Systemic Corticosteroid

Aka: Systemic Corticosteroid, Corticosteroid, Adrenocorticosteroid, Glucocorticoid, Systemic Glucocorticoid

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II. Mechanism: Natural Glucocorticoids (e.g. Cortisol)

  1. See Adrenal Gland Physiology
  2. Pathway
    1. Adrenal Cortex synthesizes and releases 21-carbon steroids in response to ACTH or Angiotensin II
    2. Glucocorticoids bind and activate cell surface Glucocorticoid receptors
    3. Triggers translocation of the Ligand-receptor complex to the nucleus
    4. In the nucleus, Glucocorticoid-responsive genes (e.g. lipocortins) are expressed
      1. Inhibits Phospholipase A2
        1. Prevents Arachidonic Acid release from phospholipid membranes
        2. Blocks synthesis of inflammatory Prostaglandins and Leukotrienes
      2. Inhibits inflammatory Cytokines
        1. Interleukin-1 (IL-1)
        2. Interleukin-6 (IL-6)
        3. Cytotoxic T-Lymphocytes
  3. Glucocorticoids mobilize available energy sources (Glucose, fats, Amino Acids)
    1. Increases Serum Glucose
      1. Stimulates liver Gluconeogenesis and glycogenolysis
      2. Decreases Insulin receptor binding
    2. Increases serum Fatty Acids by promoting lipolysis of adipose Triglyceride stores
      1. Promotes truncal Obesity
    3. Increases blood Amino Acids by breaking down Proteins (outside liver)
      1. Within liver, Cortisol induces Protein synthesis
  4. Glucocorticoid effects vary by tissue type
    1. Within the liver, anabolic (synthesis) effects predominate
    2. Within Muscle, skin, fat and connective tissue, catabolic (molecular breakdown, energy utilization) effects predominate
  5. Antiinflammatory activity
    1. Inhibit Histamine release
    2. Inhibits Lymphocyte production (but increases Neutrophil Count)
    3. Stabilizes MacrophageLysosomes and Antigen Processing
    4. Decreases Antibody production
  6. Gastrointestinal effects
    1. Increases gastric acid production and pepsin secretion
    2. Thins gastrointestinal mucosa
  7. Fluids and Electrolyte effects
    1. Increases Sodium retention
    2. Increases Potassium excretion
    3. Decreases Calcium absorption
    4. Increases clearance free water
    5. Metabolic Alkalosis
  8. Hematologic effects and Immune Effects
    1. Increases Red Blood Cell production (erythropoesis)

III. Mechanism: Synthetic Glucocorticoids (Corticosteroid analogs)

  1. As with natural Glucocorticoids, synthetic analogs have anti-inflammatory and immunomodulating activity
  2. Corticosteroid analogs are similar in structure and function to the natural 21-carbon steroids

IV. Precautions

  1. Systemic Glucocorticoids have significant adverse effects (see below)
  2. Systemic Glucocorticoids have many established indications with significant efficacy
    1. Asthma Exacerbation
    2. COPD Exacerbation
    3. Stress Dose Steroids
    4. Cancer Chemotherapy
    5. Peritonsillar Abscess
    6. Bells Palsy
    7. Acute Gout (in those unable to take NSAIDs)
    8. Extensive Allergic Contact Dermatitis (>20% of body surface area such as Rhus Dermatitis)
  3. However, many systemic steroid uses are NOT recommended (esp. for Upper Respiratory Infection) due to evidence against
    1. Not recommended in Acute Bronchitis (aside from acute COPD or Asthma Exacerbation)
      1. Hay (2017) JAMA 318(8): 721-30 [PubMed]
    2. Not recommended in mild to moderate Acute Pharyngitis (aside from Peritonsillar Abscess)
      1. Hayward (2017) JAMA 317(15): 1535-43 [PubMed]
    3. Not recommended in Acute Sinusitis
      1. Head (2016) Cochrane Database Syst Rev (4): CD011992 [PubMed]
    4. Not recommended in Allergic Rhinitis (use Inhaled Corticosteroids instead)
      1. Karaki (2013) Auris Nasus Larynx 40(3): 277-81 [PubMed]
    5. Not recommended in Carpal Tunnel Syndrome (use Carpal Tunnel Corticosteroid Injection instead)
      1. Wong (2001) Neurology 56(11): 1565-7 [PubMed]
    6. Controversial in Lumbar Radiculopathy (mixed study results)
      1. Goldeberg (2015) JAMA 313(19): 1915-23 [PubMed]

V. Dosing: Adult

  1. Betamethasone (Celestone) 0.5 to 0.9 mg IM/PO qd
  2. Cortisone (Cortone) 25-300 mg orally daily
  3. Dexamethasone (Decadron)
    1. Antiinflammatory: 0.5-10 mg/day PO/IM/IV divided every 6-12 hours
    2. Dexamethasone has high oral Bioavailability (80%) with onset of action within 1-2 hours
  4. Hydrocortisone (Cortef)
    1. See Stress Dose Steroid
    2. General
      1. Parenteral: 100 to 150 mg IV/IM q2-6 hours prn
      2. Oral: 20 to 240 mg/day PO in divided dosing
    3. Adrenal Insufficiency
      1. Adults: 100 mg IV every 8 hours (or Dexamethasone 4 mg IV)
      2. Children: 1 to 2 mg/kg IV every 8 hours
        1. Newborns: 12.5 mg IV
        2. Infants and young children: 25 mg IV
        3. School Aged Children: 50 mg IV
        4. Teens (same as adult dosing): 100 mg IV
  5. Methylprednisolone
    1. Parenteral (Solu-Medrol) 10 to 125 mg IV/IM
    2. Oral (Medrol) 4 to 48 mg PO qd
    3. Medrol Dose pack: tapers from 24 to 0 PO over 7 days
      1. Avoid Medrol dose pack (replace with Prednisone 30 mg orally daily for 5 to 6 days would have similar effect)
  6. Triamcinolone (Aristocort, Kenalog) 4 to 48 mg PO/IM daily
  7. Prednisolone (Prelone) 5-60 mg PO/IV/IM orally daily
    1. Requires no first pass metabolism via the liver (unlike Prednisone)
  8. Prednisone (Deltasone) 5-60 mg orally daily
    1. Requires first pass metabolism through the liver, but has 1:1 bioavailablity in most cases
    2. Consider Prednisolone in severe liver disease
  9. Rayos (delayed release version of Prednisone)
    1. Marketed to reduce morning inflammation in Rheumatoid Arthritis
    2. Taken at 10 pm with intended release starting at 2 am
    3. Unlikely to add significant benefit for the cost (more than $200 for thirty 5 mg tabs)
    4. (2012) Prescr Lett 19(12): 69

VI. Dosing: Child

  1. Methylprednisolone (Solu-Medrol)
    1. Dose: 1-2 mg/kg/dose PO/IV/IM q6h up to 125 mg/dose
  2. Prednisolone (Prelone)
    1. Dose: 1-2 mg/kg/dose PO qd to bid up to 60 mg/day
    2. Maximum: 60 mg per day
    3. Preparations
      1. Syrup: 15 mg/5 ml
      2. Liquid: 5 mg/5 ml
  3. Dexamethasone
    1. Dexamethasone has high oral Bioavailability (80%) with onset of action within 1-2 hours
    2. Asthma Exacerbation: 0.3 to 0.6 mg/kg/day up to 10-15 mg for 1-2 days
    3. Croup: 0.15 to 0.6 mg/kg once up to 10 mg
      1. See Dexamethasone in Croup

VII. Agents: Relative Glucocorticoid Potency (equivalent dosages)

  1. High potency
    1. Betamethasone 0.6 to 0.75 mg
    2. Dexamethasone 0.75 mg
  2. Medium potency
    1. Methylprednisolone 4 mg
    2. Triamcinolone 4 mg
    3. Prednisolone 5 mg
    4. Prednisone 5 mg
  3. Low potency
    1. Hydrocortisone 20 mg
    2. Cortisone 25 mg

VIII. Agents: Relative anti-inflammatory potency

  1. High anti-inflammatory potency
    1. Betamethasone 20-30
    2. Dexamethasone 20-30
  2. Medium anti-inflammatory potency
    1. Methylprednisolone 5
    2. Triamcinolone 5
    3. Prednisolone 4
    4. Prednisone 4
  3. Low anti-inflammatory potency
    1. Hydrocortisone 1
    2. Cortisone 0.8

IX. Agents: Relative Mineralocorticoid Potency

  1. Mineralocorticoid Activity
    1. Cortisone 2
    2. Hydrocortisone 2
    3. Prednisolone 1
    4. Prednisone 1
  2. No Mineralocorticoid Activity
    1. Betamethasone
    2. Dexamethasone
    3. Methylprednisolone
    4. Triamcinolone

X. Agents: Half Life

  1. Long Half-Life (36-54 hours)
    1. Betamethasone
    2. Dexamethasone (36 to 54 hours)
  2. Medium Half-Life (18-36 hours)
    1. Methylprednisolone
    2. Prednisolone (~36 hours)
    3. Prednisone (~36 hours)
    4. Triamcinolone
  3. Short Half-Life (8-12 hours)
    1. Cortisone
    2. Hydrocortisone

XI. Adverse Effects (typically with Long-term Corticosteroid use)

  1. See Precautions above
  2. See Prevention below
  3. Even short course Corticosteroids are associated with increased serious adverse effects
    1. Fracture (RR 1.9, NNH 140)
    2. Venous Thromboembolism (RR 3.3, NNH 454)
    3. Sepsis (RR 5.3, NNH 1250)
    4. Waljee (2017) BMJ 12:357 +PMID: 28404617 [PubMed]
  4. See Corticosteroid Associated Osteoporosis
  5. See Steroid-Induced Hyperglycemia
  6. Corticosteroid Myopathy
  7. Motor restlessness
  8. Sleep disturbance
  9. Hypertension
  10. Iatrogenic Diabetes Mellitus (or acute worsening of Diabetes Mellitus control including Diabetic Ketoacidosis)
    1. See Steroid-Induced Hyperglycemia
  11. Hyperlipidemia
  12. Fluid retention
  13. Immune Suppression
  14. Kaposi Sarcoma
    1. Associated with prolonged Immunosuppression on Corticosteroids
  15. Avascular Necrosis (e.g. Osteonecrosis of the hip)
    1. May occur even after single, short-term low dose course
    2. Dilisio (2014) Orthopedics 37(7):e631-6 +PMID: 24992058 [PubMed]
  16. Corticosteroid Induced Adrenal Insufficiency
    1. Hypothalamic-Pituitary-Adrenal (HPA) Axis suppression with high dose steroids for prolonged periods (esp. children)
    2. Typically does not occur if Prednisone 20 mg equivalent used <2-3 weeks
    3. Tapering is generally not required for shorter steroid courses (and raises total steroid dose)
    4. Medrol dose pack (6 days of Methylprednisolone) offers no benefit and adds extra cost
      1. Instead prescribe one dose for 5 to 6 days (e.g. Prednisone 30 to 40 mg orally daily for 6 days)
  17. Cardiovascular disease risk
    1. Wei (2004) Ann Intern Med 141(10):764-70 +PMID:15545676 [PubMed]
  18. Psychiatric effects
    1. Includes depression, anxiety, mania, Psychosis, Delirium and Insomnia
    2. Typically occurs in first week of therapy and resolves within a week of stopping the Corticosteroid
    3. Most have mild to moderate symptoms but may be severe in up to 5% of cases
    4. Symptoms may also occur (uncommonly) with high potency Topical Corticosteroids, Intranasal Corticosteroids
    5. Incidence of psychiatric effects increases with dose
      1. Occurs in 1% of patients on Prednisone 40 mg orally daily or less
      2. Occurs in 5% of patients on Prednisone 40 mg to 80 mg orally daily or less
      3. Occurs in 18% of patients on Prednisone 80 mg orally daily or more
    6. References
      1. (2014) Presc Lett 21(12):69-70

XII. Management: Corticosteroid Tapering

  1. Background
    1. Corticosteroid tapering is not needed for most short courses <3 weeks
    2. Avoid Medrol dose pack
      1. High priced Blister pack of an otherwise cheap medication
      2. No advantage when compared to fixed dose Corticosteroid
  2. Indications
    1. Disease flare expected with short course (e.g. slow taper in Rhus Dermatitis)
      1. See specific conditions for these protocols
    2. Corticosteroid duration >3 weeks (or frequent steroid bursts)
      1. Risk of adrenal suppression if physiologic dose (>5 or 7.5 mg daily for >3 weeks) OR
      2. Frequent Corticosteroid bursts (3 or more in 6 months)
  3. Protocol: Taper for Corticosteroid duration >3 weeks (or frequent steroid bursts)
    1. Reduce dose by 10-20% every 1 to 2 weeks (slower if on Corticosteroids for years)
    2. Consider ACTH Stimulation Test to confirm recovery of adrenal function before discontinuation
    3. Indications to slow taper
      1. Disease flare (e.g. COPD or PMR exacerbation)
      2. Adrenal Insufficiency signs of symptoms (e.g. Hypotension, myalgias, Fatigue)
  4. References
    1. (2022) Presc Lett 29(3): 13-4

XIII. Prevention: Corticosteroid complications

  1. See Corticosteroid Associated Osteoporosis
  2. See Steroid-Induced Hyperglycemia
  3. Avoid use when not truly indicated (e.g. Sinusitis, Acute Bronchitis, Pharyngitis)
    1. See Precautions above
    2. Even short course Corticosteroids (1 week) are associated with increased risk of Fractures, VTE and Sepsis
    3. (2017) Presc Lett 24(7)
    4. Waljee (2017) BMJ 357:j1415 +PMID:28404617 [PubMed]

XIV. Management: Corticosteroids Pearls

  1. Dexamethasone is ideal for single dose
    1. Dexamethasone has high oral Bioavailability (80%) with onset of action within 1-2 hours
    2. Duration of action approaches 60 hours
    3. No mineracorticoid activity
    4. However, Dexamethasone suspension is not tolerated well by children (due to taste)
      1. In Emergency Department, IV formulation (10 mg/ml) is given orally in flavor, Ibuprofen or Acetaminophen
      2. At home, Dexamethasone tablets may be given, and crushed in apple sauce
  2. Prednisone and Prednisolone may be used interchangeably
    1. Similar in cost, Half-Life and activity (antiinflammatory, mineralcorticoid)
  3. Give Prednisone or Prednisolone once daily (instead of split dosing)
    1. Once daily dosing has sufficient duration of activity
    2. Split daily dosing (with a night dose) increases adverse effects (e.g. Insomnia)
    3. Limit split dosing to those patients who have gastrointestinal side effects on daily dosing amounts

XV. References

  1. Olson (2020) Clinical Pharmacology, Medmaster, Miami, p. 155-6
  2. Swadron and Hope in Herbert (2018) EM:Rap 18(9):16-8
  3. Dvorin (2020) Am Fam Physician 101(2): 89-94 [PubMed]
  4. Lane (1998) Endocrinol Metab Clin North Am 27:465-83 [PubMed]

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