Indications
Methylprednisolone is a systemic synthetic corticosteroid that exerts a wide range of physiologic effects similar to naturally occurring glucocorticoids. Methylprednisolone is typically prescribed due to its anti-inflammatory and immunosuppressive activity in the human body. The FDA-approved indications and off-label uses for methylprednisolone therapy are listed below.
FDA-Approved Indications
The following indications for methylprednisolone administration approved by the U.S. Food and Drug Administration are categorized below by organ system.
Dermatology:
- Atopic dermatitis
- Contact dermatitis
- Pemphigus vulgaris
- Pemphigus foliaceous
- Bullous pemphigus
- Erythema multiforme
- Stevens-Johnson syndrome
- Toxic epidermal necrolysis [1][2][3][4]
Endocrinology:
- Congenital adrenal hyperplasia associated with cancer
- Hypercalcemia associated with cancer
- Primary or secondary adrenocortical insufficiency (as a second-line treatment in conjunction with mineralocorticoids)
Gastroenterology:
Hematology:
- Autoimmune hemolytic anemia
- Congenital (erythroid) aplastic anemia
- Immune thrombocytopenia [8][9][10]
Neurology:
- Multiple sclerosis (acute exacerbations) [11]
Ophthalmology:
- Uveitis
- Scleritis
- Chorioretinitis
- Iritis and iridocyclitis
- Keratitis
- Optic neuritis
- Retinal vasculitis
- Allergic conjunctivitis
Nephrology:
Pulmonology:
- Aspiration pneumonitis
- Asthma
- Chronic beryllium disease
- Disseminated pulmonary tuberculosis (as an adjunct to antituberculous chemotherapy)
- Eosinophilic pneumonia
- Symptomatic sarcoidosis [15][16][17][18]
Rheumatology:
- Acute rheumatic carditis
- Acute gout
- Ankylosing spondylitis
- Dermatomyositis and polymyositis
- Psoriatic arthritis
- Rheumatoid arthritis (including juvenile type)
- Systemic lupus erythematosus [19][20][21][22][23][24][25]
The FDA-approved indications and methods for the administration of methylprednisolone acetate formulation specifically are listed below.[26][27][28][29][30][31]
Intra-articular and soft tissue administration:
- Acute gouty arthritis
- Acute and subacute bursitis
- Acute tenosynovitis
- Epicondylitis
- Synovitis of osteoarthritis
Intralesional administration:
- Alopecia areata
- Discoid lupus erythematosus
- Keloid disease
- Lichen planus
Off-Label Uses
Methylprednisolone may be administered for the following conditions or scenarios. The U.S. Food and Drug Administration has not approved these indications.
- As adjunct therapy for patients with acute spinal cord injury.[32] The administration of methylprednisolone within 8 hours following a spinal cord injury requires careful individual consideration due to potential complications.[33]
- Myasthenia gravis [34]
- Severe urticaria [35]
- Sjögren's syndrome [36]
- Severe/refractory nausea and vomiting during pregnancy [37]
- COVID-19 requiring oxygen or ventilatory support [38]
- Amiodarone-induced thyrotoxicosis (drug-resistant) [39]
- Moderate to severe acute distress respiratory syndrome (ARDS)
- Severe alcoholic hepatitis
- As a preventive agent in bronchiolitis obliterans syndrome
- Hormonal resuscitation in cadaveric organ recovery
- Acute cellular or antibody-mediated rejection in cardiac transplant
- As adjunct therapy for patients with acute exacerbation of chronic obstructive pulmonary disease (COPD)
- As adjunct treatment of Pneumocystis pneumonia in patients with HIV
- As a palliative option for patients with castration-resistant metastatic prostate cancer
Mechanism of Action
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Mechanism of Action
Methylprednisolone and its derivatives, methylprednisolone acetate succinate and methylprednisolone sodium, are intermediate-acting synthetic glucocorticoids. They are typically prescribed as anti-inflammatory or immunosuppressive agents. As an anti-inflammatory, methylprednisolone is 5 times as potent as hydrocortisone (cortisol) while demonstrating minimal mineralocorticoid activity.[40] Methylprednisolone diffuses passively across the cellular membrane and binds to the intracellular glucocorticoid receptor. This complex translocates into the nucleus to interact with specific DNA sequences and enhance or suppress the transcription of particular genes. The methylprednisolone-glucocorticoid receptor complex blocks the promoter sites of proinflammatory genes, promotes the expression of anti-inflammatory gene products, and inhibits the synthesis of inflammatory cytokines; these actions are accomplished primarily by blocking the function of transcription factors, such as nuclear factor-kappa-B (NF-kB).[41][42][43]
As a corticosteroid, methylprednisolone also suppresses the synthesis of cyclooxygenase (COX)-2, an enzyme that produces prostaglandins in damaged tissue and contributes to the inflammation cascade.[44] Through these actions, methylprednisolone can reduce or prevent inflammation 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 inhibits cell-mediated immunologic functions, especially those dependent on lymphocytes. Glucocorticoid administration results in neutrophilic leukocytosis, reduced monocyte elevations, dramatic reductions in circulating eosinophils, and milder reductions in lymphocytes. Methylprednisolone and other glucocorticoids reduce leukocytes' ability to adhere to vascular endothelium and exit the circulation. Glucocorticoids impair various T-cell functions; moderate and high doses induce T-cell apoptosis while preserving B-cell functions, including antibody production.[45] Tissue-specific responses to steroids can occur due to specific protein regulators in each tissue 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 critical effects of methylprednisolone and other corticosteroids result from homeostatic responses by insulin and glucagon. Glucocorticoids stimulate gluconeogenesis, which elevates blood glucose levels, increases muscle protein and bone catabolism, and stimulates insulin secretion. Glucocorticoids stimulate lipolysis and lipogenesis, causing a net increase of fat deposition in some body areas (ie, face, shoulders, and back).[46] Glucocorticoids also cause wasting of lymphoid and connective tissue, fat, and skin at high doses. Catabolic effects on the bone can lead to osteoporosis in adults and growth inhibition in children.
Pharmacokinetics
Absorption: Depending on the administration route and dose, a 2-compartment (for high IV doses) or 1-compartment model (for lower IV and oral doses) is appropriate for describing methylprednisolone's pharmacokinetics. Methylprednisolone exhibits rapid and linear absorption, with peak concentrations achieved 48 minutes after administration. The onset of action of intravenous methylprednisolone succinate occurs within 1 hour. For intra-articular methylprednisone acetate, the onset of action occurs at 1 week and lasts 1 to 5 weeks. Methylprednisolone has an oral bioavailability of approximately 88%.
Distribution: Methylprednisolone succinate has a volume of distribution (Vd) of 24 ± 6 L and a steady-state volume of distribution (Vss) of 27 ± 8.2 L. This drug primarily binds to albumin in plasma.
Metabolism: Methylprednisolone undergoes hepatic metabolism to produce metabolites such as 20-carboxymethylprednisolone and 6β-hydroxy-20α-hydroxymethylprednisolone.
Elimination: Methylprednisolone is primarily excreted in urine, following a bi-exponential pattern.[47] The half-life elimination of intravenous methylprednisolone is 0.25 hours, with an oral half-life of 2-5 hours.[48][49]
Administration
Available Dosage Forms and Strengths
Methylprednisolone is available in tablet formulations of 2 mg, 4 mg, 8 mg, 16 mg, and 32 mg, injectable suspension formulations at concentrations of 20 mg/mL, 40 mg/mL, and 80 mg/mL, and as a powder for injection in doses of 40 mg, 125 mg, 500 mg, 1000 mg, and 2000 mg.
Adult Dosage
Methylprednisolone may be administered orally with food or milk to reduce gastrointestinal adverse effects. Methylprednisolone may also be administered intramuscularly or intravenously. When administered intramuscularly (methylprednisolone acetate or succinate), it should not be injected into the deltoid muscle, which may cause subcutaneous atrophy. Injections into the dermis or areas with evidence of acute local infection should be avoided. Intravenous administration (methylprednisolone succinate) is rate-dependent upon the dose and severity of the condition. Methylprednisolone is most commonly administered over 15 to 60 minutes with intermittent infusion. Large doses should be administered over a minimum of 30 minutes. Hypotension, arrhythmia, and sudden death have been reported when methylprednisolone doses of 250 mg or greater are administered in less than 30 minutes.[50]
COVID-19: For most patients with COVID-19 requiring supplemental oxygen, the National Institutes of Health (NIH) advises dexamethasone plus remdesivir; if dexamethasone is unavailable, clinicians can consider methylprednisolone, prednisone or hydrocortisone.[78]
A recent cohort study investigated the impact of intravenous (IV) methylprednisolone pulse therapy on in-hospital mortality risk in patients with acute COVID-19. Among patients receiving invasive mechanical ventilation, IV methylprednisolone pulse therapy at doses of 500 to 1000 mg daily reduced the risk of in-hospital mortality compared to those not receiving steroid pulse therapy or intermediate steroid doses.[51]
Anaphylaxis: The American Academy of Allergy, Asthma, and Immunology guidelines recommend that 1.0 to 2.0 mg/kg per dose of methylprednisolone be administered for adjunct treatment of anaphylaxis. Antihistamines and corticosteroids are adjunctive therapies for patients with anaphylaxis; epinephrine remains the primary treatment.[52]
Ulcerative colitis: The American College of Gastroenterology (ACG) recommends methylprednisolone 60 mg daily for remission in patients with severe ulcerative colitis.[53]
Lupus nephritis: According to the KDGIO 2024 guidelines, methylprednisolone pulses may be followed by a regimen of glucocorticoids during the initial treatment of active lupus nephritis upon satisfactory improvement in renal and extrarenal disease manifestations. Initial treatment typically involves IV methylprednisolone at a dose of 0.25 to 0.5 g/day for up to 3 days.[54] The study investigated the effects of high-dose methylprednisolone (above 100 mg) during cardiac arrest, revealing improved rates of sustained return of spontaneous circulation (ROSC) and overall survival at hospital discharge.[55]
Asthma exacerbation: According to the Global Initiative for Asthma (GINA) guidelines, methylprednisolone should be administered to patients 5 years or younger at 1 mg/kg, followed by oral steroids based upon clinical response.[79]
Juvenile idiopathic arthritis: Methylprednisolone can be used to treat juvenile idiopathic arthritis. However, intra-articular glucocorticoids such as triamcinolone are recommended as part of the initial therapy for active oligoarthritis.[56]
Steroid-resistant nephrotic syndrome: According to the International Pediatric Nephrology Association, pulse therapy with intravenous methylprednisolone (500 mg/m2 or 15 mg/kg) may be considered for patients with steroid-resistant nephrotic syndrome.[57]
Specific Patient Populations
Hepatic impairment: No dosage adjustments are provided in the product labeling. Caution is advised.
Renal impairment: No dose adjustment is required; caution is advised as high corticosteroid doses are associated with scleroderma renal crisis.[58]
Pregnancy considerations: The American College of Obstetricians and Gynecologists (ACOG) recommends steroids such as prednisone or methylprednisolone during pregnancy due to their conversion to less active forms facilitated by 11β-hydroxysteroid dehydrogenase in the human placenta.[59]
Breastfeeding considerations: Methylprednisolone levels in breast milk are very low, with no reported adverse effects on breastfed infants even after intravenous doses of 1 g. These infants are exposed to doses lower than their daily cortisol production, well below therapeutic neonatal doses. There is no accumulation of methylprednisolone in breast milk with consecutive daily doses. To minimize infant exposure, breastfeeding should be avoided during and for 2 hours after a 1 g intravenous dose. Smaller oral doses and local injections (eg, for tendinitis) do not require special precautions. However, systemic or joint injections, especially with medium to large corticosteroid doses, may temporarily reduce lactation.[60]
Pediatric patients: Weight-based dosing is preferred for pediatric patients.
Older patients: According to the American College of Rheumatology (ACR), intravenous glucocorticoid pulse doses are recommended for patients with giant cell arteritis (GCA), with methylprednisolone at a dosage range of 500 to 1000 mg per day for 5 days in adults.[61] Doses typically start at the lower end of the range due to the higher prevalence of reduced renal or cardiac function, concurrent diseases, and other medications.
Adverse Effects
The significant adverse effects of glucocorticoids stem from their hormonal actions, which can result in iatrogenic Cushing syndrome. Facial rounding, puffiness, fat deposition, and plethora (moon facies) are usually apparent. Fat redistributes from the extremities to the trunk, the back of the neck, and the supraclavicular fossae. Fine hair grows more quickly on the face, thighs, and trunk. Steroid-induced punctate acne may appear, and insomnia and increased appetite may be observed. With concurrent use of methylprednisolone, protein catabolism continues, diverting amino acids to glucose production, thus increasing the need for insulin and resulting in weight gain. Myopathy and muscle wasting can occur, as well as skin thinning, with striae and bruising. Hyperglycemia and osteoporosis can develop, as well as diabetes and aseptic necrosis of the hip.[62]
The adverse reactions associated with methylprednisolone and other corticosteroids are classified based on the different organ systems affected below.
Dermatology:
- Skin thinning
- Ecchymoses
- Cushingoid features
- Weight gain[63]
Ophthalmology:
- Cataracts
- Increased intraocular pressure
- Exophthalmos
Cardiovascular:
- Fluid retention
- Hypertension
- Premature atherosclerotic disease
- Arrhythmias
- Hyperlipidemia
Gastrointestinal:
- Gastritis
- Ulcer formation
- Gastrointestinal bleeding
Musculoskeletal:
- Osteoporosis
- Osteonecrosis
- Myopathy
Neuropsychiatric:
- Mood disorders
- Psychosis
- Memory impairment
Metabolic and endocrine:[64]
- Hyperglycemia
- Hypothalamic-pituitary-adrenal axis suppression [64]
Immune:
- Increased susceptibility to infections
Hematologic:
- Leukocytosis
- Neutrophilia (due to peripheral demargination) [65]
Drug-Drug Interactions
Chimeric antigen receptor T-cell therapy (CAR T-cell therapy): There is concern regarding the use of prophylactic corticosteroids due to the potential risk of diminishing CAR T-cell activity in the context of CAR T-cell therapy. Despite these concerns, existing evidence suggests that administering corticosteroids to manage adverse effects such as cytokine release syndrome (CRS) does not significantly impact the therapeutic outcomes of CAR T-cell therapy. Nonetheless, it is prudent to use corticosteroids with caution.[66]
Hepatic enzyme inducers: Co-administration with enzyme inducers such as phenobarbital, phenytoin, and rifampin may increase the metabolic clearance of methylprednisolone, necessitating potential dose adjustments to maintain therapeutic efficacy.
Hepatic enzyme inhibitors: Co-administration with enzyme inhibitors like ketoconazole/itraconazole may reduce the clearance of methylprednisolone, potentially increasing the risk of toxicity; dose titration may be required.[67]
Oral anticoagulants: The effect of methylprednisolone on oral anticoagulants can be variable, with reported cases of both enhanced and diminished anticoagulant activity. Regular monitoring of coagulation parameters is essential to ensure the desired anticoagulant effect is achieved.[68][69]
Live vaccines: The Advisory Committee on Immunization Practices (ACIP) recommends that live-virus vaccines should be avoided during and shortly after high-dose corticosteroid therapy (≥2 mg/kg or ≥20 mg/day of prednisone for ≥14 days) due to potential immunosuppression. Live virus vaccination is generally deferred for at least 1 month after discontinuing.[80]
Contraindications
Contraindications to methylprednisolone administration include documented hypersensitivity to the drug or components, systemic fungal infection, intrathecal administration, live or attenuated virus vaccine, and idiopathic thrombocytopenic purpura.[70] 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.[71]
Warning and Precautions
- Certain formulations of methylprednisolone contain benzyl alcohol, which is known to cause gasping syndrome in infants; these formulations should be avoided in premature infants. The label should be consulted for excipients before use.
- Certain formulations of methylprednisolone contain lactose, which is contraindicated in individuals with hypersensitivity to dairy products.[72]
Monitoring
Blood pressure, blood glucose, electrolytes, weight, bone mineral density, hypothalamic-pituitary-adrenal 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, and osteoporosis. Corticosteroid use raises the risk of reactivation of latent tuberculosis infection (LTBI).[73][74] The dosage should be as low as possible. Even patients maintained on low doses of methylprednisolone may require supplementary therapy during times of stress, such as during surgery, intercurrent illness, or trauma.[75]
Toxicity
Signs and Symptoms of Overdose
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 (eg, growth inhibition, diabetes, muscle wasting, osteoporosis), salt retention (although less common with methylprednisolone), and psychosis.[76]
Management of Overdose
Treatment of acute overdose involves supportive and symptomatic care. 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.[77] Additional "stress doses" may be necessary during severe illness or before major surgery to prevent adrenal insufficiency in patients who have received long-term treatment with methylprednisolone. Treatment of acute overdose involves supportive and symptomatic care.
Enhancing Healthcare Team Outcomes
Methylprednisolone is widely used in multiple fields due to its anti-inflammatory and immunosuppressive properties. Interprofessional healthcare team members, including nurses, pharmacists, advanced practice providers, and physicians, should be aware of its broad spectrum of clinical applications, both labeled and off-label 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. The healthcare team should monitor for adverse effects in inpatient and outpatient settings. Pharmacists should be involved in verifying dosing and performing medication reconciliation. Both pharmacists and nurses need to alert other members of the healthcare team if they encounter any issues of concern. All these interprofessional healthcare team members must communicate and collaborate across interprofessional lines to ensure optimal therapeutic results.
As with all glucocorticoids, methylprednisolone's adverse effects are both dose- and duration-dependent and can range from nonserious displeasing appearances to those that are life-threatening. Interprofessional coordination and care between healthcare professionals are needed to ensure that methylprednisolone dosage remains minimal and that the treatment goals are achieved in the shortest period. Preexisting comorbidities that may become exacerbated when treated with methylprednisolone require management, and 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 leads to the best outcomes. An interprofessional team approach and communication among clinicians, pharmacists, specialists, and nurses are crucial to decreasing potential adverse effects, improving disease course and quality of life, and improving patient outcomes related to methylprednisolone therapy.
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