• Adrenal cortex (90% gland wt):
  • Zona Glomerulosa: Aldosterone
  • Zona Fasciculata: Cortisol
  • Zona Reticularis: Testosterone and estradiol production from cholesterol
• Adrenal medulla: Catecholamines
• Located on upper poles of both kidneys (Image 1,2):

Image 1. Located on upper poles of both kidneys

Image 2. Located on upper poles of both kidneys

Diurnal Cycle of Release

• ACTH peaks midnight to 2 AM
• Cortisol peaks at 6-8 AM
• Varies with sleep cycle:
  • Night shift workers
  • Consider consequence of multiple shift or changing shift workers

Stress Related Cortisol Increase

• Surgery
• Trauma
• Sepsis
• Hypoglycemia
• Mediators:
  • CNS release of CRF
  • Cytokines: IL-1, IL-2, IL-6, TNF, platelet aggregating factor

Glucocorticoid Actions

• Decrease inflammatory response:
  • Inhibit phospholipase A2 → ↓ production of arachidonic acid → indirect inhibition of both prostaglandins and leukotrienes.
  • Inhibit activity of T lymphocytes (especially TH2)
  • Suppress IL-1, IL-3, IL-4, IL-5; ↓ chemotraction of eosinophils and macrophages
  • Vasoconstrict, ↓ edema, ↓ fever
  • Stabilize neutrophilic (granulocyte) lysosomes to ↓ lysosomal enzyme release

White Blood Cell Effects

• Increase neutrophils without “shift to left”:
  • Demargination (↓ adherence to vascular endothelium)
  • ↓ neutrophil egress from intravascular space
  • Stimulate marrow release of mature WBCs (not immature band cells as in infection)
• Decrease lymphocytes, eosinophils, and basophils:
  • Decrease B and T lymphocyte function
  • Basis for role in treatment of lymphomas and lymphocytic leukemia

Other Glucocorticoid effects

• ↓ protein synthesis and protein movement out of vessels
• ↑ Gluconeogenesis (hyperglycemia)
• Fat Redistribution: suppress lipolysis and lipogenesis via insulin inhibition.
• ↑ beta adrenergic responses (note value in asthma)

Mineralocorticoid actions

• Sodium retention
• Potassium loss

Clinical Use of Corticosteroids

• Goal of treatment: symptomatic, not curative:
  • Topical or oral: contact dermatitis or allergic rxn
  • Allergic rhinitis and asthma
  • Arthritis
  • Psoriasis
  • Autoimmune (lupus, polymyalgia rheumatica, non-viral hepatitis)
  • Inflammatory bowel disease
  • Lymphoma, leukemia
  • Transplant surgery: post-op/maintenance, rejection prevention
  • Prophylaxis of “dry socket” with dental surgery
  • Brain and spinal cord tumors (“cerebral edema)
  • PCP infection in AIDS patients, ARDS, sepsis
  • Hypercalcemiamultiple myeloma, bone mets, sarcoid

Choice of Agent

• Relative glucocorticoid and mineralocorticoid potency (see table)
• Relative duration of action: Not correlated to half life
• Organ specificity
  • Methylprednisolone in asthma
  • Dexamethasone for cerebral edema
• Lack of systemic absorption if topical
  • Consider skin thickness, surface area to be covered
  • Also nasal and pulmonary inhalation applications
• Cost
• Who sponsored the original clinical trials
  • Dexamethasone for cerebral edema
  • Methylprednisolone in asthma, sepsis

Relative potencies

Name	Eqivalnt dose	Antiinflam	Na retention	Duration
Cortisol	20-25 mg	1	2+	8-12 hr
Pred	5 mg	3.5	1+	18-36 hr
Methyl pred	4 mg	5	0.5+	18-36 hr
Dexa	0.75 mg	30	0	36-54 hr
Fludro			125

Dosing

• Acute:
  • Moderate to high dose for rapid resolution of symptoms; high dose “bursts” x 7-14 days
  • E.g., 60-80 mg prednisone or equivalent “burst therapy” for asthma in ER
  • 60-120 mg methylprednisolone QID for hospitalized patient
  • 4 mg QID dexamethasone for brain tumor
• Chronic (maintenance):
  • Minimum dose for shortest duration possible. Prefer to avoid all together.
  • Morning doses preferred
  • Every other day in some cases (next slide)

Every other day dosing

• Theory: use drug that works 36 hours (prednisone, methylprednisolone) every other day to allow HPA to function every other night:
  • Fewer side effect and HPA suppression possible
  • Concern over loss of therapeutic effect on evening of day 2
  • E.g. 10 mg QD slowly converted to 20 mg QOD

Tapering Principles

• Less than 10-14 days, with no prior exposure:
  • Rapid taper acceptable, even with high doses
  • Major considerations are disease exacerbation, mild flu like symptoms, mild depression
• Longer term exposure, even with low doses:
  • Slow taper mandatory, especially as approach physiologic dose equivalent.
  • Physiologic withdrawal effects may be observed (see next slide)
• Short term exposure to high doses in patient with chronic use of high doses:
  • Rapid taper from high dose may be acceptable, but do not go below the chronic dose
  • E.g. patient on 10 mg prednisone per day for 3 months. Physiologic for this person is 10 mg. Then even slower taper if trying to remove drug entirely.

Physiologic Withdrawal Signs

• Time and dose dependent.
  • Unlikely if duration less than 10-14 days
  • Avoid night time doses if >5-7 days
• CNS depression
• Flu-like symptoms
• Muscle and joint pain
• Tremor
• Hypotension (not necessarily hyponatremic)
• Hyperkalemia, arrhythmias

Physiologic Withdrawal Signs

• Takes 7-14 days, even with very high doses to suppress pituitary ACTH release and adrenal cortisol release.
• With prolonged dosing (>30 days?) HPA suppression is evident, but dose dependent.
  • 9-12 months to fully restore HPA axis after slow withdrawal and complete removal.
  • Pituitary response recovers before adrenal gland
  • May need to cover with prednisone bursts during times of stress after complete withdrawal.

Example tapering dose

• Methylprednisolone 60 mg IV QID x 3 days
• Day 4: change to prednisone 60-80 mg/ day
  • QD or split into 2-3 doses?
  • Compare to physiologic dose of 5 mg prednisone or 4 mg methylprednisolone
• Then 60 mg x 3 days, 40 mg x 3 days, 30 mg x 3 days, 20 mg x 3 days, 15 mg x 3 days, 10 mg x 5 days, 5 mg x 5 days, 2.5 mg x 5 days, then stop
• Increase dose or slow taper rate if symptoms worsen
• What if patient was taking 10 mg per day at home before exacerbation?
• What if patient is using inhaled steroids?

Another example

• Steroid naive patient receives 80 mg of prednisone in the emergency room
  • Should IV drug have been used instead of oral?
  • Assuming the symptoms resolve over 4 hours, why does the patient need a prednisone prescription for outpatient use?
  • How long should treatment continue?
  • Should the dose be tapered?
    • E.g 20 mg qd x 7-14 days without taper
    • E.g. 40 mg x 2-3 days, 30 mg x 2-3 days, 20 mg x 23 days, 10 mg x 2-3days, 5 mg x 2-3 days

Acute side effects

• Dose dependent, low risk
• Endocrine: hyperglycemia. Diabetic?
• Elevated white count: demargination vs. infection
• GI: Bleeding, “stress ulcers”
  • mucous production, local vasoconstriction
• Na retention (caution re edema, HTN, CHF)
• Hypokalemia, metabolic acidosis
• Jitteriness, euphoria, confusion (steroid psychosis)

Longer term side effects

• Continuation of short term side effects
• HPA axis suppression after 2 weeks
• Cushingoid features: fat redistribution to face and back, striae
• Muscle weakness, myopathy, protein wasting
• Thinning of skin, capillary fragility with petechiae, bruising, acne
• Osteoporosis in adults with compression fractures; aseptic necrosis of hip, growth retardation in children
• Cataracts, glaucoma
• Decreased immune response; TB activation, poor wound healing

Buffalo Hump: Accumulation of fat on back of neck and upper back

Moon Facies: fat deposition in face

Central obesity and striae

Striae (stretch marks)

Drug Interactions

• Steroids increase aspirin clearance. Risk of ASA toxicity when steroids stopped.
• Barbiturates, phenytoin, rifampin increase steroid clearance/ metabolism
• Cimetidine: decreased steroid metabolism?
• Ketoconazole: decreased cortisol production
• Hypoglycemics: steroid induced glucose increase
• Additive hypokalemia to potassium wasting diuretics
• Additive ulcerogenic property to NSAIDS?