INHALED CORTICOSTEROIDS

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INHALED CORTICOSTEROIDS

• Molecules
• Mode of action
• Pharmacokinetics
• Clinical efficacy
• Side effects -local
• -systemic
• Conclusions

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Inhaled Corticosteroids

• Jacques Hébert
• CHUL / CHUQ

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MODE OF ACTIONat the tissue level

• Restoration of epithelium
• Reduction of thickening of basement membrane
• Reduction of mucosal edema
• Reduction of leukocyte infiltrate
• Reduction of mast cell number

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MODE OF ACTIONat the tissue level

• Restoration of epithelium

• Reduction of thickening of basement membrane
• Reduction of mucosal edema
• Reduction of leukocyte infiltrate
• Reduction of mast cell number

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MODE OF ACTIONat the cellular level

• Inhibition of release of proinflamatory molecules
  (interleukines)

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MODE OF ACTIONat the molecular level

• Blockage of active sites of proinflamatory genes

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PHARMACOKINETICS

• Topical potency skin blanching
• Cs receptor binding half life
• Receptor binding affinity
• Bioavailability

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TOPICAL POTENCY
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CS RECEPTOR BINDING HALF LIFE (hr)
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RECEPTOR BINDING AFFINITY
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BIOAVAILABILITY ()
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CLINICAL EFFICACY

• Studies showing the clinical efficacy
• all the molecules are better than placebo
• the more potent the drug, the less amounts needed
  for comparable results

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CLINICAL EFFICACY

• Studies showing the clinical efficacy
• all the molecules are better than placebo
• the more potent the drug, the less amounts needed
  for comparable results

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UNWANTED EFFECTS

• Objectives
• balance between wanted and unwanted effects

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UNWANTED EFFECTSincidence of local effects
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UNWANTED EFFECTSepistaxis
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UNWANTED EFFECTSsystemic effects

• Hypothalamic-pituitary-adrenal axis effects
• Growth
• Bone
• Occular complication
• Skin
• Immunity

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EFFECTS ON HPA

• Principle
• Tests
• Results

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EFFECTS ON HPA

• Principle
• Tests
• Results

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EFFECTS ON HPA

• Principle
• Tests
• Results

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HPA AXIS tests

• Blood secretory functions
• morning cortisol levels
• 24h cortisol profile
• 24h urinary free cortisol levels
• Stimulation tests

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HPA AXIS summary

• Overall, the HPA axis is minimally suppressed
• Anecdotal reports of drop of cortisol
  produc- tion, even at low dose(BDP,BUD, FP,TAA)
• Recent reports of HPA axis suppression with FP
  at doses of 0.4-2.0 mg/day
• Not reported with nasal use only
• Effects of cumulative doses on the HPA axis is
  of prime importance

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EFFECTS ON GROWTH

• Pathogenesis
• Clinical effects

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EFFECTS ON GROWTH

• Pathogenesis
• Clinical effects

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EFFECTS ON GROWTH

• Stunting seen in patients with asthma and ICS
  -BDP or BUD low or high dose -FP at
  medium/high dose
• Period of catch-up growth after cessation of ICS
  (?)
• Analysis of large cohort shows that children on
  ICS attained normal adult height

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EFFECTS ON BONE

• Tests
• Results

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EFFECTS ON BONE

• Tests
• Results

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EFFECTS ON BONESTests

• Bone turnover
• metabolism osteocalcin and alk phosphatase
• resorption hydroxyproline and urinary Ca
• Bone density
• Incidence of fracture
• metabolism osteocalcin and alk phosphatase
• resorption hydroxyproline and urinary Ca

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EFFECTS ON BONESresults in adults

• Bone formation oral steroids gtgtgt ICS BDPgt
  BUD and FP
• Bone resorption reduced (low / high doses)
• Bone mineral density -high doses(gt1mg/day)
  of BUD/ BDP are associated with bone
  depletion -at lower dosage no significant
  effects -no prospective studies

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EFFECTS ON BONESresults in adults

• Fractures
• no increase of the overall incidence
• 2 cases reports published to date
• high dose of BDP (1.5-3.7 mg/day for gt 2years)
• major nonsteroidal risk factors

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EFFECTS ON BONESresults in children

• Bone formation -short term / low dose
  (lt0.8mg) no effect -longer treatment at low
  dose significant reduction
• Bone resorption BUD no change BDP
  reduced

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EFFECTS ON BONESresults in children

• Bone density
• BDP 2-3 y low to medium doses no effect
• BDP/ BUD 3-8y medium to high dose
  significant reduction
• BUD 3-6y 0.5mg/day (157 patients) no effect
• BDP 6m 0.3 - 0.4mg/ day
• no efect on bone density
• reduction of expected maturational increase in
  bone mass

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EFFECTS ON BONESresults in children

• Fractures
• no published surveys of fracture incidence
• no case reports

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OCCULAR COMPLICATIONS

• Cataracts
• increased prevalence of posterior subcap-sular
  cataracts (2x)
• Glaucoma
• increased risk of open-angle glaucoma with
  anti-asthma ICS ( BDP, BUD) at high doses (
  gt1.5mg/day) ?

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EFFECTS ON SKIN

• Skin atrophy with BDP and BUD at doses gt1.0
  mg/day
• With time, skin atrophy leads to
• apparent eccymoses
• laceration after trivial trauma
• slow healing

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EFFECTS ON IMMUNITY

• No effects on levels of immunoglobulins
• No increased incidence of infections

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CONCLUSIONS

• Clinical efficacy well shown for allergic and
  non allergic rhinitis
• All nasal symptoms are improved (including
  obstruction)
• The hyperreactivity caused by inflamation is
  improved
• No systemic effects
• Minimal local side effects, even at long term.