Continuing Education Activity

Methylprednisolone is an FDA-approved medication for the management and treatment of allergic conditions, arthritis, asthma exacerbations, long-term asthma maintenance, acute exacerbation of multiple sclerosis, and as an anti-inflammatory and immunosuppressive agent. It is in the systemic corticosteroid class of medications. This activity outlines the indications, action, and contraindications for methylprednisolone as a valuable agent in treating many endocrine, inflammatory, immunologic, hematologic, and respiratory disorders.

Objectives:

• Identify the mechanism of action of methylprednisolone.
• Describe the potential adverse effects for patients taking methylprednisolone.
• Review and select the appropriate monitoring for patients on methylprednisolone.
• Outline the importance of improving care coordination and communication amongst the interprofessional team to enhance care delivery and improve outcomes for patients receiving methylprednisolone.

Indications

Methylprednisolone is a systemic synthetic corticosteroid, which, just as the naturally occurring glucocorticoids, exerts a wide range of physiologic effects. Clinical use of methylprednisolone is mainly due to its anti-inflammatory and immunosuppressive activity in the human body.

Labeled indications of methylprednisolone subcategorize by its use in different organ systems:

• In dermatology, it has utility in managing atopic dermatitis, contact dermatitis, pemphigus vulgaris, and foliaceus, bullous pemphigus, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis.[1][2][3][4]
• In endocrinology, it is used to manage congenital adrenal hyperplasia, hypercalcemia associated with cancer, and as a second-line treatment in conjunction with mineralocorticoids for primary or secondary adrenocortical insufficiency.
• In gastroenterology, methylprednisolone's use is for acute exacerbations of inflammatory bowel disease.[5][6][5][7]
• In hematology, it serves to treat autoimmune hemolytic anemia, congenital (erythroid) aplastic anemia, and immune thrombocytopenia.[8][9][10]
• In neurology, it is the mainstay therapy in acute exacerbations of multiple sclerosis.[11]
• In ophthalmology, it is a therapeutic choice in severe allergic and inflammatory processes of the eye and its adnexa, such as uveitis, scleritis, chorioretinitis, iritis and iridocyclitis, keratitis, optic neuritis, retinal vasculitis, and allergic conjunctivitis,
• In nephrology, it is helpful in the management of nephrotic syndrome, idiopathic type, or secondary to lupus nephritis.[12][13][14]
• In pulmonology, its indications include aspiration pneumonitis, asthma, chronic beryllium disease as an adjunct to antituberculous chemotherapy in disseminated pulmonary tuberculosis, eosinophilic pneumonia, and symptomatic sarcoidosis.[15][16][17][18]
• In rheumatology, it has indications for the management of acute rheumatic carditis, acute gout, ankylosing spondylitis, dermatomyositis and polymyositis, psoriatic arthritis, and rheumatoid arthritis, including the juvenile type and systemic lupus erythematosus.[19][20][21][22][23][24][25]

Other miscellaneous labeled indications for methylprednisolone include:

• Intraarticular and soft tissue administration in acute gouty arthritis, acute and subacute bursitis, acute tenosynovitis, epicondylitis, and synovitis of osteoarthritis.[26][27]
• Intralesional administration in alopecia areata, discoid lupus erythematosus, keloid disease, and lichen planus.[28][29][30][31]

Off-label indications of methylprednisolone include:

• Adjunct therapy for acute spinal cord injury
• Moderate to severe acute distress respiratory syndrome and severe alcoholic hepatitis
• As a preventive agent in bronchiolitis obliterans syndrome
• Hormonal resuscitation in cadaveric organ recovery
• Treatment of acute cellular and antibody-mediated rejection in cardiac transplant
• Adjunct in the management of acute exacerbation of chronic obstructive pulmonary disease
• Severe/refractory nausea and vomiting of pregnancy
• Adjunct treatment of Pneumocystis pneumonia in HIV-infected patients
• As palliation alternative in castration-resistant metastatic prostate cancer

Mechanism of Action

Methylprednisolone and its derivatives, methylprednisolone acetate succinate, and methylprednisolone sodium, are intermediate-acting, synthetic glucocorticoids. They are used mainly as anti-inflammatory or immunosuppressive agents. Methylprednisolone is five times more potent in its anti-inflammatory properties relative to hydrocortisone (cortisol), with minimal mineralocorticoid activities compared to the latter.[32]

Methylprednisolone diffuses passively across the cellular membrane and binds to the intracellular glucocorticoid receptor. This complex translocates into the nucleus, where it interacts with specific DNA sequences, resulting in either enhancement or suppression of transcription of particular genes. The methylprednisolone-glucocorticoid receptor complex binds and blocks promoter sites of proinflammatory genes,[33] promotes expression of anti-inflammatory gene products,[34] and inhibits the synthesis of inflammatory cytokines, mainly by blocking the function of transcription factors, such as nuclear factor-kappa-B (NF-kB).[35]

Like the rest of the corticosteroids, methylprednisolone also suppresses the synthesis of cyclooxygenase (COX)-2, responsible for the production of prostaglandins in damaged tissue leading to the inflammation cascade.[36]

By reversing capillary permeability, suppressing the migration of fibroblasts and polymorphonuclear leukocytes, controlling the rate of protein synthesis, and stabilizing lysosomes at the cellular level, methylprednisolone may control or prevent inflammation through these actions as well.

Methylprednisolone inhibits cell-mediated immunologic functions, especially those dependent on lymphocytes. Glucocorticoid administration results in neutrophilic leukocytosis, smaller elevations in monocytes, dramatic reductions in circulating eosinophils, and lesser reductions in lymphocytes. The use of methylprednisolone and other glucocorticoids results in a reduced ability of leukocytes to adhere to vascular endothelium and exit from the circulation. Glucocorticoids impair a variety of T cell functions, and moderate-to-high doses induce T cell apoptosis while keeping B cell function and antibody production preserved.[37]

Tissue-specific responses to steroids can occur by the presence in each tissue of specific protein regulators controlling the interaction between the hormone-receptor complex and particular DNA response elements. This activity leads to a wide array of gene expression and physiological responses by corticosteroids.

Some of the most important effects of methylprednisolone and the rest of the corticosteroids are the result of homeostatic responses by insulin and glucagon. Glucocorticoids stimulate gluconeogenesis, which results in elevated blood glucose, catabolism of muscle protein, and stimulation of insulin secretion. Both lipolysis and lipogenesis become stimulated, with a net increase of fat deposition in certain areas (e.g., face, shoulders, and back).[38]

Methylprednisolone and the rest of the glucocorticoids cause muscle protein catabolism. Also, lymphoid and connective tissue, fat, and skin undergo wasting under the influence of high concentrations of these steroids. Catabolic effects on the bone can lead to osteoporosis. In children, growth inhibition takes place.

Administration

Methylprednisolone may be administered orally with food or milk to decrease gastrointestinal adverse effects. Administration may also be intramuscularly or intravenously. When administered intramuscularly (in the form of methylprednisolone acetate or succinate), the administration should not be into the deltoid muscle due to evidence of subcutaneous atrophy. Injections into the dermis should be avoided, and injection should not be into areas that have evidence of acute local infection.

Intravenous administration of methylprednisolone (in the form of methylprednisolone succinate) is rate dependent upon the dose and severity of the condition. Most commonly, with intermittent infusion, methylprednisolone is administered over 15 to 60 minutes. The administration of large doses should be over at least 30 to 60 minutes. 

There are reports of hypotension, cardiac arrhythmias, and sudden death when methylprednisolone administration occurs under 30 minutes in doses greater than or equal to 250 mg.[39]

The onset of action of intravenous methylprednisolone succinate is within 1 hour, while intra-articular administration of methylprednisone acetate is of 1 week, with a duration of 1 to 5 weeks. Methylprednisolone has an oral bioavailability of 88% approximately. The half-life elimination of intravenous methylprednisolone is of 0.25 hours, with an oral half-life of 2-5 hours. It has hepatic metabolism and undergoes urinary excretion.[40][41]

Adverse Effects

The significant undesirable effects of glucocorticoids result from their hormonal actions, which lead to the clinical picture of iatrogenic Cushing syndrome. Facial rounding, puffiness, fat deposition, and plethora usually appear (moon facies). Fat tends to redistribute from the extremities to the trunk, the back of the neck, and the supraclavicular fossae. There is increased growth of fine hair on the face, thighs, and trunk. Steroid-induced punctate acne may appear, and insomnia and increased appetite are also effects.

With concurrent use of methylprednisolone, protein catabolism will continue, diverting amino acids to glucose production, thus increasing the need for insulin and over time resulting in weight gain. Myopathy and muscle wasting can occur, as well as thinning of the skin, with striae and bruising. Hyperglycemia and eventually osteoporosis can develop, as well as diabetes and aseptic necrosis of the hip.[42]

A more detailed way to review the adverse effects of methylprednisolone and other corticosteroids is by classifying them based on the different organ systems affected:

• Dermatologic and side effects in appearance include skin thinning and ecchymoses, Cushingoid features, and weight gain.
• Ophthalmologic side effects include the formation of cataracts, increased intraocular pressure, and the development of exophthalmos.
• Cardiovascular side effects include fluid retention and hypertension, premature atherosclerotic disease, arrhythmias, and possible hyperlipidemia.
• Gastrointestinal effects include the increased risk of gastritis, ulcer formation, and gastrointestinal bleeding. 
• Bone and muscle effects include osteoporosis, osteonecrosis, and myopathy.
• Neuropsychiatric side effects include mood disorders, psychosis, and memory impairment.
• Metabolic and endocrine side effects consist of hyperglycemia and hypothalamic-pituitary-adrenal axis suppression.
• Immune system effects include increased susceptibility to infections.
• Hematologic side effects include leukocytosis and neutrophilia.

Contraindications

Methylprednisolone contraindications include patients with documented hypersensitivity to the drug or components, systemic fungal infection, intrathecal administration, live or attenuated virus vaccine, idiopathic thrombocytopenic purpura, or in premature infants.[43]

Like all other glucocorticoids, methylprednisolone must be used with great caution in patients with peptic ulcers, heart disease or hypertension with heart failure, certain infectious illnesses such as varicella and tuberculosis psychoses, diabetes, osteoporosis, or glaucoma.[44]

Monitoring

Blood pressure, blood glucose, electrolytes, weight, bone mineral density, HPA hypothalamic-pituitary-adrenal (HPA) axis suppression, and intraocular pressure all require monitoring in patients taking methylprednisolone. Growth and development monitoring should be in place for children.

Patients receiving methylprednisolone must be monitored carefully for the development of hyperglycemia, glycosuria, sodium retention with edema or hypertension, hypokalemia, peptic ulcers, osteoporosis, and hidden infections.

The dosage should be as low as possible. Even patients maintained on low doses of methylprednisolone may require supplementary therapy at times of stress, such as during surgery, intercurrent illness, or trauma occurs.

Toxicity

Most of the toxic effects of methylprednisolone and other glucocorticoids are predictable from their impact on the body's physiology. Some are life-threatening and include metabolic effects (growth inhibition, diabetes, muscle wasting, osteoporosis), salt retention (although less common with methylprednisolone), and psychosis.

Methods for minimizing these toxicities include local application, alternate-day therapy (to reduce pituitary suppression), and tapering the dose promptly after attaining a therapeutic response. Additional "stress doses" may be necessary during serious illness or before major surgery to prevent adrenal insufficiency in patients who have received long-term treatment with methylprednisolone.

Enhancing Healthcare Team Outcomes

Methylprednisolone is a widely-used drug in multiple fields of medicine, mainly due to its anti-inflammatory and immunosuppressive properties. Interprofessional healthcare team members, including nurses, pharmacists, mid-level practitioners, and clinicians, should be aware of its broad spectrum of clinical applications, both labeled and off-labeled indications while considering its contraindications and individualizing its use based on the patient's comorbidities and tolerance of side effects. Of particular importance, patients receiving methylprednisolone should undergo monitoring for the development of hyperglycemia, hypertension, peptic ulcer, osteoporosis, and hidden infections.

Clinicians (MDs, DOs, NPs, PAs) will be prescribing or ordering the medication. Nursing will administer if inpatient and can monitor for adverse effects in both inpatient and outpatient settings. Pharmacists should be involved to verify dosing and perform medication reconciliation. Both pharmacists and nurses need to alert the healthcare team if they encounter any issues of concern. All these interprofessional healthcare team members need to communicate and collaborate across interprofessional lines to ensure optimal therapeutic results. [Level 5]

As with all glucocorticoids, methylprednisolone's adverse effects are both dose- and duration-dependent and can range from non-serious displeasing appearance to those that are life-threatening. Interprofessional coordination and care between healthcare workers are needed to ensure that methylprednisolone dosage remains minimal and for the shortest period necessary to achieve the treatment goals. Preexisting comorbidities that may become exacerbated when treated with methylprednisolone require management, and that patients under treatment should be monitored by the pharmacist, nurse, and clinician for adverse effects, identifying who may benefit from additional intervention. An interprofessional team approach will lead to the best outcomes. [Level 5]

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