaired responses to ACTH and insulin-induced hypoglycemia).⁸⁸ The time course of recovery correlates with the total duration of previous glucocorticoid therapy and the total previous glucocorticoid dose.^88–90 However, in an individual patient, one cannot predict the duration of recovery from a course of glucocorticoid therapy at supraphysiologic doses lasting more than a few weeks. Therefore, the physician should suspect persistence of HPA suppression for 12 months after such treatment. The recovery interval after suppression of the contralateral adrenal cortex by the products of an adrenocortical tumor may exceed 12 months. The recovery from HPA suppression induced by glucocorticoid therapy may be more rapid in children than in adults.

Risks of Withdrawal

The decision to discontinue glucocorticoid therapy provokes apprehension among physicians. The potentially harmful consequences of such an action include precipitation of adrenocortical insufficiency, development of the glucocorticoid withdrawal syndrome, and exacerbation of the underlying disease. Adrenocortical insufficiency after the withdrawal of glucocorticoids is an appropriate concern. The probability of precipitating an exacerbation of the underlying disease depends on the activity and natural history of the condition under treatment. When any possibility exists of an exacerbation of the underlying illness, the glucocorticoid should be withdrawn gradually, over an interval of weeks to months, with frequent reassessment of the patient. Changes in dose should be about 10 mg of prednisone (or equivalent) at total daily doses of more than 30 mg, 5 mg at total doses of more than 20 mg, and 2.5 mg at lower doses. Sometimes smaller changes are necessary. The interval between changes in dosage may be as short as 1 day or as long as many weeks.

Treatment of Patients with Hypothalamo-Pituitary-Adrenal Suppression

No proven method is known for hastening a return to normal HPA function once inhibition has resulted from glucocorticoid therapy. The administration of ACTH does not prevent or reverse the development of glucocorticoid-induced adrenal insufficiency. Conversion to an alternate-day schedule permits recovery to occur but does not accelerate it. In children, alternate-day glucocorticoid therapy may delay recovery.

The recovery from glucocorticoid-induced adrenal insufficiency is time dependent and spontaneous. The rate of recovery is determined not only by the doses given when the glucocorticoid is being tapered but also by the doses administered during the initial phase of treatment, before tapering is commenced. During the course of recovery, a small dose of hydrocortisone (10 to 20 mg) or prednisone (2.5 to 5.0 mg) given in the morning may alleviate withdrawal symptoms. Recovery of HPA function continues to occur when a small dose of a glucocorticoid is administered in the morning. The possibility cannot be excluded, however, that a small dose of a glucocorticoid given in the morning retards the rate of recovery from HPA suppression.

Alternate-Day Glucocorticoid Therapy and Manifestations of Cushing’s Syndrome

An alternate-day regimen can prevent or ameliorate the manifestations of Cushing’s syndrome.1,2 The susceptibility to infections that characterizes Cushing’s syndrome may be diminished. Patients have been described in whom refractory infections cleared after conversion from daily to alternate-day regimens. In addition, the frequency of infections is low in patients receiving alternate-day therapy. Children treated with alternate-day steroid therapy regain or retain tonsillar and peripheral lymphoid tissue. The available information strongly suggests that alternate-day regimens are associated with a lower incidence of infections than are daily regimens but does not firmly establish this point.

Host defense mechanisms have been studied in patients receiving alternate-day therapy. Patients maintained on such schedules have normal blood neutrophil and monocyte counts, normal cutaneous inflammatory responses, and normal neutrophil T_1/2 values on the days they do not take the glucocorticoid. Patients receiving daily therapy, however, demonstrate neutrophilia, monocytopenia, decreased cutaneous neutrophil and monocyte inflammatory responses, and prolongation of the neutrophil T_1/2. Patients studied on the days they do not receive treatment do not have the lymphocytopenia observed in patients who receive daily therapy. Monocyte cellular function is normal at 4 hours and at 24 hours after a dose in patients receiving alternate-day therapy. Intermittently normal leukocyte kinetics, preservation of delayed hypersensitivity, and preservation of monocyte cellular function may explain the apparently reduced susceptibility to infection in patients receiving alternate-day therapy.94–96

Effects of Alternate-Day Glucocorticoid Therapy on Hypothalamo-Pituitary-Adrenal Responsiveness

Patients receiving alternate-day glucocorticoid therapy may have some suppression of basal corticosteroid levels, but they have normal or nearly normal responsiveness to provocative tests such as the corticotropin-releasing hormone stimulation test, the ACTH stimulation test, insulin-induced hypoglycemia, and the metyrapone test.1,2,97 They have less suppression of HPA function than do patients receiving daily therapy.

Effects of Alternate-Day Therapy on Underlying Disease

Alternate-day glucocorticoid therapy is as effective, or nearly as effective, in controlling diverse disorders as is daily therapy in divided doses.1,2 This approach has provided apparent benefit in patients with the following disorders: childhood nephrotic syndrome, adult nephrotic syndrome, membranous nephropathy, renal transplantation, mesangiocapillary glomerulonephritis, lupus nephritis, ulcerative colitis, rheumatoid arthritis, acute rheumatic fever, myasthenia gravis, Duchenne’s muscular dystrophy, dermatomyositis, idiopathic polyneuropathy, asthma, Sjögren’s syndrome, sarcoidosis, alopecia areata and other chronic dermatoses, and pemphigus vulgaris. Prospective, controlled studies demonstrate the efficacy of alternate-day therapy in membranous nephropathy and renal transplantation. The role of alternate-day therapy in giant cell arteritis is controversial.^98–100

Use of Alternate-Day Therapy

Because alternate-day therapy can prevent or ameliorate the manifestations of Cushing’s syndrome, can avert or permit recovery from HPA suppression, and is as effective (or nearly as effective) as continuous therapy, patients for whom long-term glucocorticoid administration is indicated should receive such therapy whenever possible. Many efforts fail because of lack of familiarity with the indications for, and use of, such therapy.

The benefits of alternate-day glucocorticoid therapy are demonstrable only when corticosteroids are used for a prolonged period. No need exists to use an alternate-day schedule when the anticipated duration of therapy is a few weeks or less.

Alternate-day glucocorticoid therapy may not be necessary or appropriate during the initial stages of therapy or during exacerbation of the underlying disease. Conversely, patients with many chronic disorders have been treated with an alternate-day regimen as initial therapy with apparent benefit.1,2 In patients with rheumatoid arthritis, it may be easier to establish treatment with alternate-day corticosteroids than to convert from daily therapy. Physicians treating recipients of renal transplants initially use daily therapy and then convert to an alternate-day schedule.

Alternate-day therapy may be hazardous in the presence of adrenocortical insufficiency of any cause because patients are not protected against glucocorticoid insufficiency during the last 12 hours of the 48-hour cycle. In patients who have been taking glucocorticoids for more than a brief period, or in those who may have adrenal insufficiency on another basis, the adequacy of HPA function should be determined before the initiation of an alternate-day program. It may be possible to address this issue by giving a small dose of a short-acting glucocorticoid (i.e., 10 mg of hydrocortisone) during the afternoon of the second day; this approach has not been studied systematically.

Alternate-day glucocorticoid therapy may fail to prevent or ameliorate the manifestations of Cushing’s syndrome or HPA suppression if a short-acting glucocorticoid is not used, or if it is used incorrectly. For example, the use of prednisone four times a day on alternate days may be less successful than the use of the same total dose once every 48 hours.

An abrupt alteration from daily to alternate-day therapy should be avoided. First, the prolonged use of glucocorticoids in divided daily doses may have caused HPA suppression. In addition, patients with normal HPA function may experience withdrawal symptoms and have an exacerbation of the underlying disease.

No schedule of conversion from daily therapy in divided doses to alternate-day therapy has been shown to be optimal. One approach is to reduce the frequency of drug administration until the total dose for each day is given in the morning, and then to increase the dose gradually on the first day of each 2-day period and to decrease the dose on the second day. Another approach is to double the dose on the first day of each 2-day cycle, to give this as a single morning dose if possible, and then to taper the dose gradually on the second day.¹⁰¹ It is not clear how often changes in dosage should be made with any approach. This depends on many variables, including the disease under treatment, the duration of previous glucocorticoid therapy, the personality of the patient, and the physician’s ability to use adjunctive therapy. Nonetheless, the conversion should be made as quickly as the patient can tolerate it. If adrenal insufficiency, the glucocorticoid withdrawal syndrome, or an exacerbation of the underlying disease develops, the previously effective regimen should be reinstituted and then tapered more gradually. Occasionally it is necessary to resume full daily doses temporarily.

Optimal results from alternate-day glucocorticoid therapy may not be achieved because of failure to use supplemental (steroid-sparing) therapy for the underlying disorder. Conservative (non-glucocorticoid) therapy often is used until a glucocorticoid is initiated, at which time these less toxic therapeutic measures are ignored. Adjunctive therapeutic measures may facilitate the use of the lowest possible glucocorticoid dose. With alternate-day therapy, these measures should be used especially during the end of the second day when symptoms may be prominent. Supplemental therapy may be especially helpful in disorders in which patients are likely to experience symptoms of the disease on the day off therapy, such as asthma and rheumatoid arthritis. In illnesses in which disabling symptoms are less likely to appear on the alternate day, such as the childhood nephrotic syndrome, less difficulty may be encountered.

Alternate-day therapy may be unsuccessful because of failure to inform patients about the purposes of this regimen. Because glucocorticoids may induce euphoria, patients may be reluctant to accept modification of a schedule of frequent doses. A careful explanation about the risks of glucocorticoid excess, attuned to each patient’s intellectual and emotional ability to comprehend, enhances the prospects of success.

Antiinflammatory or Immunosuppressive Therapy

The glucocorticoid dose required for antiinflammatory or immunosuppressive therapy is variable and depends on the disease under treatment. In general, the dose ranges from just above that needed for long-term replacement therapy up to 60 to 80 mg of prednisone or its equivalent daily. Although much larger dosages sometimes are recommended for diseases such as asthma, systemic lupus erythematosus, and cerebral edema, controlled studies have not shown the need for such large quantities. The role of massive doses of corticosteroids in asthma is controversial.105,106 Most studies report no advantage of high-dose therapy (e.g., >60 to 80 mg of prednisone per day). Many physicians use intravenous pulse therapy (e.g., 1 g/day of methylprednisolone intravenously for 3 consecutive days) for severe manifestations of systemic lupus erythematosus, rapidly progressive glomerulonephritis, or other entities. No controlled studies compared pulse therapy with a dose of 60 to 80 mg/day of prednisone, so the superiority of pulse therapy has not been demonstrated.^107,108

When alternate-day therapy is used, the dose is variable and depends on the disease under treatment. It may range from just above that needed for long-term replacement therapy to 150 mg of prednisone every other day.

Perioperative Management

Traditional doses of glucocorticoids recommended for perioperative coverage in glucocorticoid-treated patients (for example, hydrocortisone, 100 mg intravenously every 8 hours, or methylprednisolone, 20 mg intravenously every 8 hours on the day of surgery, with a gradual taper over the ensuing days) are arbitrary and have no empirical basis.⁸⁰ A study in cynomolgus monkeys explored the doses required to prevent postoperative hypotension.¹⁰⁹ Bilateral adrenalectomies were performed, and replacement glucocorticoid (hydrocortisone) and mineralocorticoid doses were given for 4 months. The animals were then divided into three groups, given normal, one-tenth normal, or 10 times the normal replacement doses of glucocorticoid (hydrocortisone) for 4 days before surgery (a cholecystectomy) while the mineralocorticoid replacement continued. The animals that received the one-tenth normal replacement dose had an increased mortality rate, decreased peripheral vascular resistance, and hypotension. The group that received a normal replacement dose of steroids had no more hypotension or postoperative complications than did the group receiving 10 times the replacement dose. A double-blind study in patients yielded similar results.¹¹⁰ The investigators studied patients who had taken at least 7.5 mg of prednisone per day for several months and had an abnormal response to an ACTH test. All patients received their usual daily dose of prednisone on the day of surgery. One group of 12 patients received perioperative injections of saline. The other group of six patients received hydrocortisone in saline. No significant difference in outcome appeared between the groups in this small study. It appears that patients with adrenal suppression due to glucocorticoid therapy do not experience hypotension or tachycardia when given only their usual daily dose of steroids for surgical procedures such as joint replacements and abdominal operations.

Based on an analysis of the literature, an interdisciplinary group suggests the use of variable doses, depending on the magnitude of the surgical stress.⁸⁰ For minor surgical stress (e.g., an inguinal herniorrhaphy), the glucocorticoid target dose is 25 mg of hydrocortisone or equivalent. For moderate surgical stress (e.g., a lower-extremity revascularization or total joint replacement), the target is 50 to 75 mg of hydrocortisone or equivalent. This might constitute continuation of the patient’s usual dose of prednisone, such as 10 mg/day, and 50 mg of hydrocortisone intravenously intraoperatively. For major surgical stress (e.g., esophagogastrectomy or cardiopulmonary bypass), the patient might receive his or her usual steroid dose (for example, prednisone, 40 mg) and 50 mg of hydrocortisone intravenously every 8 hours after the initial dose for the first 48 to 72 hours.

Glucocorticoid therapy should not be tapered inadvertently to a dosage below that known to control the underlying disease.

Other Considerations

The glucocorticoid dose may have to be modified in patients with certain diseases, in the setting of hypoalbuminemia, in elderly patients, and in patients receiving certain other medications. These considerations are addressed elsewhere in this chapter.

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