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Pharmacologic use of glucocorticoids

Pharmacologic use of glucocorticoids
Author:
Lynnette K Nieman, MD
Section Editor:
André Lacroix, MD
Deputy Editor:
Kathryn A Martin, MD
Literature review current through: Oct 2022. | This topic last updated: May 04, 2022.

INTRODUCTION — Natural and synthetic glucocorticoids are used in both endocrine and nonendocrine disorders.

In endocrine practice, glucocorticoids are given only to establish the diagnosis and cause of Cushing's syndrome and for treatment of adrenal insufficiency using physiologic replacement doses and for treatment of congenital adrenal hyperplasia, for which the dose and schedule may not by physiologic.

Pharmacologic (usually supraphysiologic) doses of glucocorticoids are used to treat patients with inflammatory, allergic, and immunological disorders [1]. If chronic, this supraphysiologic therapy has many adverse effects, ranging from suppression of the hypothalamic-pituitary-adrenal (HPA) axis and Cushing's syndrome to infections and changes in mental status. (See "Major side effects of systemic glucocorticoids".)

A number of factors that influence both the therapeutic and adverse effects of glucocorticoids will be reviewed here, including the biologic potency, pharmacokinetic properties of the glucocorticoid, daily dose, timing of doses during the day, individual differences in steroid metabolism, and the duration of treatment (table 1).

Other issues, including the determinants of steroid dosing and the approach to glucocorticoid withdrawal to prevent adrenal insufficiency and minimize the likelihood of recurrent activity of the underlying disease are discussed separately. (See "Determinants of glucocorticoid dosing" and "Glucocorticoid withdrawal".)

STRUCTURES OF COMMON SYNTHETIC STEROIDS — Chemical modification of natural steroids in the 1950s revealed a number of structural features essential for biological activity. The delta-4,3-keto-11-beta,17-alpha,21-trihydroxyl configuration (figure 1) is required for glucocorticoid activity and is present in all natural and synthetic glucocorticoids [2,3]. The introduction of a double bond between the 1 and 2 positions of hydrocortisone (cortisol) yields prednisolone (delta-1-hydrocortisone), which has approximately four times more glucocorticoid activity than cortisol (figure 2) [4,5].

PHARMACOKINETICS — Most of the cortisol in serum is bound to proteins, primarily corticosteroid-binding globulin (CBG) and albumin. In addition, much of the biologically available cortisol may be bound to erythrocytes [6]. Because they have little or no affinity for CBG [7], synthetic steroids other than prednisolone either bind weakly to albumin (two-thirds) or circulate as free steroid (one-third) [6,8].

Plasma disappearance half-life — The half-lives of synthetic glucocorticoids are generally longer than that of cortisol, which is approximately 80 minutes at concentrations within the binding capacity of CBG (ie, less than approximately 25 mcg/dL [690 nmol/L]) [9,10]. This topic is reviewed in detail separately. (See "Determinants of glucocorticoid dosing" and "Glucocorticoid withdrawal".)

Activation and inactivation in target cells — The 11-beta-hydroxysteroid dehydrogenase type 1 isoenzyme, which converts inactive cortisone to cortisol, is expressed in many glucocorticoid target tissues. The type 2 isoenzyme, which converts cortisol to cortisone, is found mainly in mineralocorticoid target tissues (kidney, colon, salivary glands) and in the placenta, in which it protects the cell from cortisol activation of the corticosteroid type 1 (mineralocorticoid) receptor. Glucocorticoids that are fluorinated at the 6-alpha or 9-alpha position (dexamethasone, fludrocortisone, betamethasone) or methylated at the 6-alpha position (methylprednisolone), or methyloxazoline at position 16,17 (deflazacort), are protected from oxidation inactivation by the type 2 isoenzyme [11]. Prednisone is more effectively oxidized by 11 beta-hydroxysteroid dehydrogenase type 2 than is cortisol, which may explain why prednisone has less salt-retaining activity than cortisol.

Many glucocorticoids are both substrates for P-glycoprotein mediated efflux from cells, and inducers of P-glycoprotein production. Polymorphisms of the MDR-1 gene may influence the therapeutic response to steroids [12].

Polymorphisms in the glucocorticoid receptor gene may increase or decrease sensitivity to glucocorticoids and, thus, affect the response to both endogenous cortisol and exogenous agents [13,14].

Metabolism — Exogenous glucocorticoids are subject to the same hepatic reduction, oxidation, hydroxylation, and conjugation reactions as endogenous steroids. Certain drugs (eg, phenobarbital, phenytoin, rifampin, mitotane) increase the metabolism of synthetic and natural glucocorticoids similarly, particularly by increasing hepatic 6-beta-hydroxylase activity of CYP3A4 [15-19]. (See "Determinants of glucocorticoid dosing", section on 'Drug interactions'.)

Assays of biologic activity — The potencies of synthetic glucocorticoids have been assessed in bioassays that do not account for their variable absorption and metabolism. The results of several studies from a number of sources are summarized in the table, which also shows the ability of the glucocorticoid to inhibit sodium excretion in adrenalectomized rats (an index of mineralocorticoid activity) and the ability of the agents to bind to the cytosolic glucocorticoid receptor (table 1) [20-24]. (See "Determinants of glucocorticoid dosing", section on 'Bioequivalence and bioavailability'.)

Like cortisone, which must be converted to cortisol by hepatic 11-beta-hydroxysteroid dehydrogenase, prednisone must be converted to prednisolone to exert any glucocorticoid action [25].

CRITERIA FOR INITIATING THERAPY

Medical emergencies — High doses of glucocorticoids can be administered for a few days with little risk. It may, therefore, be warranted to use them in emergency situations in which therapeutic benefit has not been demonstrated but might be anticipated, but they should not be given for more than a few days for these conditions. Their use must never replace or delay more specific primary therapies, such as antibiotics in septic shock or epinephrine and antihistamines in anaphylaxis.

Chronic therapy — In less urgent circumstances, more careful consideration must be given to the evidence for glucocorticoid efficacy; the particular preparation to be used; its dose, frequency, and route of administration; and the disease indexes to be monitored to assess therapeutic efficacy. Glucocorticoids cannot be given chronically without the risk of adverse effects. As an example, prednisone doses as low as 5 mg/day can lead to bone loss. (See "Clinical features and evaluation of glucocorticoid-induced osteoporosis".)

The criteria one should apply before initiating chronic glucocorticoid therapy are listed in the table (table 2). Use of objective criteria of response deserves special emphasis. In addition to the potential placebo effects of any therapy, glucocorticoids tend to make almost everyone feel better acutely. Therefore, subjective improvement is not a useful criterion of response. Rather, air flow in asthma, serum aminotransferase concentrations in autoimmune hepatitis, and similar quantifiable end points in other diseases should be used to determine if glucocorticoids are achieving their desired effect.

ROUTE OF ADMINISTRATION — Dose and route of administration depend on the disorder being treated.

Parenteral therapy — Parenteral administration of high doses may be warranted in emergencies, such as septic shock and severe acute asthma. Intravenous ("pulse") bolus doses of 1 to 2 g of methylprednisolone have been used to treat transplant rejection and some autoimmune diseases such as rheumatoid arthritis (see "Use of glucocorticoids in the treatment of rheumatoid arthritis", section on 'Pulse glucocorticoids' and "Kidney transplantation in adults: Treatment of acute T cell-mediated (cellular) rejection", section on 'Banff grade I rejection'). The mechanism of action of such massive doses remains to be established. Pulse glucocorticoid administration may impair cytokine generation [26]. (See "Glucocorticoid effects on the immune system".)

Another possible mechanism is a direct effect upon cell membranes. In extremely high doses, glucocorticoids dissolve in cell membranes, thereby altering their physicochemical properties and the activities of membrane-associated proteins [27], which may explain why only high doses are effective in treating acute exacerbations of immunologically mediated diseases.

Oral administration — Oral preparations are usually used for chronic therapy. They are absorbed within approximately 30 minutes [28].

Nonsystemic administration — When possible, nonsystemic glucocorticoid therapy should be used in an attempt to deliver higher local concentrations while minimizing systemic exposure. Intraarticular injection for joint inflammation, inhalation therapy for asthma, and topical application for inflammatory skin disorders are examples.

Injected glucocorticoids vary considerably in the rate of their absorption. Hydrocortisone salts are absorbed from an intramuscular injection site within minutes, and less soluble esters are absorbed within one hour. Cortisone acetate is more slowly absorbed, and triamcinolone salts and esters are absorbed even more slowly. Absorption from intraarticular sites can be highly variable. (See "Intraarticular and soft tissue injections: What agent(s) to inject and how frequently?".)

All topical and inhaled glucocorticoids result in some, though variable, systemic absorption and, therefore, have the potential for causing hypothalamic-pituitary-adrenal (HPA) axis suppression and Cushing's syndrome [29-31] (see "Major side effects of inhaled glucocorticoids"). In particular, inhaled fluticasone propionate appears to have greater systemic absorption and a greater association with adrenal suppression [31].

The degree of absorption of topically administered glucocorticoids varies depending on (see "Topical corticosteroids: Use and adverse effects"):

The area of the body on which it is applied (eg, intertriginous areas > forehead > scalp > face > forearm) [32]

Whether the vehicle contains urea, dimethylsulfoxide, or other agents (eg, salicylic acid) that increase absorption

Whether the area is covered with an occlusive dressing, which may increase absorption as much as 10-fold [33]

The skin integrity; glucocorticoids are absorbed through areas of inflammation and desquamation better than normal skin

The patient's age; infants and young children, whose stratum corneum is much thinner than that of adults, absorb topical steroids more readily [34]

DOSE — Apart from the treatment of adrenal insufficiency, glucocorticoid therapy usually involves giving supraphysiologic doses. In some diseases, such as mild rheumatoid arthritis, chronic control may be achieved with doses equivalent to or even less than normal daily adrenal production [35,36].

The glucocorticoid most often used is prednisone, which has a relatively short half-life in plasma; the rate of clearance may determine the risk of side effects (figure 3). This phenomenon has not been studied carefully, but presumably prednisone, usually given as a single dose early in the morning, does not suppress the circadian peak in cortisol secretion the next morning. Thus, the patient is exposed to the sum of the exogenous prednisone plus his own normal or near-normal cortisol production. The dose equivalents of other oral glucocorticoids are shown in the table (table 1). (See "Major side effects of systemic glucocorticoids".)

Alternate-day administration — Alternate-day regimens were devised in an attempt to alleviate the undesirable side effects of chronic, high-dose, daily glucocorticoid therapy [37,38]. Approximately twice the usual daily dose is given on alternate days, the rationale being that the patient is not exposed to high glucocorticoid concentrations every day and therefore has less chance of developing Cushing's syndrome or pituitary suppression. Unfortunately, alternate-day therapy is unsuccessful in virtually all adult patients who require high doses of glucocorticoids. (See "Major side effects of systemic glucocorticoids", section on 'General treatment considerations and monitoring'.)

COMPLICATIONS OF CHRONIC USE — The goal of glucocorticoid therapy, as with any therapy, is to obtain maximum benefit with minimum adverse side effects. Potent synthetic glucocorticoids (eg, prednisone, methylprednisolone, triamcinolone, dexamethasone, and betamethasone) have little mineralocorticoid, androgenic, or estrogenic activity. As a result, the major systemic side effects are those of suppression of hypothalamic-pituitary-adrenal (HPA) function and Cushing's syndrome. (See 'Cushing's syndrome (iatrogenic)' below.)

HPA axis suppression — Both endogenous and exogenous glucocorticoids exert negative feedback control on the hypothalamic-pituitary-adrenal (HPA) axis by suppressing hypothalamic corticotropin-releasing hormone (CRH) production and pituitary corticotropin (ACTH) secretion [39]. This leads to adrenal atrophy and loss of cortisol secretory capability.

The time required to achieve suppression depends upon the dose and varies among patients, probably because of differences in their rates of glucocorticoid metabolism (figure 3). Patients can be categorized as being not suppressed, suppressed, or "uncertain suppression" based upon their history of glucocorticoid use (dose and duration). This issue is reviewed in detail separately. (See "The management of the surgical patient taking glucocorticoids", section on 'Approach based upon HPA axis suppression'.)

Cushing's syndrome (iatrogenic) — As with HPA axis suppression, development of Cushing's syndrome depends upon the dose, timing, and duration of glucocorticoid administration and varies among patients. (See "Major side effects of systemic glucocorticoids" and "Causes of secondary and tertiary adrenal insufficiency in adults", section on 'Chronic high-dose glucocorticoid therapy' and "Glucocorticoid withdrawal", section on 'Estimation of HPA suppression'.)

MINIMIZING GLUCOCORTICOID SIDE EFFECTS — In addition to minimizing the exposure to glucocorticoids, certain measures may ameliorate their undesirable side effects.

Exercise programs may reduce the risk of myopathy and osteoporosis.

Exercise, calcium, vitamin D, bisphosphonates and, in postmenopausal women, estrogen therapy, may minimize glucocorticoid-induced lumbar vertebral bone mineral loss, but none of these treatments appear to prevent loss from the femoral neck or distal radius. (See "Prevention and treatment of glucocorticoid-induced osteoporosis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Oral steroid medicines (The Basics)")

SUMMARY — Factors that influence both the therapeutic and adverse effects of glucocorticoids include the biologic potency, pharmacokinetic properties of the glucocorticoid, daily dose, timing of doses during the day, individual differences in steroid metabolism, and the duration of treatment. (See 'Pharmacokinetics' above.)

Acutely, high doses of glucocorticoids can be given parenterally for a few days without causing adverse effects. (See 'Parenteral therapy' above.)

For chronic therapy, glucocorticoids should be chosen only if there is good evidence that they are effective and optimal treatment. (See 'Criteria for initiating therapy' above.)

Treatment efficacy should be monitored with quantitative measurements rather than subjective well-being.

The smallest effective dose for the least amount of time is the goal.

When possible, nonsystemic glucocorticoid therapy should be used to minimize adverse effects of systemic exposure. (See 'Nonsystemic administration' above.)

All nonsystemic steroids have some systemic absorption.

Topical steroid absorption depends on the area of the body on which it is applied, the type of the vehicle, use of an occlusive dressing, skin integrity, and the patient's age.

Complications of glucocorticoid therapy include suppression of hypothalamic-pituitary-adrenal (HPA) function and iatrogenic Cushing's syndrome. (See 'Complications of chronic use' above.)

The time required to develop these complications depends upon the dose and duration of therapy and varies among patients.

Suppression is unlikely in patients receiving nonparenteral steroids for less than three weeks or alternate-day glucocorticoids at physiologic doses.

Suppression can be assumed in patients receiving more than 20 mg of prednisone a day for more than three weeks and any patient who has clinical Cushing's syndrome.

Certain measures may ameliorate undesirable side effects, including exercise programs to reduce the risk of myopathy and osteoporosis; calcium, vitamin D, bisphosphonates; and, in postmenopausal women, estrogen therapy to minimize lumbar vertebral bone mineral loss. (See 'Minimizing glucocorticoid side effects' above.)

DISCLOSURE — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.

  1. Becker DE. Basic and clinical pharmacology of glucocorticosteroids. Anesth Prog 2013; 60:25.
  2. Dluhy RG, Newmark SR, Lauler DP, Thorn GW. Pharmacology and chemistry of adrenal glucocorticoids. In: Steroid therapy, Azarnoff DL (Ed), WB Saunders, Philadelphia 1975. p.1.
  3. Christy NP. Principles of systemic corticosteroid therapy in nonendocrine disease. In: Current Therapy in Endocrinology and Metabolism, 3rd Ed, Bardin CW (Ed), BC Decker, New York 1988. p.104.
  4. HERZOG HL, NOBILE A, TOLKSDORF S, et al. New antiarthritic steroids. Science 1955; 121:176.
  5. STAFFORD RO, BARNES LE, BOWMAN BJ, MEINZINGER MM. Glucocorticoid and mineralocorticoids activities of delta1-fluorohydrocortisone. Proc Soc Exp Biol Med 1955; 89:371.
  6. Migeon CJ, Lawrence B, Bertrand J, Holman GH. In vivo distribution of some 17-hydroxycorticoids between the plasma and red blood cells of man. J Clin Endocrinol Metab 1959; 19:1411.
  7. Pugeat MM, Dunn JF, Nisula BC. Transport of steroid hormones: interaction of 70 drugs with testosterone-binding globulin and corticosteroid-binding globulin in human plasma. J Clin Endocrinol Metab 1981; 53:69.
  8. Ballard PL. Delivery and transport of glucocorticoids to target cells. In: Glucocorticoid Hormone Action, Baxter JD, Rousseau GG (Eds), Springer-Verlag, Berlin 1979. p.25.
  9. NUGENT CA, EIK-NES K, SAMUELS LT, TYLER FH. Changes in plasma levels of 17-hydroxycorticosteroids during the intravenous administration of adrenocorticotropin (ACTH). IV. Response to prolonged infusions of small amounts of ACTH. J Clin Endocrinol Metab 1959; 19:334.
  10. PETERSON RE. Metabolism of adrenocorticosteroids in man. Ann N Y Acad Sci 1959; 82:846.
  11. Diederich S, Eigendorff E, Burkhardt P, et al. 11beta-hydroxysteroid dehydrogenase types 1 and 2: an important pharmacokinetic determinant for the activity of synthetic mineralo- and glucocorticoids. J Clin Endocrinol Metab 2002; 87:5695.
  12. Youssef DM, Attia TA, El-Shal AS, Abduelometty FA. Multi-drug resistance-1 gene polymorphisms in nephrotic syndrome: impact on susceptibility and response to steroids. Gene 2013; 530:201.
  13. Koetz KR, van Rossum EF, Ventz M, et al. BclI polymorphism of the glucocorticoid receptor gene is associated with increased bone resorption in patients on glucocorticoid replacement therapy. Clin Endocrinol (Oxf) 2013; 78:831.
  14. Giordano R, Marzotti S, Berardelli R, et al. BClI polymorphism of the glucocorticoid receptor gene is associated with increased obesity, impaired glucose metabolism and dyslipidaemia in patients with Addison's disease. Clin Endocrinol (Oxf) 2012; 77:863.
  15. BURSTEIN S, KLAIBER EL. PHENOBARBITAL-INDUCED INCREASE IN 6-BETA-HYDROXYCORTISOL EXCRETION: CLUE TO ITS SIGNIFICANCE IN HUMAN URINE. J Clin Endocrinol Metab 1965; 25:293.
  16. WERK EE Jr, MACGEE J, SHOLITON LJ. EFFECT OF DIPHENYLHYDANTOIN ON CORTISOL METABOLISM IN MAN. J Clin Invest 1964; 43:1824.
  17. Yamada S, Iwai K. Letter: Induction of hepatic cortisol-6-hydroxylase by rifampicin. Lancet 1976; 2:366.
  18. BLEDSOE T, ISLAND DP, NEY RL, LIDDLE GW. AN EFFECT OF O,P'-DDD ON THE EXTRA-ADRENAL METABOLISM OF CORTISOL IN MAN. J Clin Endocrinol Metab 1964; 24:1303.
  19. Guengerich FP. Cytochrome P-450 3A4: regulation and role in drug metabolism. Annu Rev Pharmacol Toxicol 1999; 39:1.
  20. Meikle AW, Tyler FH. Potency and duration of action of glucocorticoids. Effects of hydrocortisone, prednisone and dexamethasone on human pituitary-adrenal function. Am J Med 1977; 63:200.
  21. LIDDLE GW. Studies of structure-function relationships of steroids. II. The 6 alpha-methylcorticosteroids. Metabolism 1958; 7:405.
  22. DULIN WE. Anti-inflammatory activity of delta1-9alpha-fluorohydrocortisone acetate. Proc Soc Exp Biol Med 1955; 90:115.
  23. SOFFER LJ, ORR RH. Symposium: newer hydrocortisone analogs. Metabolism 1958; 7:383.
  24. DULIN WE, BARNES LE, GLENN EM, et al. Biologic activities of some C21 steroids and some 6 alpha-methyl C21 steroids. Metabolism 1958; 7:398.
  25. Meikle AW, Weed JA, Tyler FH. Kinetics and interconversion of prednisolone and prednisone studied with new radioimmunogassays. J Clin Endocrinol Metab 1975; 41:717.
  26. Yokoyama H, Takabatake T, Takaeda M, et al. Up-regulated MHC-class II expression and gamma-IFN and soluble IL-2R in lupus nephritis. Kidney Int 1992; 42:755.
  27. Buttgereit F, Wehling M, Burmester GR. A new hypothesis of modular glucocorticoid actions: steroid treatment of rheumatic diseases revisited. Arthritis Rheum 1998; 41:761.
  28. Kehlet H, Binder C, Blichert-Toft M. Glucocorticoid maintenance therapy following adrenalectomy: assessment of dosage and preparation. Clin Endocrinol (Oxf) 1976; 5:37.
  29. Walsh P, Aeling JL, Huff L, Weston WL. Hypothalamus-pituitary-adrenal axis suppression by superpotent topical steroids. J Am Acad Dermatol 1993; 29:501.
  30. Keipert JA, Kelly R. Temporary Cushing's syndrome from percutaneous absorption of betamethasone 17-valerate. Med J Aust 1971; 1:542.
  31. Ng PC, Fok TF, Wong GW, et al. Pituitary-adrenal suppression in preterm, very low birth weight infants after inhaled fluticasone propionate treatment. J Clin Endocrinol Metab 1998; 83:2390.
  32. Fisher DA. Adverse effects of topical corticosteroid use. West J Med 1995; 162:123.
  33. FELDMANN RJ, MAIBACH HI. PENETRATION OF 14C HYDROCORTISONE THROUGH NORMAL SKIN: THE EFFECT OF STRIPPING AND OCCLUSION. Arch Dermatol 1965; 91:661.
  34. Feiwel M, James VH, Barnett ES. Effect of potent topical steroids on plasma-cortisol levels of infants and children with eczema. Lancet 1969; 1:485.
  35. Garber EK, Fan PT, Bluestone R. Realistic guidelines in corticosteroid therapy of rheumatic disease. Semin Arthritis Rheum 1981; 11:231.
  36. Laan RF, van Riel PL, van de Putte LB, et al. Low-dose prednisone induces rapid reversible axial bone loss in patients with rheumatoid arthritis. A randomized, controlled study. Ann Intern Med 1993; 119:963.
  37. HARTER JG, REDDY WJ, THORN GW. STUDIES ON AN INTERMITTENT CORTICOSTEROID DOSAGE REGIMEN. N Engl J Med 1963; 269:591.
  38. Fauci AS. Alternate-day corticosteroid therapy. Am J Med 1978; 64:729.
  39. Sagar R, Mackie S, W Morgan A, et al. Evaluating tertiary adrenal insufficiency in rheumatology patients on long-term systemic glucocorticoid treatment. Clin Endocrinol (Oxf) 2021; 94:361.
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