Overview of the pharmacologic use of glucocorticoids

INTRODUCTION — Natural and synthetic glucocorticoids (also called steroids) can be used for a variety of disorders. These agents are most commonly given in pharmacologic doses to manage conditions that require the suppression of inflammation. Less often, they are used to establish the diagnosis and cause of Cushing syndrome and for hormone replacement in adrenal insufficiency and congenital adrenal hyperplasia.

This article will review key points in the pharmacology of glucocorticoids and factors involved in choosing a glucocorticoid regimen. Other aspects of glucocorticoid use are discussed separately:

●Use of topical corticosteroids (see "Topical corticosteroids: Use and adverse effects")

●Effects of glucocorticoids on the immune system (see "Glucocorticoid effects on the immune system")

●Glucocorticoid withdrawal (see "Glucocorticoid withdrawal")

●Perioperative management for patients taking glucocorticoids (see "The management of the surgical patient taking glucocorticoids")

●Glucocorticoid use in pregnancy and lactation (see "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Glucocorticoids')

●Adverse effects (see "Glucocorticoid effects on the immune system" and "Major adverse effects of systemic glucocorticoids" and "Major side effects of inhaled glucocorticoids" and "Joint aspiration or injection in adults: Complications", section on 'Glucocorticoid-associated toxicity')

GENERAL PRINCIPLES OF USE AND INDICATIONS — Glucocorticoids are widely available, quick acting, and often well tolerated when used for short periods at low doses. However, their wide range of adverse effects and cumulative toxicity highlight the importance of reserving their use for specific scenarios.

General principles of use — In general, we use the following guidelines for pharmacological glucocorticoid therapy:

●Only use glucocorticoids for symptoms or diagnoses for which there is published evidence of an objective therapeutic benefit. (See 'Indications for pharmacologic glucocorticoids' below.)

●Only use glucocorticoids when more specific therapies are insufficient, ineffective, or contraindicated. (See 'Indications for pharmacologic glucocorticoids' below.)

●Choose a glucocorticoid preparation, route, and dose that will maximize benefit and minimize risk for the patient. (See 'Choosing a glucocorticoid regimen' below.)

●Monitor response to glucocorticoids with objective criteria related to a specific therapeutic goal.

●Give glucocorticoids for a sufficient duration to achieve the desired response, but no longer than necessary.

●Stop glucocorticoids when maximum benefit has been achieved, if complications arise, or if the objective therapeutic goal is not observed when expected.

●Monitor for adverse effects related to glucocorticoids. (See 'Adverse effects' below and "Major adverse effects of systemic glucocorticoids", section on 'Monitoring and treatment of adverse effects'.)

Natural patterns of endogenous cortisol — It is important to understand baseline levels and rhythms of endogenous glucocorticoids like cortisol to anticipate the effects of adding exogenous glucocorticoids. Cortisone is normally produced in the adrenal glands and must be converted to the active form, cortisol. The biosynthesis of endogenous glucocorticoids is described in detail elsewhere. (See "Adrenal steroid biosynthesis".)

Healthy patients produce a daily amount of cortisol that is equal to approximately 7 to 10 mg per day [1] and can, rarely, increase this up to 400 mg when subjected to significant physiologic stress [2,3]. This is why patients taking pharmacologic doses of glucocorticoids that are less than this physiologic amount (eg, less than prednisone 5 mg per day) are at slightly lower risk for developing adrenal insufficiency. Similarly, it is why patients who have adrenal insufficiency may require temporarily higher doses of pharmacologic glucocorticoids when they experience stress physiology.

Cortisol levels vary during the day, peaking in the early morning around 6:00 to 9:00 AM and reaching a nadir in the evening between 8:00 PM and 2:00 AM [4]. This is one reason for administering pharmacologic glucocorticoid doses in the morning to better mimic the natural circadian rhythm.

Indications for pharmacologic glucocorticoids — There are numerous indications for different types of glucocorticoid therapy. We reserve glucocorticoid use for symptoms or diagnoses for which there is published evidence of an objective therapeutic benefit and only when more specific therapies are insufficient, ineffective, or contraindicated. While the following list is not comprehensive, some examples include:

●Inflammatory, allergic, and immunological disorders – Pharmacologic (usually supraphysiologic) doses of glucocorticoids are used to treat patients with inflammatory, allergic, and immunological disorders [5]. Often glucocorticoid courses are short, but occasionally patients will require therapy for years. Examples of conditions where glucocorticoids may be used include oral preparations in polymyalgia rheumatica, inhaled preparations in asthma, and topical preparations in atopic dermatitis (eczema). Glucocorticoids can also be used to achieve intentional immunosuppression in patients receiving organ transplantation. (See "Treatment of polymyalgia rheumatica", section on 'Systemic glucocorticoids' and "An overview of asthma management in children and adults", section on 'Initiating pharmacologic treatment' and "Treatment of atopic dermatitis (eczema)", section on 'Topical corticosteroids'.)

●Endocrine disorders – In endocrine practice, glucocorticoids are given to establish the diagnosis and cause of Cushing syndrome. They are also used for treatment of adrenal insufficiency using physiologic replacement doses and for treatment of congenital adrenal hyperplasia. (See "Establishing the diagnosis of Cushing syndrome", section on 'Low-dose dexamethasone suppression tests' and "Treatment of adrenal insufficiency in adults", section on 'Glucocorticoid replacement for all patients' and "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults", section on 'Glucocorticoid therapy for all patients'.)

●Medical emergencies – High doses of glucocorticoids may be warranted in emergency situations in which therapeutic benefit has not been clearly demonstrated but might be anticipated, such as anaphylaxis, septic shock, or macrophage activation syndrome.

PHARMACOLOGY

Mechanisms of action — Glucocorticoids primarily exert effects via up- or downregulation of gene transcription, but other mechanisms have also been proposed [4]. Mechanisms include:

●Interaction with glucocorticoid receptors – Glucocorticoids passively diffuse through the cell membrane and bind to cytoplasmic glucocorticoid receptors [4]. The glucocorticoid receptor-glucocorticoid complex ultimately influences the activation and repression of gene transcription in a complex process that may involve a variety of factors including coactivators, corepressors, and receptor phosphorylation. Glucocorticoid response elements (GREs) are contained in gene promotors and interact with glucocorticoid receptor homodimers to promote gene transcription.

●Interaction with proinflammatory transcription factors – Glucocorticoids and glucocorticoid receptors directly interact with proinflammatory transcription factors, specifically nuclear factor kB and activator protein 1, and therefore reduce transcription of proinflammatory genes [4].

●Other mechanisms – Data supporting other mechanisms than those described above are limited. However, it is theorized that alternative mechanisms may be responsible for the effect of pulse dose glucocorticoids, since glucocorticoid receptors are estimated to be saturated after a dose equivalent to prednisolone 100 to 200 mg [6]. Potential mechanisms may include downstream effects of interaction with glucocorticoid or non-glucocorticoid receptors independent of gene transcription, as well as interaction with cell and lysosomal membranes [7-9].

Polymorphisms in the glucocorticoid receptor gene may increase or decrease sensitivity to glucocorticoids and, therefore, affect the response to both endogenous cortisol and exogenous agents [10,11]. Likewise, polymorphisms of the multidrug-resistant transporter 1 gene may influence the therapeutic response to steroids [12].

The downstream effects of glucocorticoids on the immune system are described elsewhere. (See "Glucocorticoid effects on the immune system".)

Bioequivalence and bioactivity — Different preparations of oral glucocorticoids have the same rate of absorption and are roughly bioequivalent (ie, the active moieties are equally absorbed and the same amount of each gets to the site of action). However, some glucocorticoids (eg, prednisone, prednisolone, dexamethasone) may differ in their potency and kinetics or have slight variations in their mechanisms of action. As an example, the systemic bioavailability of prednisone and dexamethasone are equal, but their potencies, relative antiinflammatory activity, and duration of action are different (table 1) [13,14].

Bioavailability of synthetic glucocorticoids varies by route of administration and drug formulation:

●Oral glucocorticoids – The bioavailability of various forms of oral glucocorticoids is between 60 and 100 percent [4]. Incomplete bioavailability of oral glucocorticoids has occasionally been noted in certain patients. As an example, in one study, 20 percent of patients given methylprednisolone showed poor bioavailability (23 to 65 percent) compared with only 1 of 12 patients given prednisone [15].

●Inhaled glucocorticoids – The bioavailability of inhaled glucocorticoids varies with the physical properties of the particular agent. Eighty percent of inhaled glucocorticoids are swallowed, with the remainder deposited in the lungs. Correct use of a spacer with inhaler devices may improve drug delivery. (See "The use of inhaler devices in adults" and "The use of inhaler devices in children".)

The absorption of inhaled glucocorticoids also varies with the specific agents. Drugs that are highly lipophilic (such as fluticasone and beclomethasone) are relatively poorly absorbed orally (less than 11 percent) and are retained longer in lung tissue when deposited there. By comparison, agents which are not lipophilic (such as budesonide) are somewhat better absorbed orally (less than 20 percent). Since all of the drug deposited in the lung eventually enters the systemic circulation, overall absorption of inhaled glucocorticoids varies between 20 and 40 percent of the administered dose [16].

Many synthetic glucocorticoids bind to transcortin (also called corticosteroid-binding globulin) and/or albumin and are not able to interact with glucocorticoid receptors when they are bound [4]. Consequently, patients with lower albumin levels may see higher concentrations of free glucocorticoid and more adverse effects [17]. Synthetic glucocorticoids do not bind as well to transcortin. When comparing the relative affinity for binding transcortin between glucocorticoids, prednisolone has approximately 60 percent, prednisone has 5 percent, and methylprednisolone, dexamethasone, betamethasone, and triamcinolone have less than 1 percent affinity compared with cortisol.

Metabolism — There are two key enzymes involved in activating or inactivating glucocorticoids in target cells:

●The 11-beta-hydroxysteroid dehydrogenase type 1 isoenzyme converts inactive cortisone to active cortisol. Many glucocorticoid target tissues express this isoenzyme.

●The 11 beta-hydroxysteroid dehydrogenase type 2 isoenzyme converts active cortisol to inactive cortisone. It is found mainly in mineralocorticoid target tissues (kidney, colon, salivary glands) and in the placenta, where it protects the cell from cortisol activating the corticosteroid type 1 (mineralocorticoid) receptor. Several glucocorticoid preparations are protected from oxidation inactivation by the type 2 isoenzyme and therefore have greater mineralocorticoid effects, including glucocorticoids that are fluorinated at the 6-alpha or 9-alpha position (dexamethasone, fludrocortisone, betamethasone), methylated at the 6-alpha position (methylprednisolone), or methyloxazoline at position 16,17 (deflazacort) [18]. High amounts of cortisol can also saturate the isoenzyme and lead to increased mineralocorticoid receptor activation. By contrast, 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.

Glucocorticoids are ultimately converted to hydrophilic inactive metabolites and renally excreted. 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 cytochrome P450 3A4 (CYP3A4) [19-23]. (See 'Drug interactions' below.)

Clearance — The clearance of prednisolone is 210 mL/min per 1.73 m², with an elimination half-life of approximately three hours. Clearance decreases with age; as an example, children less than 12 years of age have a 33 percent higher clearance than older children and adults [15].

Glucocorticoids exhibit dose-dependent kinetics. Total prednisolone clearance increases by 75 percent as the intravenous dose increases from 5 to 40 mg [24,25]. Free prednisolone clearances also change with administered dose, but to a lesser degree and require larger doses to demonstrate such kinetics [26]. The clinical consequence of these properties is that a somewhat greater, nonlinear drug effect is observed at prednisolone doses over 40 mg compared with doses between 10 to 20 mg.

Clearances also vary with the time of day. Both prednisolone and methylprednisolone clearance is lower (18 to 28 percent) in the morning than the evening [27,28]. This property, in combination with the disruption of the usual cortisol diurnal rhythm with exogenous glucocorticoids, may result in variations in efficacy when glucocorticoids are administered at different times during the day [29,30]. In one study, for example, the efficacy of prednisolone was assessed in seven asthmatic patients in whom the drug was given at 8:00 AM and 3:00 PM, and at 3:00 PM and 8:00 PM [31]. The earlier dosing regimen was more effective in improving nocturnal pulmonary function and symptoms. Less physiological exogenous glucocorticoids administration (eg, twice daily) results in greater efficacy but also greater toxicity.

CHOOSING A GLUCOCORTICOID REGIMEN — When using glucocorticoids, providers should choose a preparation, route, and dose that will maximize benefit and minimize risk for the patient. They should also be aware of the need for adjustments in certain diseases and physiologic states, as well as potential drug interactions.

Common glucocorticoid preparations — There are multiple preparations of systemic glucocorticoids that vary in their duration of action and potency. These differences and equivalent doses are summarized in the table (table 1). All preparations share key structural features that are essential for biological activity, including the delta-4,3-keto-11-beta,17-alpha,21-trihydroxyl configuration (figure 1 and figure 2) that is present in all natural and synthetic glucocorticoids [32,33]. Some of the more common glucocorticoid preparations are:

●Hydrocortisone – Hydrocortisone is the synthetic version of cortisol and is an active form of glucocorticoid. It is short acting.

●Prednisolone and prednisone – Prednisolone is the active form of prednisone. Prednisone metabolizes to prednisolone after oral ingestion. Both are intermediate acting and have approximately four times more glucocorticoid activity than cortisol [34,35].

●Methylprednisolone – Methylprednisolone is an active form of synthetic glucocorticoid. It is intermediate acting and has five times more glucocorticoid activity than cortisol.

●Dexamethasone – Dexamethasone is an active form of synthetic glucocorticoid. It is long acting and has approximately 30 times more glucocorticoid activity than cortisol.

Route of administration — Synthetic glucocorticoids may be given in multiple ways, including parenteral, oral, and locally administered (eg, topical, inhaled, intraarticular) routes. Locally targeted administration is preferred when possible to minimize adverse effects.

●Parenteral therapy – Parenteral administration of high doses may be warranted in emergencies, such as septic shock and severe acute asthma. This route may also be preferred when it is critical to ensure adequate delivery (eg, concern for malabsorptive state such as lupus enteritis).

●Oral administration – Oral preparations are typically used for chronic therapy. They are absorbed within approximately 30 minutes [36].

●Local administration – When possible, local glucocorticoid therapy should be used in an attempt to deliver higher local concentrations while minimizing systemic exposure. As examples, providers may use intraarticular injection for joint inflammation, inhalation therapy for asthma, and topical application for inflammatory skin disorders.

All topical and inhaled glucocorticoids result in some, though variable, systemic absorption and therefore have the potential for causing hypothalamic-pituitary-adrenal axis suppression and Cushing syndrome [37-39]. In particular, inhaled fluticasone propionate appears to have greater systemic absorption and a greater association with adrenal suppression [37]. (See "Topical corticosteroids: Use and adverse effects", section on 'Systemic' and "Major side effects of inhaled glucocorticoids", section on 'Systemic adverse effects'.)

Additional considerations for locally administered glucocorticoids include the following:

•Injected glucocorticoids – 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?".)

•Topical glucocorticoids – The degree of absorption of topically administered glucocorticoids varies depending on multiple factors, including the site of application on the body, skin integrity, thickness of the stratum corneum, presence of agents in the glucocorticoid preparations that increase absorption, and using an occlusive dressing over the glucocorticoid. This is reviewed in more detail elsewhere. (See "Topical corticosteroids: Use and adverse effects", section on 'Vehicles and formulations'.)

Different formulations of glucocorticoid preparations are being developed to improve delivery of these drugs (eg, palmitate large porous particles, oral dissolvable film formulations, nanosuspensions in soft contact lenses, multidose dry powder inhalers), which may improve the usefulness of glucocorticoids [40-43].

Glucocorticoid dosing — Occasionally, exogenous glucocorticoids are dosed near or below physiologic levels (typically 10 mg or less of prednisone or its equivalent), such as in patients with adrenal insufficiency or those with polymyalgia rheumatica. More commonly, they are given at supraphysiologic doses. In rare circumstances, they may be given as "pulse" doses (typically 500 to 1000 mg of intravenous methylprednisolone) for severe manifestations of autoimmune diseases, such as systemic lupus erythematosus. (See "Treatment of adrenal insufficiency in adults", section on 'Glucocorticoid replacement for all patients' and "Treatment of polymyalgia rheumatica", section on 'Systemic glucocorticoids' and "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'Escalation of therapy based on disease activity and severity'.)

Glucocorticoid dosing is also sometimes categorized as low to moderate versus high in an attempt to define a threshold above which toxicities become more common with prolonged use. The threshold between low to moderate and high is often defined as up to 1 mg/kg per day of prednisone in children or 40 mg of prednisone per day in adults. However, adverse effects can appear at much lower doses. (See "Glucocorticoid effects on the immune system", section on 'Dose ranges' and "Major adverse effects of systemic glucocorticoids", section on 'Glucocorticoid dose and duration'.)

Patients with primary or iatrogenic adrenal insufficiency may require higher doses of glucocorticoids when under physiologic stress. While the American College of Rheumatology (ACR) does not suggest "stress doses" of glucocorticoids at the time of surgery for joint replacement for patients with rheumatic diseases who are on daily glucocorticoids, other types of surgeries and patient populations have not been addressed [44]. (See "Treatment of adrenal insufficiency in adults", section on 'Circumstances requiring glucocorticoid dose adjustment' and "The management of the surgical patient taking glucocorticoids".)

Glucocorticoid dosing may need to be adjusted to account for potential drug interactions. (See 'Drug interactions' below.)

Impact of selected diseases and physiologic states — The pharmacokinetics of glucocorticoids vary with certain diseases and pathophysiologic conditions.

End-stage kidney disease — Patients with end-stage kidney disease (ESKD) typically do not require dose adjustments for synthetic glucocorticoids, although the pharmacokinetics may be altered. Among patients treated with hemodialysis, the clearance of total prednisolone is dose dependent, while the clearance of unbound prednisolone is constant [45]. Hemodialysis also removes significant amounts of methylprednisolone, thereby resulting in a 32 percent reduction in plasma half-life relative to those without ESKD [46]. The removal rate of unbound cortisol in patients treated with peritoneal dialysis is similar to that in patients without ESKD [46,47].

Nephrotic syndrome — Patients with nephrotic syndrome have low serum concentrations of albumin and cortisol-binding globulin. However, there are no data suggesting the need for dosing changes in these patients. Although their bound and therefore total glucocorticoid concentrations are reduced, the physiologically important unbound (free) serum concentrations of prednisone and prednisolone are similar to nonnephrotic individuals.

Perhaps because of the differences in protein binding, nonrenal clearance is higher and renal clearance is lower in patients with the nephrotic syndrome than in those without nephrotic syndrome [48]. The total prednisolone clearances are higher in nephrotic patients, since the increase in nonrenal clearance is of greater magnitude than the reduction in renal clearance.

Severe liver disease — In the presence of severe liver disease, we commonly use prednisolone rather than prednisone or methylprednisolone for these patients. This is because the activation of prednisone via metabolism to 6-beta-hydroxyl compounds may be impaired, potentially affecting the efficacy of glucocorticoid therapy [49].

Patients who undergo liver transplantation because of hepatic C viral infection should receive the lowest dose of glucocorticoids following transplantation that is feasible. The cumulative glucocorticoid dose is correlated closely with post-transplantation hepatitis C viral load and with mortality rates [50].

Hyperthyroidism — The clearance of prednisolone is increased in hyperthyroidism and may require slightly higher dosing. In one small study, total prednisolone clearance was increased by 58 percent and nonrenal clearance (principally hepatic) was increased by 84 percent [51]. There were also small changes in absorption and binding. These differences did not result in measurable change efficacy, but vigilance is appropriate.

Obesity — Dosing of glucocorticoids in a person with obesity should be based upon the ideal, rather than total, body weight. Obesity can affect the uptake, storage, and metabolism of glucocorticoids, although results are somewhat contradictory.

●In one study, the volume of distribution and clearance of prednisone in a person with obesity weighing more than 133 percent of ideal body weight was 20 to 30 percent higher than in a person without obesity [52].

●Another report indicated that each 1 percent higher baseline body mass index (BMI) was associated with a 2.9 percent decline in wake-up and total area under curve (AUC) cortisol, suggesting that a higher BMI suppresses cortisol [53].

●One report examining the metabolism of methylprednisolone and dexamethasone found that clearance among patients with obesity was decreased by approximately 40 percent when compared with those without obesity [54].

Cystic fibrosis — When using prednisolone in patients with cystic fibrosis, more frequent dosing may be necessary due to total prednisolone clearance increasing by over 50 percent [55].

Pregnancy and lactation — Fluorinated glucocorticoids including betamethasone and dexamethasone are used when an effect on the fetus is desired (eg, to speed fetal lung maturity in when anticipating premature delivery) because these cross the placenta. By contrast, the placenta inactivates prednisolone and prednisone and therefore little active drug reaches the fetus [56]. Glucocorticoids are excreted in small amounts in human milk and adjustment to breastfeeding may be indicated for certain doses. A more detailed discussion of the effects of glucocorticoids in pregnancy and lactation is available elsewhere. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Glucocorticoids'.)

Drug interactions — The major drug interactions with systemic glucocorticoids, a summary of effect(s), and management suggestions are listed in the table (table 2). For additional interactions, see the drug interactions program included with UpToDate.

Medications that strongly inhibit or induce cytochrome P450 3A4 (CYP3A4) and/or P-glycoprotein transporters may significantly alter the glucocorticoid serum concentration [4,57]. Glucocorticoids undergo metabolism in the liver and other tissues by CYP3A4 and other transformations. In vitro data suggest that dexamethasone, methylprednisolone, and prednisolone are also substrates of P-glycoprotein membrane efflux transporters. A list of medications that inhibit or induce CYP3A4 can be found in this table (table 3). Common examples of medications to consider include:

●Medications that increase the systemic glucocorticoid concentration include estrogen derivatives, such as oral contraceptives [58-61], and strong inhibitors of CYP3A4 (table 3) including some antibiotics (eg, clarithromycin, ritonavir, telaprevir) [62-64] and antifungals (eg, posaconazole, voriconazole) [4,65,66].

●Medications that reduce the systemic glucocorticoid concentration include aluminum/magnesium containing antacids, which decrease prednisone bioavailability due to decreased oral absorption [67,68], and strong inducers of CYP3A4 (eg, carbamazepine, phenobarbital, phenytoin and rifampin) (table 3) [69-74].

Intranasal and inhaled glucocorticoids can also be affected by coadministration of drugs that inhibit or induce CYP3A4, which is discussed in detail elsewhere. (See "Major side effects of inhaled glucocorticoids", section on 'Medication interactions' and "Pharmacotherapy of allergic rhinitis", section on 'Glucocorticoid nasal sprays'.)

A number of agents often used with glucocorticoids appear to have no substantial interaction with them. These include azathioprine, methotrexate, histamine antagonists (eg, famotidine, cimetidine, ranitidine), proton pump inhibitors (eg, omeprazole, pantoprazole, rabeprazole), and diazepam [69,75-79].

ADVERSE EFFECTS — There are numerous potential adverse effects from glucocorticoids, which are most notable for patients receiving high doses and/or those with a high cumulative steroid burden over time (table 4). However, adverse effects can happen even at lower doses, underscoring the importance of prescribing glucocorticoids judiciously. Adverse effects and recommended monitoring are described in more detail elsewhere:

●(See "Glucocorticoid effects on the immune system".)

●(See "Major adverse effects of systemic glucocorticoids".)

●(See "Major side effects of inhaled glucocorticoids".)

●(See "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects'.)

●(See "Joint aspiration or injection in adults: Complications", section on 'Glucocorticoid-associated toxicity'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Side effects of anti-inflammatory and anti-rheumatic drugs".)

SUMMARY AND RECOMMENDATIONS

●General principles of use and indications – Glucocorticoids are widely available, quick acting, and often well tolerated when used for short periods at low doses. However, their wide range of adverse effects and cumulative toxicity highlight the importance of reserving their use for specific scenarios. (See 'General principles of use and indications' above.)

●Pharmacology – Glucocorticoids work through various mechanisms, including interaction with glucocorticoid receptors and proinflammatory transcription factors. Various formulations of glucocorticoids may differ in their bioactivity, metabolism, and clearance. (See 'Pharmacology' above.)

●Choosing a glucocorticoid regimen

•Preparations and route of administration – Glucocorticoids are commonly available in multiple preparations (eg, prednisone, prednisolone) and routes of administration (eg, parenteral, oral, and locally administered). Locally targeted administration is preferred when possible to minimize adverse effects. (See 'Common glucocorticoid preparations' above and 'Route of administration' above.)

•Dosing – Occasionally, exogenous glucocorticoids are dosed near or below physiologic levels (typically 10 mg or less of prednisone or its equivalent), such as in patients with adrenal insufficiency or those with polymyalgia rheumatica. More commonly, they are given at supraphysiologic doses. In rare circumstances, they may be given as "pulse" doses (typically 500 to 1000 mg of intravenous methylprednisolone) for severe manifestations of autoimmune diseases (eg, systemic lupus erythematosus). (See 'Glucocorticoid dosing' above.)

•Impact of selected diseases and physiologic states – The pharmacokinetics of glucocorticoids vary with certain diseases and pathophysiologic conditions, such as severe liver disease and hyperthyroidism. Providers may need to adjust the glucocorticoid formulation or dosing depending on the condition. (See 'Impact of selected diseases and physiologic states' above.)

•Drug interactions – The major drug interactions with systemic glucocorticoids, a summary of effect(s), and management suggestions are listed in the table (table 2). This includes medications that strongly inhibit or induce cytochrome P450 3A4 (CYP3A4) and/or P-glycoprotein transporters. (See 'Drug interactions' above.)

●Adverse effects – There are numerous potential adverse effects from glucocorticoids, which are most notable for patients receiving high doses and/or those with a high cumulative steroid burden over time (table 4). However, adverse effects can happen even at lower doses, underscoring the importance of prescribing glucocorticoids judiciously. (See 'Adverse effects' above.)