A Different Look at CorticosteroidsCreate your own flash cards! Supporting users have an ad free experience! Integmediate Library Browse Search Browse. Term prototype glucocorticosteroid agonist. Term prototype mineralocorticosteroid agonist. Term prototype glucocorticoid antagonist. Term prototype mineralocorticoid antagonist.
Systemic corticosteroids play an integral role in the management of many inflammatory and immunologic conditions, but these agents are also associated with serious risks. This comprehensive article reviews these adverse events and provides practical recommendations for their prevention and management based on both current literature and the clinical experience of the authors.
They are used as replacement therapy in adrenal insufficiency at physiologic doses as well as in supraphysiologic doses for the management of various dermatologic, ophthalmologic, rheumatologic, pulmonary, hematologic, and gastrointestinal GI disorders.
In the field of respirology, systemic corticosteroids are used for the treatment of acute exacerbations of chronic obstructive pulmonary disease COPD and severe, uncontrolled asthma, as well as for inflammatory parenchymal lung diseases such as hypersensitivity pneumonitis and immune-mediated vasculitis.
These are just some of the many important uses of this group of medications that are utilized in almost all areas of medicine. Systemic corticosteroid uses are not limited to those listed in this table. These agents can be used in almost all areas of medicine. Despite their beneficial effects, long-term systemic oral or parenteral use of these agents is associated with well-known adverse events AEs including: The objectives of this article are to: Corticosteroids are synthetic analogues of the natural steroid hormones produced by the adrenal cortex.
Mineralocorticoids affect ion transport in the epithelial cells of the renal tubules and are primarily involved in the regulation of electrolyte and water balance. Primary effects of glucocorticoids GCs [ 1 ]. Most of the anti-inflammatory and immunosuppressive actions of GCs are attributable, either directly or indirectly, to their interaction with the cytosolic GC receptor, which alters gene transcription to either induce transactivate or repress transrepress gene transcription in both inflammatory leukocytes and in structural cells, such as epithelium [ 2 - 4 ].
A number of systemic corticosteroid compounds are commercially available in Canada. Properties, dosing equivalents and therapeutic indications of systemic corticosteroids, relative to hydrocortisone. Relative potency for intra-ocular or intramuscular administration may vary considerably. Prednisone is perhaps the most widely used of the systemic corticosteroids. Given its high GC activity relative to mineralocorticoid activity, it is generally used as an anti-inflammatory and immunosuppressive agent.
Although similar to prednisone and prednisolone, methylprednisolone has even less mineralocorticoid activity and, therefore, may be preferred when mineralocorticoid effects e. Dexamethasone also has minimal mineralocorticoid activity, but it is much more potent and has a longer duration of action than prednisone and prednisolone. Given its high potency, long-term treatment with dexamethasone is associated with severe hypothalamic-pituitary-adrenal HPA axis suppression; therefore, it is generally reserved for short-term use in very severe, acute conditions.
Also, its long duration of action makes it unsuitable for alternate-day therapy [ 9 ]. Cortisone and hydrocortisone are the least potent GCs. Because these agents have both mineralocorticoid and GC activity, they are generally preferred for use in patients with adrenal insufficiency.
Fludrocortisone has much greater mineralocorticoid vs. GC potency and, therefore, is commonly used to replace aldosterone in Addison's disease and the classic salt-wasting form of congenital adrenal hyperplasia [ 1 , 8 ]. A thorough review of corticosteroid dosing is beyond the scope of this manuscript since dosages must be individualized based on the pharmacokinetics of the different preparations, the underlying condition being treated, potential drug interactions with concurrently administered non-steroid agents, and patient response to GC treatment.
In non-endocrine disorders, GCs are commonly given in pharmacologic therapeutic doses to suppress inflammation. In endocrine disorders, however, corticosteroid doses are often given at or close to physiologic doses rather than in therapeutic ranges. GC-associated toxicity appears to be related to both the average dose and cumulative duration of GC use. The following section provides a comprehensive review of the most common AEs associated with long-term systemic corticosteroid use.
The most common GC-associated AEs noted in adults include: Kanis and colleagues examined 42, subjects from seven prospectively studied cohorts followed for , patient-years and found that prior and current use of corticosteroids increased fracture risk in both adult men and women, regardless of BMD and prior fracture history [ 15 ].
Osteonecrosis is also being increasingly reported in children and adolescents treated for acute lymphoblastic leukemia ALL and non-Hodgkin lymphoma [ 17 , 18 ]. Although the risk of osteonecrosis appears to increase with higher doses and prolonged treatment, it may also occur with low doses or after short-term GC exposure.
Excessive alcohol intake, hypercoaguable states, sickle cell disease, radiation exposure and human immunodeficiency virus HIV infection have also been associated with the development of osteonecrosis [ 19 ]. A study of adult cases of GC-induced osteonecrosis of the femoral head indicated that this condition was often misdiagnosed as lumbar disorders [ 20 ]. In this study, only one patient did not report any pain associated with osteonecrosis.
Adrenal suppression AS refers to decreased or inadequate cortisol production that results from exposure of the HPA axis to exogenous GCs [ 21 ]. Duration of GC therapy and doses of GC treatment are not reliable predictors of which patients will develop AS [ 22 , 23 ]. It is important to recognize that inhaled, topical and intraocular GCs may also be absorbed systemically to the degree that they can cause AS [ 24 - 26 ].
Longer-acting GC formulations tend to be associated with a higher risk of AS [ 27 ]. Timing of GC administration may also influence the development of AS, with morning administration being potentially less suppressive than evening doses [ 27 , 28 ]. Alternate-day therapy is also theoretically less suppressive than daily GCs based on the physiology of the HPA axis; however, there is currently no solid clinical evidence to support this proposition.
The physiologic effects of cortisol are wide-ranging and are particularly important during times of physiologic stress i. AS often occurs following abrupt discontinuation of GC therapy [ 29 ]. However, there are currently no evidence-based guidelines for tapering of GCs. Gradual GC tapering is frequently part of treatment protocols to reduce the risk of relapse and, therefore, comparative studies looking at AS without tapering would be difficult to perform.
A study of patients with rheumatic disease found that rapidity of steroid taper did not make a difference in HPA-axis recovery [ 30 ]. Despite the lack of supportive evidence, many centres follow empiric tapering regimes based on the knowledge that AS is often seen following abrupt GC withdrawal. Prolonged corticosteroid therapy commonly causes weight gain and redistribution of adipose tissue that result in Cushingoid features truncal obesity, facial adipose tissue [i.
Cushingoid features may develop within the first two months of GC therapy, and the risk of these complications appears to be dependent on both the dose and duration of treatment. Another study found the rate of Cushingoid features to increase linearly with dose: Exogenous corticosteroid use is associated with hyperglycemia, and high-dose therapy increases insulin resistance in patients with pre-existing and new-onset diabetes.
The effects of GC administration on glucose levels are observed within hours of steroid exposure [ 35 ], and appear to be dose-dependent. A population-based study of over 11, patients found that the risk for hyperglycemia increased substantially with increasing daily steroid dose; odds ratios ORs for hyperglycemia were 1.
GCs also appear to have a greater impact on postprandial compared to fasting glucose levels [ 37 ]. In general, GC-induced hyperglycemia improves with dose reductions and usually reverses when steroid therapy is discontinued, although some patients may develop persistent diabetes. The risk of both cataracts and glaucoma is increased in patients using GCs, and this risk appears to be dose-dependent.
GC use is typically associated with the development of posterior subcapsular cataracts PSCC [ 40 ], as opposed to nuclear or cortical cataracts. There is inter-individual variation in susceptibility to PSCC and the incidence varies per individual. Although PSCC are frequently seen in patients treated systemically, or even occasionally in those receiving inhaled corticosteroids ICSs [ 41 ], they are more commonly caused secondary to local treatment e. Glaucoma is the more serious ocular complication of GC therapy.
Systemic corticosteroids can painlessly increase intraocular pressure, leading to visual field loss, optic disc cupping, and optic nerve atrophy. Once systemic therapy is discontinued, the elevation in intraocular pressure often resolves within a few weeks, but the resultant damage to the optic nerve is often permanent.
While all patients using systemic steroids are at risk for elevation in intraocular pressure and glaucoma, certain groups appear to be at higher risk. Ocular hypertension and glaucomatous visual field defects have been reported in patients using systemic steroids with a personal or family history of open angle glaucoma, diabetes, high myopia or connective tissue disease particularly rheumatoid arthritis [ 42 ].
To reduce the risk of steroid-induced glaucoma, it is important to screen patients for these risk factors. All patients who may require long-term systemic GC therapy with a positive history for glaucomatous risk factors should be referred to an ophthalmologist for a comprehensive ocular assessment see Ophthalmologic Examination section.
This type of chorioretinopathy is associated with the formation of subretinal fluid in the macular region which leads to separation of the retina from its underlying photoreceptors. This manifests as central visual blur and reduced visual acuity. Corticosteroids induce atrophic changes in the skin that can lead to skin thinning and fragility, purpura and red striae.
Skin thinning and purpura are usually reversible upon discontinuation of therapy, but striae are permanent. Purpura generally affect the sun exposed areas of the dorsum of the hands and forearms, as well as the sides of the neck, face, and lower legs, and are usually not accompanied by palpable swelling [ 44 , 45 ].
Red striae generally appear on the thighs, buttocks, shoulders and abdomen. Impairment of wound healing is another common, and potentially serious, side effect of systemic GC use. Corticosteroids interfere with the natural wound-healing process by inhibiting leukocyte and macrophage infiltration, decreasing collagen synthesis and wound maturation, and reducing keratinocyte growth factor expression after skin injury [ 44 ].
Some topical and systemic agents may help counter the effects of corticosteroids on wound healing, including epidermal growth factor, transforming growth factor beta, platelet-derived growth factor, and tetrachlorodecaoxygen [ 45 ].
GC therapy has been associated with an increased risk of several adverse GI events including gastritis, ulcer formation with perforation and hemorrhage, dyspepsia, abdominal distension and esophageal ulceration.
Despite the commonly held perception that steroid use increases the risk of peptic ulcer disease, large meta-analyses of randomized, controlled trials have failed to show a significant association between GC use and peptic ulcers [ 46 , 47 ].
Recent evidence suggests that the risk of peptic ulcer disease due to corticosteroids alone is low, but increases significantly when these agents are used in combination with non-steroidal anti-inflammatory drugs NSAIDS [ 48 ].
Acute pancreatitis has also been reported to be an adverse effect of corticosteroid use. A Swedish population-based, case—control study demonstrated an increased risk of acute pancreatitis after exposure to GC therapy [ 51 ]. Overall, the OR for developing acute pancreatitis was 1. However, other evidence suggests that the underlying disease processes for which GC therapy is prescribed particularly systemic lupus erythematosus [SLE] may be more likely causes of pancreatitis than GC use [ 52 ].
GC use is associated with AEs that are known to be associated with a higher CVD risk, including hypertension, hyperglycemia, and obesity. Another large, retrospective case—control study found current GC use to be associated with a significantly increased risk of heart failure adjusted OR, 2.
CV risk was found to be greater with higher GC doses and with current vs. Population-based studies conducted in Northern Europe have also noted an increased risk of new-onset atrial fibrillation AF and flutter in GC users [ 55 , 56 ]. In these studies, the risk of AF was significantly greater with current or recent use i. Serious CV events, including arrhythmias and sudden death, have also been reported with pulse GC therapy. However, these events are rare and have occurred primarily in patients with underlying kidney or heart disease [ 57 ].
Although it is unclear whether these serious AEs are due to GC use or the underlying condition, some experts recommend continuous cardiac monitoring in patients with significant cardiac or kidney disease receiving pulse therapy. Findings from studies examining the relationship between GC use and dyslipidemia have been conflicting. Despite the conflicting evidence, regular monitoring of lipids as well as other traditional risk factors for CVD is recommended in patients using GCs at high doses or for prolonged periods see CV Risk and Dyslipidemia section.
Corticosteroids have direct catabolic effects on skeletal muscles that can lead to reductions in muscle protein synthesis and protein catabolism and, ultimately, muscle weakness. Myopathy generally develops over several weeks to months of GC use. Patients typically present with proximal muscle weakness and atrophy in both the upper and lower extremities; myalgias and muscle tenderness, however, are not observed.
Also, the higher the GC dose utilized, the more rapid the onset of muscle weakness.