Corticosteroid Therapy

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Introduction   

When many people hear of steroids, they may think of athletes. However, the steroids that some athletes misuse to enhance their strength and training abilities are not the same as those administered for allergic reactions and some inflammatory conditions. The steroids used by some athletes are called anabolic steroids. The steroids used for the treatment of disease are called corticosteroids.  

Steroids are hormones naturally produced in the body (made from cholesterol) to regulate the function of various bodily systems [2]. Some steroid hormones are produced by the adrenal glands of the endocrine system (a set of two glands that rest atop the kidneys). The adrenal glands produce the hormone types: glucocorticoids, mineralocorticoids, and adrenal androgens [2]. Corticosteroid medication mimics glucocorticoids, more specifically a glucocorticoid called “cortisol.” 

The Immune System 

Corticosteroids are well-known for increasing a patient’s risk for infection. This is due to the medication’s effect on the immune system, particularly its anti-inflammatory properties. It is important to have a clear understanding of how the immune system works as well as the inflammatory process that takes place when a foreign pathogen enters the body. 

How Does the Immune System Work? 

In a typical immune system the immune system is triggered by an antigen – a marker in the body that alerts cells of the immune system that there’s a foreign invader present, like a pathogen or foreign object. Subsequently, a series of events follows. Like in a war, the body rounds up the first line of defense soldiers to fight the pathogen.  

These include [11]: 

• Proteins (called “the inflammasome”) to active inflammatory responses. 
• Macrophages to engulf and digest pathogens. 
• Neutrophils to help kill pathogens and rid of the leftover debris. 
• Endothelial cells to help rid of the dead pathogens/debris. 

The influx of these cells to the site of injury or infection is the beginning of inflammation.  

What is Inflammation? 

Inflammation is more than just “swelling.” Inflammation is a process in which a cascade of events occurs to help the immune system fight against pathogens and foreign bodies. The inflammatory process encompasses a variety of signs/symptoms including redness, warmth, swelling, and drainage [11].  

For example, when a person sustains a traumatic injury to the skin causing an open wound, the accompanying redness (or erythema) is caused by a rush of red blood cells through the site [5]. The dilation of the blood vessels is what causes this “rush” of cells. The increased blood flow also causes the localized warmth that typically occurs. Blood vessel dilation is responsible for the associated swelling as well. The pus that forms is a combination of fluid, dead immune/pathogen cells, and debris from the fight, essentially, the “casualties at war” that must be removed from the body [5]. 

As with fever, inflammation aids in the fight against pathogens and therefore should not be inhibited unless it is likely to be damaging or fatal in and of itself. [11]. This inflammatory process is acute in nature, and typically goes away on its own or with the help of medication. While acute inflammation from a normal immune response is natural and beneficial, chronic inflammation is harmful and can lead to permanent damage of tissues and body systems.  

Chronic inflammation can be seen in conditions including inflammatory bowel disease, cancer, heart disease, and autoimmune disorders like rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus [11]. Chronic inflammation is typically caused by an overactive immune system or autoimmune disease (when the immune system mistakenly attacks normal tissues). In cases like these, inhibiting the inflammatory process by suppressing the immune system is most beneficial. This is where corticosteroids come into play. 

Corticosteroids: The Basics 

Corticosteroids are a group of steroidal therapy medications that are often the go-to for reducing inflammation in the body. Once referred to as “a miracle drug,” these medications are helpful in the treatment of acute and chronic inflammatory conditions and autoimmune diseases.  

Corticosteroids are also useful in emergency situations, for example during asthma attacks or allergic reactions – when the inflammation is life-threatening. Corticosteroids are synthetically formulated to mimic the hormone cortisol. 

What is Cortisol? 

As mentioned earlier, the adrenal glands of the endocrine system produce three different types of steroid hormones, one of which is glucocorticoids. Cortisol is a major glucocorticoid hormone.  

There are two major structures of the adrenal glands – the outer layer (cortex) and inner portion (medulla) – each producing its own hormones. The outer layer (cortex) produces cortisol, hence the name “corticosteroid” [6].  

Cortisol levels in the body rise when a person is stressed [2]. This hormone helps to regulate metabolism, growth, reproduction, and the immune system [2]. Cortisol also aids in cardiovascular function by making blood vessels more sensitive to natural vasoconstrictors in the body (like adrenaline) [2].  

How Do Corticosteroids Work? 

Corticosteroids work by suppressing the immune system which in turn reduces inflammation. In patients with an overactive immune system or acute flareups from a triggering agent, the inflammation can cause troubling symptoms, become prolonged, and spread to other areas within the body. If left untreated, inflammation can lead to tissue scarring (or damage to affected structures) and loss of bodily functions [11]. 

The challenge with administering corticosteroids to suppress an overactive immune system is balancing the benefits of inflammatory symptom relief and the risks of infection due to the resulting underactivity of the immune system. In this case, clinicians are encouraged to start with the lowest therapeutic dose possible, carefully monitor its use in patients with infections, and ensure that the benefits exceed the risks [6]. 

Corticosteroids also stop the body from producing its own natural cortisol. In a sense, a course of corticosteroids gives the adrenal glands a break. In a short course of corticosteroids, once the medication is discontinued, the adrenal glands can start back releasing cortisol. However, the adrenal glands do not resume releasing cortisol right away and need time to start working again.  

This is why corticosteroids (oral and parenteral forms) should not be stopped abruptly when taken for more than about two weeks [6]. If stopped abruptly, patients may develop adrenal insufficiency during this period, which can be life-threatening. 

Corticosteroid Pharmacology 

Common corticosteroid formulations include intravenous (IV), intramuscular (IM), intra-articular (injected directly into a joint), oral, inhaled, intranasal (nasal spray), topical, ophthalmic (eye drops), and otic (ear canal). The increased risk of infection is most associated with systemic formulations (oral and parenteral).  

The following sections will cover the pharmacology of systemic corticosteroids, including indications, mechanisms of action, pharmacokinetics, precautions, adverse effects, drug interactions, and warnings [7]. 

Indications 

Corticosteroids are useful in the treatment of many medical conditions. Some indications for corticosteroids among adults include the following diseases, conditions, and situations (maybe drug- or route-specific) [6][7]. 

Allergic Reactions 

Corticosteroids are well-known for treating mild to severe allergic reactions. These include anaphylaxis, angioedema, and laryngeal edema (non-infectious). Others include hypersensitivity reactions to medications or food, severe seasonal allergies (like allergic rhinitis), contact dermatitis (or rash), and itching. 

Autoimmune Diseases 

Corticosteroids are used to treat autoimmune disorders including systemic lupus erythematosus, Crohn’s disease, rheumatoid arthritis, and plaque psoriasis. Others include autoimmune hepatitis, hemolytic anemia, celiac disease (gluten intolerance), sarcoidosis (marked by lumps of inflammatory cells throughout the body) and myasthenia gravis (marked by weakness in voluntary muscles). 

Pulmonary Exacerbations 

Corticosteroids are useful in the treatment of exacerbations from asthma and chronic obstructive pulmonary disease (COPD). 

Adrenal Insufficiency 

Corticosteroids may be used to treat both primary and secondary adrenocortical insufficiency. This includes Addison’s disease, congenital adrenal hyperplasia, and adrenogenital syndrome. 

Inflammatory Bowel Disease 

Inflammatory bowel disease, such as the aforementioned Crohn’s disease, and ulcerative colitis may be treated with corticosteroids. 

Neuro/Musculoskeletal Disorders 

Corticosteroids are used in the treatment of ankylosing spondylitis (chronic inflammation of spinal joints), bursitis, polymyalgia rheumatica (marked by muscle pain and stiffness), osteoarthritis, and psoriatic arthritis. Corticosteroids can also treat neurological conditions like multiple sclerosis and Bell’s palsy (facial paralysis, often temporary). 

Inflammatory Eye Conditions 

Corticosteroids are useful in the systemic treatment of inflammatory ophthalmic conditions including optic neuritis, allergic conjunctivitis, and other conditions that cause inflammation of various structures of the eye. 

Organ Transplant Rejection Prophylaxis 

Renal transplant guidelines recommend corticosteroids in combination with other medications to prevent kidney rejection after transplantation (called induction therapy or immunosuppressant therapy). Corticosteroids are also indicated for heart and liver transplant rejection prophylaxis. 

Cancer 

Corticosteroids may be used for the palliative treatment of cancers including multiple myeloma and chronic lymphocytic leukemia (CLL). They may also be used to treat Hodgkin lymphoma (in conjunction with cancer medications), aggressive non-Hodgkin lymphoma, peripheral T-cell lymphoma, and neoplastic-associated hypercalcemia. 

COVID-19 

Although still in the investigative stages, the World Health Organization (WHO) recommends systemic corticosteroids as an adjunctive treatment for severe COVID-19 [6][13]. 

Mechanism of Action 

As already mentioned, corticosteroids suppress the immune system. This is done by preventing protein synthesis in certain cells of the immune system (like macrophages and neutrophils), ultimately inhibiting their fighting potential [6][11]. More specifically, corticosteroids repress the activity of DNA within the immune cell – an activity that would otherwise serve as the beginning of protein synthesis.  

Within immune cells, DNA sends messages to protein-making structures within the cell that prompts them to start making protein. However, the message must be “translated” or “decoded” (transcription) first before the structures can “understand” what to do [6][12]. Messenger RNA (mRNA) is the transcribed version of DNA. Corticosteroids work by making it difficult for DNA to be transcribed into mRNA.  

Pharmacokinetics 

The pharmacokinetics of corticosteroids differ based on drug type and route. The following is the pharmacokinetics of three common systemic corticosteroid drugs: prednisone, methylprednisolone, and dexamethasone [6]. 

Prednisone 

Prednisone comes in oral forms, both immediate-release (IR) and delayed-release. Prednisone IR is quickly absorbed in the gastrointestinal (GI) tract with a peak effect after one to two hours. Delayed-release tablets are released four hours after ingestion and peak after about six hours. Prednisone is metabolized by the liver and excreted by the kidneys. 

Methylprednisolone  

Methylprednisolone is rapidly absorbed orally and peaks within one to two hours. After IV administration, effects can occur within one hour with nearly complete excretion in 12 hours. When given as an injection in the joint, methylprednisolone absorption can occur over several days. This medication is distributed into various organs and body structures including the kidneys, intestines, skin, liver, and muscle. Methylprednisolone is metabolized by the liver and excreted by the kidneys. 

Dexamethasone 

Oral dexamethasone peaks in one to two hours. Absorption times for parenteral forms depends on the dosage and indication. For example, in patients with cerebral edema, treatment response from an IV dose of dexamethasone followed by an IM dose occurs in 12 to 24 hours [1]. Dexamethasone is rapidly distributed into the skin, intestines, liver, muscle, and kidneys. As with prednisone and methylprednisolone, this medication is metabolized by the liver and excreted by the kidneys. 

Contraindications and Precautions 

Clinicians should not prescribe/administer prednisone to patients with an allergy to the drug or any components of its formulation. Precautions should be taken in patients with an allergy to other corticosteroids as cross-sensitivity can occur. Clinicians should also be aware that high-dose systemic corticosteroids place patients at risk for immunosuppression, especially when prescribed/administered with other immunosuppressant medications.  

Although carrying a lower risk, moderate-dose and low-dose corticosteroid preparations should be monitored as well. Clinicians should avoid prescribing/administering these medications to patients with fungal or bacterial infections that are not well controlled with anti-infective medications.  

Pregnancy and Breastfeeding Precautions 

While corticosteroids are not contraindicated for pregnant or breastfeeding patients, clinicians have reason to be cautious when prescribing/administering these medications [6]. The following are precautions for pregnant and breastfeeding patients. 

Pregnancy 

If corticosteroids must be prescribed/administered during pregnancy, precaution should be taken as these medications cross the placenta and may be harmful to the fetus/infant (may cause adrenal insufficiency in the infant). Although the risks are small and inconsistent, oral or facial clefts (like cleft palate) may occur if systemic corticosteroids are prescribed/administered during the first trimester. 

Breastfeeding 

Corticosteroids are distributed into breastmilk. While no reported side effects have been reported in breast-fed infants, lower doses are recommended as high doses may cause problems with the infant’s growth and development. Corticosteroids can interfere with the infant’s ability to produce their own glucocorticoid hormones. With prednisone in particular, peak concentrations in breastmilk occur in about one hour after the dose is taken and it is recommended for patients to avoid breastfeeding during this time. However, the total daily dose of prednisone reaching the infant has been shown to be approximately 0.1% of the mother’s total daily dose [6]. 

Adverse Effects 

Corticosteroids given systemically can affect multiple body systems, particularly with prolonged use. Short-term use in high doses typically does not cause adverse effects [6]. Adverse effects of corticosteroids can be as mild as a rash to as severe as psychosis or a ruptured heart wall.  

The following are adverse effects categorized by body systems [6]. 

Neurological 

Corticosteroids may increase intracranial and intraocular pressure which can lead to optic nerve damage and visual impairments. These medications can also lower seizure thresholds. Other neurological findings include headache, vertigo, and peripheral neuropathy. 

Pulmonary 

Corticosteroids can reactivate tuberculosis (TB) in patients who have a history of active TB. 

Cardiovascular 

Sodium retention, edema, and low potassium may occur in patients with high blood pressure or congestive heart failure (can also occur with renal failure/insufficiency). Left ventricular free-wall rupture can occur in patients with a recent myocardial infarction. Corticosteroids may also exacerbate arrhythmias and cause blood clots which may lead to a stroke. 

Endocrine 

Corticosteroids are known to decrease glucose tolerance and raise blood glucose levels. This can aggravate existing diabetes mellitus. Hypothalamic-pituitary-adrenal (HPA) suppression or signs/symptoms of Cushing’s syndrome (marked by high cortisol levels) can also occur with prolonged systemic use. 

Gastrointestinal/Genitourinary 

Corticosteroids can increase the risk of GI perforation and should therefore be monitored in patients with peptic ulcer disease, diverticulitis, or GI abscess. Additionally, esophageal ulcers and GI bleed may occur with use. Corticosteroids may cause weight loss, but can stimulate the appetite as well, leading to weight gain conversely. Menstrual irregularity may occur as well. 

Musculoskeletal 

Osteopenia (loss of bone density) and osteoporosis (more severe bone loss) can occur due to decreased bone formation, increased bone resorption, and inhibition of osteoblast function. Bone fractures (primarily in elderly patients) can occur as well. Acute generalized myopathy leading to quadriparesis (weakness in all extremities) may occur in patients with neuromuscular disease or those receiving neuroblocking medications. Muscle pain and waste can also occur due to protein depletion. 

Skin 

Corticosteroids may cause impaired wound healing due to protein depletion. Sweating, abnormal hair growth, and striae (stretch marks) can also occur with use. While corticosteroids may be useful in the treatment of rashes and itching, they can cause these symptoms as well. 

Psychiatric 

Psychiatric problems can occur with corticosteroid use, including euphoria, severe depression, anxiety, hallucinations, psychosis, personality changes, and withdrawn behavior. Patients may also experience insomnia, impaired cognition, mood swings, irritability, and restlessness. 

Laboratory Changes 

A common lab finding with corticosteroid use is leukocytosis (without an infectious or inflammatory cause). It is important for clinicians to differentiate between infectious and corticosteroid-related leukocytosis. Other lab findings may include low neutrophil count and abnormal electrolyte levels (high sodium, low calcium, and low potassium).   

Black Box Warning 

Black box warnings are issued by the U.S Food and Drug Administration (FDA) to warn the public about the serious adverse effects of some medications. The most recent black box warning for corticosteroids was issued in 2014. The FDA warned against administering corticosteroid injections into the epidural space of the spine for the treatment of neck/back pain and radiating pain in the extremities [4]. When administered in this way, serious (although rare) adverse effects can occur including vision loss, stroke, paralysis, and death. 

Drug Interactions 

The therapeutic effect of corticosteroids may be counteracted or enhanced when administered with certain medications. Clinicians should perform an accurate medication reconciliation when prescribing/administering corticosteroids to ensure effective and safe treatment.  

The following are medications that interact with corticosteroids categorized by a decreased or increased therapeutic effect [1]. Corticosteroid doses should be adjusted accordingly. 

Decreased Therapeutic Effect 

Medications that can decrease the level of corticosteroids in the blood when administered together include: 

• Barbiturates 
• Carbamazepine 
• Ephedrine 
• Phenytoin 
• Rifampin 
• Cholestyramine (affects oral corticosteroids in particular) 

Increased Therapeutic Effect 

Medications that can increase the level of corticosteroids in the blood when administered together include: 

• Ketoconazole 
• Macrolide antibiotics 

Clinical Guidelines on Corticosteroid Use in the Critically Ill 

Clinical practice guidelines for corticosteroid therapy were developed to assist clinicians and providers in ensuring optimal prescribing and administration practices. Currently, guidelines are in place for corticosteroid use in critical illness. The most recent 2024 guidelines were reestablished for the treatment of septic shock, acute respiratory distress syndrome, and community-acquired bacterial pneumonia, particularly in adult patients.  

In the following sections, these guidelines are compared with prior 2017 recommendations [3]. Clinicians practicing in acute care settings can use the following guidelines when prescribing/administering corticosteroids to patients who are critically ill. 

Sepsis and Septic Shock 

Previously, the guidelines recommend against administering corticosteroids in adult patients with sepsis without shock. Instead, corticosteroids were recommended in patients with septic shock not responsive to fluid and moderate- to high-dose vasopressor therapy. 

Current Recommendation: Administer corticosteroids to adult patients with septic shock. Do not administer high dose/short duration corticosteroids for adult patients with septic shock (no more than 400 mg per day of a hydrocortisone equivalent for no more than three days). 

Acute Respiratory Distress Syndrome  

Previously, the guidelines recommended corticosteroid use in patients with early moderate to severe acute respiratory distress syndrome (PaO2/FIO2 of less than 200 and within 14 days of onset). 

Current Recommendation: Administer to adult hospitalized patients with acute respiratory distress syndrome. 

Community-Acquired Bacterial Pneumonia 

Previously, the guidelines recommended corticosteroid use for five to seven days at a daily dose of less than 400 mg IV hydrocortisone (or equivalent) in hospitalized patients with community-acquired pneumonia. 

Current Recommendation: Administer to adult patients hospitalized with severe bacterial community-acquired pneumonia. There is no recommendation for adult patients hospitalized with less severe bacterial community-acquired pneumonia.  

Clinical Guidelines on Corticosteroid Use for COVID-19 

While data is limited and still developing, both the World Health Organization (WHO) and the National Institutes of Health (NIH) developed clinical practice guidelines for the use of corticosteroids as a treatment for COVID-19.  

Clinicians practicing in acute care settings can use the following guidelines when prescribing/administering corticosteroids to patients with COVID-19. 

Global Guidelines for Corticosteroid Use for COVID-19 

As mentioned earlier, the WHO recommends corticosteroids for the treatment of severe COVID-19 [6]. The 2020 “Corticosteroids for COVID-19: Living Guidance” recommendations are as follows [13]: 

• The WHO recommends systemic corticosteroids rather than no corticosteroids for the treatment of patients with severe and critical COVID-19. 
• The WHO suggests not to use corticosteroids in the treatment of patients with non-severe COVID-19. 

National Guidelines for Corticosteroid Use for COVID-19 

The National Institutes of Health (NIH) developed the 2023 “Therapeutic Management of Hospitalized Adults with COVID-19” guidelines outlining various drug therapy recommendations for patients with COVID-19, including corticosteroids. Recommendations are as follows [9][10]: 

• The panel recommends against the use of dexamethasone (or other systemic corticosteroids) for the treatment of COVID-19 in patients who do not require supplemental oxygen. 
• The panel recommends against the use of dexamethasone (or other systemic corticosteroids) in nonhospitalized patients in the absence of another indication. 
• The panel recommends patients with COVID-19 receiving dexamethasone (or another corticosteroid) for an underlying condition to continue this therapy as directed by their health care provider. 

Patient Education 

Therapeutic and safe corticosteroid use is dependent on safe prescribing and administration practices, as well as patient compliance. Optimal patient education is vital for successful treatment with corticosteroids.  

The following are teaching points to share with patients about corticosteroid use [1][6][7]. 

• Adverse Effects: Patients should be informed of common adverse effects, particularly elevated blood sugar, mood changes, appetite changes, and weight gain. 
• Vaccine Safety: Patients should be encouraged to check with their health provider before receiving vaccines (Corticosteroids should not be given with live vaccines) 
• Infection Risk: Patients should be informed of the risk for developing an infection when corticosteroid doses are high or used to suppress the immune system, and to therefore avoid exposure to chickenpox or measles. 
• Administration: Patients should be instructed to avoid abruptly stopping corticosteroids to prevent adrenal insufficiency and potentially death. They should also be made aware that stress on the body (for example, when having surgery) may require additional doses of corticosteroids. 

Future Implications 

Corticosteroid use may be on the rise. As aforementioned, corticosteroids are useful in the treatment of autoimmune disease. In the U.S., researchers anticipate a rise in autoimmune diseases in the future.  

In a 2020 study in Arthritis and Rheumatology, researchers noted that the prevalence of antinuclear antibodies (ANA) (markers of autoimmune disease) is increasing in the U.S. [8]. The study analyzed the antibodies of over 14,000 participants (age 12 and older) over the course of three time periods. Results revealed the following: 

• From 1988 – 1991, 22 million people had antibodies. 
• From 1999 – 2004, 27 million people had antibodies. 
• From 2011 – 2012, 41 million people had antibodies. 

The study also found that antibody prevalence is highest among males, non-Hispanic whites, adults over age 50, and adolescents. Young people age12 to 19 had the highest antibody prevalence. While it is unclear why this is the case among the youth, the study findings may suggest an increase in the use of corticosteroids in the future. Further, clinicians might anticipate changes in clinical guidelines for safe prescribing/administration practices. 

Conclusion

Corticosteroids are helpful in the treatment of many medical conditions and diseases. While the use of these medications is common, there are equally associated risks, many of which can be life-threatening. Safe prescribing/administration practices are imperative. Clinicians can ensure that treatments are safe and effective through the gathering of accurate health histories, careful evaluation of each patient’s situation, weighing of risks and benefits, and provision of effective education to patients. 

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