Corticosteroids are hormone mediators produced by the cortex of adrenal glands that are further categorized into glucocorticoids (major glucocorticoid produced by the body is cortisol), mineralocorticoids (major mineralocorticoid produced in the body is aldosterone), and androgenic sex hormones. Endogenous cortisone was first isolated in 1935 and synthesized in 1944. In 1948, Dr. Philip S Hench published administered cortisone (called Compound E at that time) to a 29-year-old woman who was bed-ridden secondary to active rheumatoid arthritis. The patient was able to walk after three days of treatment. This case was published in 1949, and in 1950, Philip S. Hench, Edward C. Kendall, and Tadeusz Reichstein were awarded the Nobel Prize in Physiology or Medicine "for their discoveries relating to the hormones of the adrenal cortex, their structure, and biological effects."
Glucocorticoids (GCs) are a group of drugs structurally and pharmacologically similar to the endogenous hormone cortisol with various functions like anti-inflammatory, immunosuppressive, anti-proliferative, and vaso-constrictive effects. Their actions are used medically for the treatment of various conditions indicated below. The list of indications of glucocorticoids is extremely long. We have categorized and mentioned the most important and broad-spectrum indication below.
As a Replacement Therapy
Systemic Symptomatic Treatment
Mineralocorticoids are primarily involved in the regulation of electrolyte and water balance by modulating ion transport in the epithelial cells of the collecting ducts of the kidney. The use of mineralocorticoid drugs is limited to their replacement therapy in acute adrenal crisis and Addison disease.
Due to several roles played by corticosteroids in the human body, they see extensive use in medical practice for the treatment of various diseases. As a result, their side-effects, have, in turn, become another significant medical issue requiring special attention.
ANTI-INFLAMMATORY and IMMUNOSUPPRESSIVE EFFECTS
The anti-inflammatory and immunosuppressive effects of glucocorticoids are dose-dependent, with immunosuppressive effects seen mostly at higher doses. The pharmacological anti-inflammatory and immunosuppressive effects of glucocorticoids are extensive and can be the genomic or non-genomic mechanisms. Most effects of glucocorticoids are via the genomic mechanisms, which takes time, while immediate effects via the non-genomic mechanisms can occur with high doses of glucocorticoids (such as pulse therapy). Clinically, it is not possible to separate these effects.
Being small, lipophilic substances, glucocorticoids readily pass the cell membrane by diffusion and enter the cytoplasm of the target cells, where most of their action is mediated by binding to the intra-cytoplasmic glucocorticoid receptors. Glucocorticoid receptors have two isoforms, α, and β. Glucocorticoids bind to the α-isoform only. Glucocorticoid resistance in some patients has been partly attributed to higher levels of the β-isoform in these patients. Binding of the glucocorticoid to the glucocorticoid receptor results in shedding of heat-shock proteins, which are otherwise bound to the glucocorticoid receptor, and this results in the formation of the activated glucocorticoid receptor-glucocorticoid complex which easily translocates to the nucleus. In the nucleus of the target cells, this complex reversibly binds to several specific DNA sites resulting in stimulation (transactivation) and suppression (transrepression) of a large variety of gene transcription. Tranpression of transcription factors such as nuclear factor-κB [NF-κB], activator protein-1 and interferon regulatory factor-3 results in suppression of synthesis of pro-inflammatory cytokines such as IL-1, IL-2, IL-6, IL-8, TNF, IFN-gamma, Cox-2, VEGF, and prostaglandins. Transactivation of transcription factors, including glucocorticoid response elements (GREs), leads to activation of synthesis of anti-inflammatory cytokines such as IL-10, NF-κB inhibitor, and lipocortin-1.
The immediate effects of high dose-glucocorticoids are mediated via non-genomic mechanisms. At high doses, glucocorticoids bind the membrane-associated glucocorticoid receptors on target cells such as T-lymphocytes, resulting in impairment of receptor signaling and immune response of the T lymphocytes. High dose glucocorticoids also interact with the cycling of calcium and sodium across the cell membrane resulting in a rapid decrease in inflammation.
By altering the cytokine production via the genomic and non-genomic mechanisms, glucocorticoids lead to suppression of the immune system and decreased inflammation. They target a wide variety of cells, including T-lymphocytes, macrophages, fibroblasts, neutrophils, eosinophils, and basophils. Notably, glucocorticoids have almost no effect on B-cell function and immunoglobulin production. The downstream effects of glucocorticoids are summarized below:
EFFECTS ON HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS
Glucocorticoids exert negative feedback effects on the HPA axis. They directly suppress adrenocorticotropic hormone (ACTH) and corticotropin-releasing hormone (CRH) secretion. Additionally, by suppressing the release of pro-inflammatory cytokines that stimulate ACTH and CRP secretion, glucocorticoids further suppress ACTH and CRH secretion indirectly in inflammatory diseases. Chronic HPA axis suppression by glucocorticoids leads to functional adrenal atrophy (sparing the mineralocorticoid producing outer adrenal cortex that is functionally independent of ACTH). The risk of this functional adrenal atrophy and insufficiency is challenging to predict, and varies from patient to patient but is largely dependant on the dose and duration of glucocorticoid therapy. The adrenal function generally recovers by slow tapering of glucocorticoids.
Glucocorticoids bind to mineralocorticoid receptors (MRs) and produce their mineralocorticoid effect (i.e., increasing sodium and decreasing potassium), but only when used at the high dose and for the extended period.
Several preparations of glucocorticoids are available, each with varying efficacy. Dexamethasone and betamethasone are long-acting with the highest glucocorticoid efficacy with a biological half-life of 36 to 54 hours. Cortisone and cortisol are short-acting with a biological half-life of under 12 hours, and not frequently used. Prednisone, prednisolone, methylprednisolone, and triamcinolone are intermediate-acting with a biological half-life of 18 to 36 hours. The glucocorticoid and mineralocorticoid effects of each available preparation varies, with cortisol and cortisone having almost 1 to 1 glucocorticoid and mineralocorticoid effects while all others with almost no mineralocorticoid effects. Equivalent glucocorticoid doses can be calculated for these various preparations. 5 mg of prednisone is equivalent in its glucocorticoid effects to 5 mg of prednisolone, 4 mg of methylprednisolone, 4 mg of triamcinolone, 0.75 mg of dexamethasone, 0.60 mg of betamethasone, 20 mg of cortisol and 25 mg of cortisone.
Parenteral intravenous administration of high doses of glucocorticoids may be warranted in emergencies, such as septic shock, COPD exacerbation, and severe acute asthma. Pulse therapy of glucocorticoids (1000 mg intravenous methylprednisolone divided over 3 to 4 daily doses) for several days has been studied in several rheumatological conditions and is recommended only for organ-threatening or life-threatening situations including lupus nephritis (Class III or IV), giant cell arteritis with vision loss, ANCA-associated vasculitis, etc. Americal College of Rheumatology also recommends using intravenous glucocorticoids in patients with acute gout who are unable to take medications orally.
Oral preparations are usually useful in both acute and chronic indications. For acute exacerbations of underlying chronic illness (such as asthma, COPD, gout, pseudogout, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), etc.), short duration of moderate to high doses of oral corticosteroids is usually efficacious in treating the flare. Tapering dose packs starting at high dose and tapering daily over 7 to 9 days are commercially available and can be used in these situations as well. Long term oral corticosteroid therapy may be necessary for chronic illnesses such as polymyalgia rheumatica, SLE, RA, vasculitis, myositis, IgG4-related disease, chronic myelogenous leukemia (CML), lymphoma, leukemia, multiple sclerosis, organ transplantation, etc. Clinicians must make every effort to use the glucocorticoids at the lowest possible dose and for the shortest possible duration in these cases. A slow taper shall be attempted in patients with prolonged exposure to glucocorticoids to prevent adrenal crisis.
Glucocorticoid administration can be via several non-systemic routes, including intra-articular joint injections for joint inflammation, inhalational for asthma, topical for dermatological problems, ocular drops for eye conditions, and intra-nasal for seasonal rhinitis. Clinicians generally avoid intramuscular (IM) glucocorticoids due to the risk of local muscle atrophy due to depot effect and the only indications for intramuscular glucocorticoids are for IM triamcinolone acetonide for specific inflammatory disorders and IM injection of betamethasone to a pregnant mother less than 37 weeks of gestation to stimulate fetal lung maturity. When appropriate, a non-systemic route is preferable to the systemic route of administration to minimize systemic adverse effects.
Factors influencing the adverse effects of glucocorticoids
Given the diversity in the mechanism of action of glucocorticoids, they can cause a wide array of adverse effects ranging from mild to severe, some of which are unavoidable. Of all the factors influencing the adverse effects of glucocorticoids, dose, and duration of therapy are the most important independent and well-documented risk factors. It is usually at “supra-physiologic” doses of corticosteroid administration where multiple and especially severe adverse effects of glucocorticoids occur, ranging from mild suppression of hypothalamic-pituitary axis to severe, life-threatening infections. However, long term use of low to moderate doses of glucocorticoids can lead to several serious adverse effects as well. Adverse effects of corticosteroids are both dose and time-dependent. Some adverse effects follow a linear dose-response pattern where the incidence increases with an increase in the dose (ecchymosis, cushingoid features, parchment-like skin, leg edema, and sleep disturbance). Other adverse effects may follow a threshold dose-response pattern with an elevated frequency of events beyond a specific threshold value (weight gain and epistaxis at prednisone dose greater than 5 mg daily, glaucoma, depression, hypertension at prednisone dose greater than 7.5 mg daily, etc.).
Several other factors may influence the adverse effects of glucocorticoids. Older age, comorbid conditions (such as diabetes mellitus), concomitant use of other immunosuppressive agents, severity, and nature of the underlying disease and poor nutritional status can all influence the occurrence and magnitude of side-effects.
Musculoskeletal adverse effects
Glucocorticoids induced Osteoporosis is one of the well-known and devastating adverse effects of long-term use of glucocorticoids. Up to 40% of patients on long-term glucocorticoids develop bone loss leading to fractures. Several mechanisms play a role, including osteoclast activation by promoting RANK-ligand as well as a decrease in function and number of osteoblasts and osteocytes. The trabecular bone is initially affected, with cortical bone loss seen with longer-term use. The loss of trabecular bone can occur within the first 6 to 12 months of therapy.
Steroid-induced myopathy, which is a reversible painless myopathy and is a direct result of muscle breakdown, can occur in both the upper and lower extremities, usually with high-dose long-term use of glucocorticoids. Muscle enzymes (CK and Aldolase) are typically normal, and findings on electromyography are non-specific. Muscle biopsy reveals Type-II fiber atrophy without inflammation. Withdrawal of glucocorticoids and exercises usually results in resolution of the myopathy. “Critical illness myopathy” may also develop in patients admitted in the intensive care unit (ICU) requiring large doses of IV glucocorticoids and neuromuscular blocking agents. It characteristically presents with a severe, diffuse, proximal, and distal weakness that develops over several days. Although it is usually reversible, critical illness myopathy can lead to prolonged ICU admissions, increased length of hospital stays, severe necrotizing myopathy, and increased mortality.
Osteonecrosis can be seen especially with long-term use of prednisone more than 20 mg daily. Patients with SLE and children are at higher risk. Hips and knees are the most commonly involved joints with less common involvement of shoulders and ankles. Pain is the initial feature, which may eventually become severe and debilitating. Magnetic resonance imaging is the most sensitive test, especially for early detection. Plain radiographs may be negative initially but can be useful for follow-up. Treatment is by decreased weight-bearing and immobilization initially, but if severe, surgery and/or joint replacement may be necessary.
Metabolic and endocrine adverse effects
Systemic glucocorticoids cause a dose-dependent increase in fasting glucose levels and a more significant increase in postprandial values in patients without preexisting diabetes mellitus, but the development of de novo diabetes in a patient with initially normal glucose tolerance is uncommon. Risk factors for new-onset hyperglycemia during glucocorticoid therapy appear to be the same as those for other patients. However, patients with diabetes mellitus or glucose intolerance exhibit higher blood glucose levels while taking glucocorticoids, leading to increased difficulty with glycemic control.
The development of cushingoid features (redistribution of body fat with truncal obesity, buffalo hump, and moon face) and weight gain are dose and duration-dependent and can develop early. Cushingoid features showed a linear increase in frequency with dosing. Glucocorticoid therapy is the most common cause of Cushing syndrome. The clinical presentation in the pediatric population is similar to that in adults and includes truncal obesity, skin changes, and hypertension. In children, growth deceleration is also a feature.
Administration of glucocorticoids can suppress the hypothalamic-pituitary-adrenal (HPA) axis decreasing corticotropin-releasing hormone (CRH) from the hypothalamus, adrenocorticotropic hormone (ACTH) from the anterior pituitary gland and endogenous cortisol. Prolonged ACTH suppression cause atrophy of adrenal glands, and abrupt cessation or rapid withdrawal of Glucocorticoids in such patients may cause symptoms of adrenal insufficiency. The clinical presentation of adrenal suppression is variable. Many of the signs and symptoms are non-specific and can be mistaken for symptoms of intercurrent illness or the underlying condition that is receiving treatment (weakness/fatigue, malaise, nausea, vomiting, diarrhea, abdominal pain, headache usually in the morning, fever, anorexia/weight loss, myalgia, arthralgia, psychiatric symptoms, poor growth and weight gain in children). Adrenal suppression is the most common cause of adrenal insufficiency in children and is associated with higher mortality in the pediatric population. In adults, the symptoms of adrenal suppression are non-specific; therefore, the condition may go unrecognized until exposure to physiological stress (illness, surgery, or injury), resulting in an adrenal crisis. Children with adrenal crisis secondary to adrenal suppression may present with hypotension, shock, decreased consciousness, lethargy, unexplained hypoglycemia, seizures, and even death.
The impairment of growth in young children and delay in puberty commonly presents in children receiving glucocorticoids for chronic illnesses like nephrotic syndrome and asthma. The effect is most pronounced with daily therapy, and less marked with an alternate-day regimen and can also occur with inhaled glucocorticoids. Although growth impairment can be an independent adverse effect of corticosteroid therapy, it can also be a sign of adrenal suppression.
Moderate to high dose use of glucocorticoids poses a significant risk of infections, including common mild infections as well as serious life-threatening infections. There is a linear increase in the risk with dose and duration of therapy, especially with common bacterial, viral, and fungal pathogens. Concomitant use of other immunosuppressive agents and the elderly age further increases the risk of infections. Prednisone dose of less than 10 mg daily pose minimal to no risk of infection. Patients taking glucocorticoids may not manifest common signs and symptoms of infection as clearly, due to the inhibition of cytokine release and the associated reduction in inflammatory and febrile responses leading to a failure in early recognition of infection.
Cardiovascular adverse effects
Mineralocorticoid effects, especially as seen with cortisol and cortisone, can lead to fluid retention, edema, weight gain, hypertension, and arrhythmias by increasing renal excretion of potassium, calcium, and phosphate. Hypertension usually occurs with higher doses only. Long-term use of medium-high dose glucocorticoids has implications in premature atherosclerosis in a dose-dependent pattern.
Dermatologic adverse effects
Several cutaneous adverse effects can occur even at a low dose use of glucocorticoids, although the risk increases linearly with the increasing dose and duration of glucocorticoid therapy. Although cutaneous adverse effects appear to be clinically significant by physicians, they are usually of most concern to the patients. These adverse effects include ecchymosis, skin thinning and atrophy, acne, mild hirsutism, facial erythema, stria, impaired wound healing, thinning of hair, and perioral dermatitis.
Ophthalmologic adverse effects
The risk of cataract is significantly high in patients taking prednisone more than 10 mg daily for more than one year, with a dose-dependence in a linear fashion. However, an increased risk of cataracts has been reported even with low-dose glucocorticoids. Cataracts are usually bilateral and slowly progressing. Increased intraocular pressure, especially in patients with a family history of open-angle glaucoma, is seen in patients receiving intraocular glucocorticoids, and high dose systemic glucocorticoids. Glaucoma is often painless and can lead to visual field loss, optic disc cupping, and optic nerve atrophy. After the discontinuation of systemic therapy, the elevation in intraocular pressure usually resolves within a few weeks, but the damage to the optic nerve is often permanent. A rare adverse effect of systemic or even topical use of glucocorticoids is central serous chorioretinopathy; this leads to the formation of subretinal fluid in the macular region, which leads to separation of the retina from its underlying photoreceptors. This condition manifests as central visual blur and reduced visual acuity.
Gastrointestinal (GI) adverse effects
Glucocorticoids increase the risk of adverse GI effects, such as gastritis, gastric ulcer formation, and GI bleeding. The use of NSAIDs and glucocorticoids is associated with a 4-fold increased risk of a GI adverse effect compared with the use of either drug alone. Other complications associated with glucocorticoid use include pancreatitis, visceral perforation, and hepatic steatosis (fatty liver) that can rarely lead to systemic fat embolism or cirrhosis.
Neuropsychiatric adverse effects
Patients receiving glucocorticoids often experience an improved sense of well-being within several days of starting the medications; mild euphoria or anxiety may also occur. Hypomanic reactions and activated states are more common early in the therapy than depression, but the prevalence of depression is greater in patients on more longstanding therapy. Psychosis can occur but does so almost exclusively at doses of prednisone above 20 mg per day given for a prolonged period. Disturbances in sleep are reported, especially with split doses that may interfere with the normal pattern of diurnal cortisol production. Akathisia (motor restlessness) is a common glucocorticoid side effect. The risk of developing a given neuropsychiatric disorder following glucocorticoid therapy may increase among patients with a history of the condition. Rare cases of pseudotumor cerebri have also correlated with glucocorticoid use.
There is specific documentation of neuropsychiatric adverse effects with glucocorticoid therapy in children with acute lymphoblastic leukemia (ALL) receiving dexamethasone or prednisone for the induction and maintenance of treatment. The risk is higher in preschool-age children, and the symptoms typically present during the first week of glucocorticoid therapy. Glucocorticoid-induced acute neuropsychiatric impairment may present with a wide variety of behavioral symptoms, including euphoria, aggression, insomnia, mood fluctuations, depression, manic behavior, and even frank psychosis. Although these psychiatric disturbances tend to wear off with time on cessation of glucocorticoid therapy, a small minority of the patients may experience persistent symptoms even after discontinuation of the drug.
General contraindications include hypersensitivity.
Clinicians can administer live virus vaccines to patients who are on:
Baseline assessment and monitoring
Preexisting conditions that should be assessed for and treated when starting glucocorticoids include:
Before initiating long-term systemic glucocorticoid therapy, the clinician should perform a thorough history and physical examination to assess for risk factors or preexisting conditions that may potentially be exacerbated by glucocorticoid therapy, such as above.
Baseline measures of body weight, height, blood pressure, BMD (bone mineral density) via DEXA scan, and ophthalmological examination should be obtained along with laboratory assessments that include a complete blood count (CBC), blood glucose values (Fasting blood sugar, 2-hour OGTT, Hb1Ac), and lipid profile (LDL-C, HDL-C, TC, non-HDL-C, TG). In children, the clinician should also examine nutritional and pubertal status.
Assessment of Bone Health
American College of Rheumatology has published specific guidelines addressing this issue to help prevent and manage GiOp.
Assessment of Hypothalamic: Pituitary-Adrenal (HPA) Function
The HPA axis should undergo assessment if the patient has received systemic corticosteroids for more than two consecutive weeks or more than three cumulative weeks in the last six months or if the patient has persistent symptoms of adrenal suppression. Screening is by measuring early morning salivary cortisol after tapering off the dose of cortisol. If morning cortisol is normal, but the patient has symptoms of adrenal suppression, perform a low-dose ACTH stimulation test to confirm the diagnosis. Consider endocrinology referral for confirmation of diagnosis.
Assessment of Growth (Children and Adolescents)
Growth in children and adolescents on chronic glucocorticoid therapy shall be monitored every six months and plotted on a growth curve.
Assessment of Dyslipidemia and Cardiovascular Risk (Adults)
Lipid profile shall be monitored one month after glucocorticoid initiation, and then every 6 to 12 months. Glycemic control requires assessment via screening for classic symptoms at every visit: polyuria, polydipsia, weight loss. Monitor glucose parameters for at least 48 hours after glucocorticoids initiation, then every 3 to 6 months for the first year and annually afterward. In children, an annual oral glucose tolerance test merits consideration if the child is obese or has risk factors for diabetes.
Assessment of Ophthalmological Complications
An annual ophthalmological examination shall be considered, especially for those with symptoms of cataracts, and early referral for intraocular pressure assessment should take place if there is personal or family history of open-angle glaucoma, diabetes mellitus, or high myopia.
Prevention of adverse effects
Although some adverse effects of glucocorticoids are unavoidable, some can be prevented by:
Patients who also require concomitant treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or anticoagulants shall receive therapy with proton pump inhibitors (PPI). There is no consensus on PPI treatment of patients on glucocorticoids alone without NSAIDs and no other risk factors for peptic complications
Patients who require an extended course of glucocorticoids, especially high doses, shall receive appropriate immunizations before the institution of therapy. Prophylaxis for opportunistic infection with Pneumocystis jirovecii pneumonia (PCP) is also a recommendation in patients receiving prednisone at a dose of 20 mg or more for more than two weeks. The prophylaxis can stop once the dose of prednisone is below 20 mg daily dose. Symptoms of and/or exposure to serious infections should also be assessed as corticosteroids are relatively contraindicated in patients with untreated systemic infections. Concomitant use of other medications also merits attention before initiating therapy as significant drug interactions exist between glucocorticoids and several drug classes.
Withdrawal of glucocorticoid therapy
Abrupt cessation of chronic glucocorticoid therapy can be dangerous as there is a risk of HPA axis suppression. Withdrawal of glucocorticoid therapy needs tapering over the period. In general, patients who are given acute corticosteroid therapy for less than 14 to 21 days do not develop HPA axis suppression, and treatment can stop with no need for any tapering regime in them. If the therapy has been ongoing for greater than three weeks, tapering is needed (e.g., over two months), but there is no universally accepted optimal regimen.
Acute psychosis can develop in patients receiving high-dose glucocorticoids. Immediate cessation of the drug on the appearance of symptoms is the first step. Although many drugs, including antipsychotics, antidepressants, benzodiazepines, and hydrocortisone have been tried with variable success, currently there is no consensus on the ideal therapeutic remedy to stop and reverse the corticosteroid-induced neuropsychiatric adverse effects in adults or children. Their specific adverse effects further limit the use of the medications mentioned above. The outcome of limited interventional trials has shown a decrease in corticosteroid-induced neuropsychiatric symptoms with chlorpromazine and lorazepam, albeit at the cost of drowsiness, orthostatic hypotension, and paradoxical agitation. Physiologic doses of hydrocortisone have shown to improve mild to moderate psychosocial disturbances and insomnia experienced by children who developed severe behavioral problems with dexamethasone-based treatment regime administered to treat ALL. Recently, oral potassium chloride (KCl) administered at a median dose of 0.5 mEq/kg/ day in two divided doses per day reportedly was to be moderately effective in reducing corticosteroid-induced psychiatric events in the majority of children with ALL. No adverse effects were found with oral KCl supplementation.
Glucocorticoids are widely used to manage many acute and chronic inflammatory disorders. The adverse effects of glucocorticoids are extensive and can involve many organ systems. While short-term use of corticosteroids is associated with mild side effects, long-term use can result in several severe adverse effects, some of which are irreversible. Physicians shall consider adverse effects and patients' underlying comorbidities before prescribing glucocorticoids and use glucocorticoids judiciously. The clinician should use the lowest possible dose for the shortest possible. Patient education is vital in recognizing the adverse effects early. Children are particularly vulnerable to the side effects of corticosteroids, and parents need to understand the benefits and adverse effects of glucocorticoids. Pharmacists shall alert physicians about possible drug interactions. The nursing team can play a crucial role in communication with the patient and early detection of adverse effects and to ensure regular monitoring. Close communication with other health professionals is necessary to ensure that the patient is not left unmonitored.
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