Corticosteroids (CS)

Systemic

  • 4 ring structure of cholesterol: 3 hexanes & 1 pentane
  • Active molecules have a hydroxyl group at C11
  • Inactive forms e.g. cortisone & prednisone, must undergo hepatic hydroxylation (11β-Hydroxysteroid dehydrogenase type 1)
  • By adding different groups (hydroxyl, methyl or fluorine) different steroids are formed

Short acting

  • Cortisone, hydrocortisone

Intermediate acting

  • Prednisone, prednisolone, mythelpred, triamcinolone

Long acting

  • Dexamethasone, betamethasone (Biological duration of action based on adrenocorticotropic hormone suppression rather than half life)

Normal hypothalamic pituitary adrenal axis 

  • Corticotropin-releasing hormone  (hypothalamus) then  Adrenocorticotropic hormone (ACTH) (Anterior pituitary) then 20 -30 mg cortisol (adrenal)
  • Controlled via circadian cycle, -ve feedback, & neural control (emotion/stress)
  • Some effect on androgen, negligible on mineralocorticoid renin-angiotensin-aldosterone system (RAAS)
  • Pregnancy Category C

  • Oral, intramuscular, intravenous

Oral Prednisone

  • Physiologic 5-7.5 mg
  • Low dose <40 mg
  • Moderate 40-60 mg
  • High dose ≥ 60 mg
  • Short term  < 3 weeks
  • Long term > 4 weeks
  • Give in morning & favor alternate day regimen (↓ all side effect except cataracts & osteoporosis)
  • 1mg/kg/dose 2-4 years old (4-6 as per Bolognia)

IM Triamcinolone & Methylprednisolone

  • Longest acting intramuscular agents

IV Methylprednisolone

  • Pulse: 0.5-1g/day over 2hrs x 1-5 days
  • 10-15 mg/kg/day divided into 3-4 doses (cardiac monitoring: rapid electrolyte shift & arrhythmias/Atrial fibrillation)

* Taper dose:  If given above physiological doses for more than 3-4 weeks

Pharmacokinetics

  • Absorbed in jejunum, food delays absorption, but does not decrease it
  • Plasma bound to corticosteroid-binding globulin (Transcortin) > albumin
  • Decreased binding in hypothyroidism, liver, renal disease & obesity, increased binding in pregnancy, estrogen therapy & hyperthyroidism
  • Renally excreted
  • Inverse correlation between duration of action & the relative mineralocorticoid effect/ Adrenocorticotropic hormone (ACTH) suppression

Binds glucocorticoid receptor & forms a complex with heat-shock protein 🡪 translocate into nucleus and binds to GREs 🡪 alters transcription of multiple genes

1) Cytokines/integrins/ selectins/chemokines

  • Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) inhibition 
  • Activator protein-1 transcription factor inhibition (Decreased tumor necrosis factor, granulocyte-colony stimulating factor (G-CSF), Interleukin-1, 2, 6, 8, E-selectin, intercellular adhesion molecule 1 (ICAM1))

2) Cellular Immunity

  • Decreased Lymphocytes
  • Decreased Interleukin-2 🡪 ↓T cell activation/proliferation
  • Increased Regulatory T cells activity

3) Humoral Immunity

  • Decreased Immunoglobulin production (at high doses)

4) Innate immunity

  • Eosinophil apoptosis 
  • Monocyte & mast cell number & function
  • Neutrophilia, but decreased diapedesis  

5) Other

  • Phospholipase-A2 (PLP-A2) & cyclooxygenase-2 (COX-2) inhibition (decreased eicosanoids)
  • Decreased angiogenesis
  • Decreased permeability 
  • Decreased collagen & ground substance production (Fibroblasts)
  • Increased Vasoconstriction

Overall effects:

  • cell trafficking > function, cellular > humoral immunity

Glucocorticoid Effects (catabolic state)

  • Gluconeogenesis 
  • Peripheral insulin resistance
  • Lipolysis (Cushing pattern)

Mineralocorticoid

  • Aldosterone-like effect via renin-angiotensin-aldosterone system (RAAS) (sodium retention/ potassium wasting)

Food & drug administration (FDA)

  • Pemphigus vulgaris
  • Bullous pemphigoid
  • Steven-Johnson syndrome / toxic epidermal necrolysis
  • Erythema multiforme  
  • Systemic lupus
  • Dermatomyositis 

Off-label

  • Immunobullous
  • Autoimmune connective tissue disease
  • Vasculitis 
  • Neutrophilic dermatoses
  • Eczema
  • Erythroderma
  • Lichen planus
  • Others (urticaria, sarcoidosis, sunburn)

Intravenous Methylprednisolone

  • Pemphigus vulgaris, bullous pemphigoid
  • Alopecia areata
  • Sweets syndrome
  • Vasculitis

Absolute

  • Allergy to IV preparations
  • Systemic fungal infections
  • Active tuberculosis
  • Herpes simplex virus keratitis

Relative

  • Neurological: prior psychosis, severe depression
  • Ocular: Cataracts, glaucoma
  • Cardiac: hypertension, Congestive heart failure
  • Gastrointestinal: Active peptic ulcer disease, recent anastomosis
  • Diabetes II
  • Infections: Positive tuberculin skin test
  • Musculoskeletal: Osteoporosis

* Pregnancy (Category C)

Hypothalamic pituitary adrenal axis

  • Steroid withdrawal (fatigue, mood, gastrointestinal, arthralgia), Addisonian crisis

Central nervous system

  • Pseudotumor cerebri, epidural lipomatosis, peripheral neuropathy, seizure

Psychiatric

  • Psychosis, agitation/personality changes, & depression

Ophthalmologic

  • Cataracts, glaucoma, infection, refractive changes, hemorrhage

Cardiovascular

  • Hypertension, congestive heart failure, atherosclerosis

Gastrointestinal

  • Nausea, vomiting, peptic ulcer disease, bowel perforation, pancreatitis, Gastroesophageal reflux disease, esophagitis

Metabolic

  • Hyperglycemia, hypertriglyceridemia, increased appetite/weight, non-alcoholic steatohepatitis (NASH), cushingoid changes, hypokalemia, hypocalcaemia

Gynecologic

  • Menstrual irregularity, fetal effects

Musculoskeletal

  • Osteoporosis (30-50%), osteonecrosis, growth retardation, muscle atrophy & myopathy

Infectious 

  • Tuberculosis, opportunistic, prolonged Herpes simplex virus /Varicella zoster virus

Cutaneous

  • Decreased wound healing, striae, atrophy, steroid acne, flushing, telangiectasia, purpura, infections, telogen effluvium, hirsutism, acanthosis nigricans

* Bolded = life-threatening side effects

Intramuscular injection site side effects

  • Cold abscess, subcutaneous fat atrophy, crystal deposition

(CYP3A4 mainly)

Increased levels of CS

  • Azoles, macrolides, oral contraceptive pills (cytochromeP-450 inhibitors)

Decreased levels of CS

  • Anticonvulsants, anti-tuberculosis, cholestyramine, ephedrine (cytochromeP-450 inducers)

Synergic effects

  • Diuretics, Amphotericin B: hypokalemia
  • Immunosuppressant: infections
  • Non-steroidal anti-inflammatory drugs (NSAIDs), Aspirin:  peptic ulcer disease

Higher doses of drug needed with corticosteroids

  • Insulin, anti-tuberculosis, salicylates

Increased risk for toxicity

  • Female
  • Postmenopausal: osteoporosis
  • Elderly/pediatrics
  • Lupus, Dermatomyositis, Rheumatoid arthritis, renal transplant: ↑ cardiovascular side effect & osteonecrosis
  • Liver disease or hypoalbuminemia: ↑ Corticosteroid levels & side effects
  • Smoker & alcohol ingestion: increased risk of peptic ulcer disease & osteoporosis

Baseline

  • History & physical examination (Blood pressure, weight, growth curve (children), ophthalmologic exam for cataracts
  • Quantiferon > Tuberculin skin test & chest x-ray, fasting glucose, triglycerides, potassium level
  • Consider Hepatitis B, C, & human immunodeficiency virus (HIV) screen, + screening for Strongyloides (at risk patient)

Follow-up

  • Blood pressure, weight, growth curve, check for SE at 1 month then q2-3 months
  • Ophthalmologic exam q6-12 months
  • Potassium, fasting glucose, triglycerides at 1 month & q3-4 months
  • +/-  Dual-energy X-ray absorptiometry scan q1-3 years
  • Near cessation consider AM cortisol

Pulse IV Methylprednisolone 

  • Cardiac monitoring 
  • Daily electrolyte & glucose levels

Additional measures to consider

  • Calcium 1200 mg + vitamin D 800 IU daily +/-  bisphosphonate
  • Proton pump inhibitor for GI prophylaxis 
  • Pneumocystis pneumonia prophylaxis 
  • Vaccinations 

Glucocorticoid relative potency

  • Cortisone: 0.8
  • Hydrocortisone: 1
  • Prednisone/olone: 4
  • Methylprednisolone: 5
  • Triamcinolone: 5
  • Dexamethasone: 20-30
  • Betamethasone: 20-30

* Underlined= No mineralocorticoid activity