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.
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. So, their actions are used medically for the treatment of various conditions indicated below.
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 in limited to their replacement therapy in acute adrenal crisis and Addison disease.
Due to these number of roles played by corticosteroids in the human body, it is evident that they are widely used in medical practice for treatment of various diseases and due to this, their side-effects, in turn, have become another significant medical issue that requires special attention.
Glucocorticoids have widespread endocrine and non-endocrine effects via genomic/indirect and non-genomic/direct effects over the body. The direct effects of glucocorticoids are acute (within minutes), usually occur at high doses and are as follows:
Both are anti-inflammatory effects.
The indirect effects of glucocorticoids are through their interaction with their cytoplasmic glucocorticoid receptors in the cell. This interaction makes a complex that translocates inside the nucleus and interacts with glucocorticoid responsive elements (GREs) making alterations in gene expressions at various levels in the body, but it needs longer time (hours or days). These effects are as follows:
Anti-Inflammatory and Immunosuppressive Effect
Glucocorticoids exert this effect by triggering cell apoptosis and inhibiting fibroblast proliferation.
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.
Natural and synthetic glucocorticoids are used in both endocrine and non-endocrine disorders. Pharmacologic (usually supraphysiologic) doses of glucocorticoids are used to treat patients with inflammatory, allergic, and immunological disorders. Due to excessive side effects of corticosteroids, every effort should be made to use these drugs locally. For example, rectal enemas are preferred for inflammatory bowel disease whenever possible, over oral or intravenous (IV), systemic steroid use. Following are the most frequent ways available for glucocorticoid administration.
Parenteral administration of high doses may be warranted in emergencies, such as septic shock, COPD exacerbation, and severe acute asthma.
Oral preparations are usually used for chronic therapy. They are absorbed within approximately 30 minutes. This preparation is used mostly in chronic conditions like asthma, COPD, allergic conditions of skin , kerato-conjunctivitis, rheumatoid arthritis, immune-mediated systemic diseases like systemic lupus erythematosus (SLE), chronic myelogenous leukemia (CML), lymphoma, leukemia, polymyositis, multiple sclerosis, organ transplantation, nephrotic syndrome, chronic hepatitis (flare-ups), cerebral edema, IgG4-related disease, and prostate cancer.
This minimizes systemic side-effect and provides a maximal local response. Examples are intra-articular injections for joint inflammation, inhalational for asthma, topical for dermatological problems, ocular drops for eye conditions, among others. The intra-articular injections with crystal suspension of hydrocortisone or triamcinolone have the benefit of long-lasting effect and decrease the frequent need to puncture the joints.
There is no intramuscular (IM) administration of glucocorticoids as it can cause severe local muscle atrophy and due to depot effect, it can disturb the circadian rhythms of endogenous glucocorticoids secretions. The only exception is IM injection of betamethasone to the pregnant mother less than 37 weeks of gestation to stimulate fetal lung maturity.
Synthetic steroids used for medical purposes may have both glucocorticoid and mineralocorticoid activity, or they may have either. For example, aldosterone has predominant mineralocorticoid activity, 9a-fluorocortisol (synthetic) has even more potent mineralocorticoid activity, cortisol has a predominant glucocorticoid effect and slight mineralocorticoid activity as well. Prednisolone, methylprednisolone, and dexamethasone are synthetic preparations resembling cortisol in having both glucocorticoid and mineralocorticoid effects but are 4-, 5-, and 30-times more potent than cortisol respectively.
Factors Affecting Adverse Effects of Corticosteroid Use
Adverse effects depend upon dose, duration of use, route of administration, the bioavailability of individual drugs, and mechanism of action of individual corticosteroids.
A linear and threshold pattern of dose-related adverse effects have been described for different adverse effects. A "linear" pattern is one in which with increasing dose, the incidence of certain adverse effects is increased the, e.g., the appearance of ecchymosis, leg edema, mycosis, parchment-like skin, shortness of breath, and sleep disturbance. A "threshold" pattern, describes an elevated frequency of events beyond a certain threshold value, for example, at doses of prednisone greater than 7.5 mg/day there is an increased frequency of glaucoma, depression, and elevated blood pressure.
Another important factor is the underlying disease condition for which corticosteroids are being administered. The severity and nature of that disease will also influence the appearance of side-effects. Also, other co-morbid conditions (e.g., diabetes), old age, nutritional status of patients will also affect the occurrence and magnitude of side-effects.
It is usually at “supra-physiologic” doses of corticosteroid administration that multiple adverse effects of corticosteroids are seen, ranging from mild suppression of hypothalamic-pituitary axis to severe, life-threatening infections.
Dermatological changes: Skin thinning, purpura, acne, mild hirsutism, facial erythema, and striae. Purpura generally affects the sun-exposed areas of the dorsum of the hands and forearms, as well as the sides of the neck, face, and lower legs. Red striae generally appear on the thighs, buttocks, shoulders, and abdomen. Impairment of wound healing is another common and a potentially serious side effect of systemic glucocorticoid 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.
Cushing syndrome, cushingoid features and weight gain: 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 dose. 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 observed.
Ophthalmologic: The risk of both cataracts and glaucoma (open-angle) is increased in patients on glucocorticoids and is dose-dependent in a linear fashion. This form of glaucoma occurs most commonly in patients using eye drops. Glaucoma (increase in intra-ocular pressure) is often painless and leads to visual field loss, optic disc cupping, and optic nerve atrophy. Once systemic therapy is discontinued, 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, local, 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 manifests as central visual blur and reduced visual acuity.
Cardiovascular: Glucocorticoid use has been associated with a variety of adverse cardiovascular effects including fluid retention, premature atherosclerotic disease (increased risk of heart attack and stroke) and arrhythmias. Cardiovascular disease risk is dose-dependent.
Gastrointestinal (GI): Glucocorticoids increase the risk for 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 non-use of either drug. Other complications associated with glucocorticoid use include visceral perforation and hepatic steatosis (fatty liver) that can rarely lead to systemic fat embolism or cirrhosis.
Bone and Muscle: This includes osteoporosis, osteonecrosis, increased risk of fractures, muscle weakness and myopathy. Corticosteroids stimulate osteoclastic activity initially (first 6 to 12 months of therapy), followed by a decrease in bone formation by suppressing osteoblastic activity in the bone marrow, decreasing osteoblast function and lifespan, and promoting the apoptosis of osteoblasts and osteocytes. Myopathy is a direct result of muscle breakdown and occurs in both upper and lower limbs. It is reversible and painless. “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 is characterized by 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.
Neuropsychiatric: Patients receiving glucocorticoids often experience an improved sense of well-being within several days of starting the medications; mild euphoria or anxiety may also be seen. 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 Glucocorticoids therapy may be increased among patients with a history of that condition. Rare cases of pseudotumor cerebri have also been associated with glucocorticoid use.
Metabolic and endocrine: Systemic glucocorticoids cause a dose-dependent, usually mild, increase in fasting glucose levels and a greater 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 are thought 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.
Immune system: Systemic glucocorticoids have many effects upon innate and acquired immunity that predispose to infection, resulting in a linear increase in the risk of infection, especially with common bacterial, viral, and fungal pathogens. In addition, patients taking glucocorticoids may not manifest signs and symptoms of infection as clearly, due to the inhibition of cytokine release and the associated reduction in inflammatory and febrile responses. This can impair the early recognition of infection.
Hematologic effects: Pharmacologic doses of glucocorticoids often result in an increased white blood cell count (leukocytosis) that is due primarily to an increase in neutrophils (neutrophilia). This phenomenon is due to a decreased proportion of neutrophils that are adhering to the endothelium (Marginal pool).
Hypothalamic-pituitary-adrenal axis suppression: 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 being treated (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.
Adrenal insufficiency 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), results in adrenal crisis. Children with adrenal crisis secondary to adrenal suppression may present with hypotension, shock, decreased consciousness, lethargy, unexplained hypoglycemia, seizures, and even death.
Growth impairment: The impairment of growth in young children and delay in puberty is commonly seen 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. This can also occur with inhaled Glucocorticoids. It is important to note that although growth impairment can be an independent adverse effect of corticosteroid therapy, it can also be a sign of adrenal suppression.
General contraindications include hypersensitivity.
Live virus vaccines may be administered to patients who have taken:
Baseline Assessment and Monitoring
Preexisting conditions that should be assessed for and treated when glucocorticoids are to be instituted include:
Before initiating long-term systemic glucocorticoid therapy, a thorough history and physical examination should be performed to assess for risk factors or pre-existing 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, nutritional and pubertal status should also be examined.
Assessment of Bone Health
The bone health in adults should be assessed as followed:
Assessment of Hypothalamic: Pituitary-Adrenal (HPA) Function
HPA axis should be assessed if the patient has received systemic corticosteroids for more than 2 consecutive weeks or more than 3 cumulative weeks in the last 6 months or Patient has persistent symptoms of adrenal suppression. Screening is done by Measuring early morning salivary cortisol after tapering off 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 is monitored every 6 months and plotted on a growth curve.
Assessment of Dyslipidemia and Cardiovascular Risk (Adults)
Order a lipid profile 1 month after Glucocorticoids initiation, then every 6 to 12 months and assess glycemic control by 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, perform annual OGTT (oral glucose tolerance test) if the child is obese or has multiple risk factors for diabetes.
Assessment of Ophthalmological Complications
An ophthalmological examination is done annually by an ophthalmologist, but earlier examination for those with symptoms of cataracts and early referral for intra-ocular pressure assessment should be ensured if there is personal or family history of open-angle glaucoma, diabetes mellitus, high myopia or some connective tissue disease, particularly rheumatoid arthritis.
Prevention of Side-Effects
The adverse effects of glucocorticoids can be limited by taking the following steps:
Patients who also require concomitant treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or anticoagulants may require prophylaxis to prevent gastro-duodenal toxicity (with PPIs or misoprostol).
Patients who require an extended course of glucocorticoids should receive appropriate immunizations before the institution of therapy. Sometimes the use of prophylaxis for an opportunistic infection with Pneumocystis jirovecii pneumonia (PCP) is also recommended. Symptoms of and/or exposure to serious infections should also be assessed as corticosteroids are contraindicated in patients with untreated systemic infections. Concomitant use of other medications should also be assessed before initiating therapy as significant drug interactions have been noted between glucocorticoids and several drug classes.
Osteoporosis prevention can be ensured right at the start of therapy with adequate dietary calcium (1000 to 1200 mg per day) and vitamin D intake (800 IU per day) in high-risk men (T-score on baseline DEXA is between -1 and -2.5) and post-menopausal women. Bisphosphonates can be started if T-score is less than -2.5 on baseline DEXA when glucocorticoid therapy is started to prevent bone complications.
Withdrawal of Corticosteroid Therapy
Abrupt cessation of chronic glucocorticoid therapy can be dangerous as there is a risk of HPA axis suppression. So, withdrawal of glucocorticoid therapy needs tapering over the period of certain time. In general, patients who are given acute corticosteroid therapy for less than 14 to 21 days do not develop HPA axis suppression. Therefore, treatment can be suspended with no need for any reduction regime. If the therapy has been continued for greater than 3 weeks, tapering is needed (e.g., over 2 months) but there is no universally accepted optimal regimen.
Corticosteroids are widely used medication to manage many acute and chronic inflammatory disorders. These side effects affect many organ systems and hence, all healthcare workers including nurses and pharmacist need to be aware of them. While short-term use of corticosteroids is associated with mild side effects, long-term use can result in hypertension, peptic ulcer disease, ocular damage, neuropsychiatric effects, hematologic and musculoskeletal effects. To prevent irreversible damage, these patients need close monitoring and follow up. Children are particularly vulnerable to the side effects of corticosteroids. Close communication with other health professionals is necessary to ensure that the patient is not left unmonitored. Treatment with corticosteroids should be tapered as soon there is a clinical improvement. Finally, patients should be educated about the side effects of these agents and when to return for followup.