Inhaled corticosteroids in clinical practice

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Inhaled corticosteroids in clinical practice

Presented by Sasikarn Suesirisawad, MD.

Inhaled corticosteroids in clinical practice

  1. 1. Sasikarn Suesirisawad, MD
  2. 2.  Mechanism of action Structure of ICS PK/PD ICS comparison Device comparison Side effect Clinical response
  3. 3.  Suppression of inflammation Increased expression of beta 2-receptors and enhanced coupling of beta 2-receptors to G- proteins
  4. 4. Fernando M et al.Am J Respir Crit CareMed Vol 185, Iss. 1, pp 12–23, Jan 1, 2012
  5. 5.  Anti-inflammatory gene activation Switching off inflammatory genes Inflammatory cell inhibition
  6. 6.  2 types of glucocorticoid receptors (GR)  GR alpha  GR beta Glucocorticoid action facilitated by GR alpha, but inhibited by GR beta.
  7. 7. Clark AR et al.J Endocrinol.
  8. 8.  Increased beta 2-agonist effects. Protection from down-regulation of beta 2- receptors that associated with long-term beta 2-agonist used. Reversal or prevention of uncoupling of beta 2-receptors from G proteins Nino G et al. JACI
  9. 9. Melanie Hubner et al. Immunol Allergy Clin N Am ( ) –
  10. 10. Melanie Hubner et al. Immunol Allergy Clin N Am ( ) –
  11. 11. Johnson M et al. JACI. 1996;97(1 Pt 2):169.
  12. 12. Franklin Cerasoli et al. Chest 2006;130;54S-64S
  13. 13. Melanie Hubner et al. Immunol Allergy Clin N Am ( ) –
  14. 14. Stuart W. Stoloff et al. Current Opinion in Allergy and Clinical Immunology 2011, 11:000–000
  15. 15.  BDP and ciclesonide are prodrugs. Advantage of prodrugs can be minimization of oropharyngeal adverse effects because parent compound that inhaled through inhalation device is not active. Ciclesonide metabolized to des-CIC through cytosolic esterases in airways Melanie Hubner et al. Immunol Allergy Clin N Am ( ) –
  16. 16.  Dexamethasone has binding affinity of 100 MF: the highest receptor affinity with 2200 FP: 1800 Beclomethasone monopropionate: 1345 Des-CIC: 1200 Budesonide: 935 Triamcinolone acetonide: 233 Flunisolide: 180 BDP: 53 Ciclesonide: 12 Melanie Hubner et al. Immunol Allergy Clin N Am ( ) –
  17. 17.  Pulmonary bioavailability of ICS is rate and extent drug reaches its site of action Systemic bioavailability shows rate and extent of drug that reaches blood(correlates with adverse effects) High pulmonary bioavailability and low oral bioavailability desired. Oral bioavailability depends on delivery device used. Oral bioavailability can be determined by measuring plasma levels or amount of drug excreted in urine over specific period.  Belomethasone-17-monopropionate : 26%.  Flunisolide: 7%.  FP & ciclesonide: < 1%  MF: <1%, 11% Melanie Hubner et al. Immunol Allergy Clin N Am ( ) –
  18. 18. Stuart W. Stoloff et al. Current Opinion in Allergy and Clinical Immunology 2011, 11:000–000
  19. 19. Franklin Cerasoli et al. Chest 2006;130;54S-64S
  20. 20. Franklin Cerasoli et al. Chest 2006;130;54S-64S
  21. 21. Franklin Cerasoli et al. Chest 2006;130;54S-64S
  22. 22. Zia R Tayab et al. Expert opin. Drug Deliv. (2005) 2(3):519-532
  23. 23. Budesonide BeclomethasoneFluticasone
  24. 24. Stuart W. Stoloff et al. Current Opinion in Allergy and Clinical Immunology 2011, 11:000–000
  25. 25.  Depends on several factors 1. physical properties of agent (density, hygroscopy charge, velocity) 2. particle size and shape of inhaled drug 3. delivery device 4. technique Melanie Hubner et al. Immunol Allergy Clin N Am25 2005 469-488
  26. 26. Melanie Hubner et al. Immunol Allergy Clin N Am25 2005 469-488
  27. 27. Melanie Hubner et al. Immunol Allergy Clin N Am25 2005 469-488
  28. 28. Melanie Hubner et al. Immunol Allergy Clin N Am25 2005 469-488
  29. 29.  3 types Small volume nebulizer (SVN) Metered-dose inhaler (MDI) Dry powder inhaler (DPI) Deborah et al. American Association for respiratory care 2011
  30. 30. Deborah et al. American Association for respiratory care 2011
  31. 31. Deborah et al. American Association for respiratory care 2011
  32. 32. Mestitz H et al. Chest 1989;96:1237-1240
  33. 33. Deborah et al. American Association for respiratory care 2011
  34. 34. ADVANTAGES DISADVANTAGES Aerosol doses are generally smaller  Lung deposition is relatively low than systemic doses. fraction of total dose. Onset of effect is faster than oral.  Correct breathing pattern & use of device can affect lung deposition. Drug delivered directly to lung, minimal systemic exposure.  Difficulty coordinating hand action and inhalation with MDIs. Systemic side effects are less frequent and severe.  Lack of knowledge of use of devices. Less painful and comfortable.  Number and variability of device types confuses pts and clinicians. Deborah et al. American Association for respiratory care 2011
  35. 35. Rau JL Jr. Respiratory care pharmacology, 6th ed. St. Louis: Mosby; 2002: 39
  36. 36. National Asthma Education and Prevention Program, Expert Panel II: Guidelines for diagnosis and management of asthma, Bethesda, MD; 1997. National Institutes of Health.
  37. 37. ADVANTAGE DISADVANTAGE Aerosolize many drug solution.  Treatment may range from 5-25 min. Aerosolize drug mixture (>1 drug)  Equipment required may be large and Minimal pt cooperation cumbersome. Useful in very young, very old, distressed pt  Need for power source. Drug concentration and dose can be  Potential drug delivery into eye with face modified. mask. Normal breathing pattern can be used and  Variability in performance characteristics breath-hold is not required for efficacy among different types, brand and model.  Assembly and cleaning are required.  Contamination is possible. Deborah et al. American Association for respiratory care 2011
  38. 38. Deborah et al. American Association for respiratory care 2011
  39. 39. Deborah et al. American Association for respiratory care 2011
  40. 40. Deborah et al. American Association for respiratory care 2011
  41. 41. Deborah et al. American Association for respiratory care 2011
  42. 42. Deborah et al. American Association for respiratory care 2011
  43. 43. Deborah et al. American Association for respiratory care 2011
  44. 44. Deborah et al. American Association for respiratory care 2011
  45. 45. ADVANTAGE DISADVANTAGE  Hand-breath coordination required Portable, light, compact  Fixed drug concentration and doses Multiple dose convenience  Reaction to propellant Short treatment time  FB aspiration from debris-filled Reproducible emitted doses mouthpiece  High oropharyngeal deposition No drug preparation required  Difficult to determine dose Difficult to contamination remaining in canister without dose counter Deborah et al. American Association for respiratory care 2011
  46. 46. Deborah et al. American Association for respiratory care 2011
  47. 47. Deborah et al. American Association for respiratory care 2011
  48. 48. ADVANTAGE DISADVANTAGE Reduce mouth/throat drug  Large and cumbersome compared impaction and loss to pMDI alone Increase inhaled drug by 2-4 times  More expensive and bulky than pMDI alone  Some assembly may be needed Allow use pMDI when pt is short of  Pt error in firing multiple puffs into breath chamber prior to inhaling or delay No drug preparation between actuation and inhalation Simplifies coordination pMDI  Possible contamination with actuation and inhalantion inadequate cleaning Deborah et al. American Association for respiratory care 2011
  49. 49. Deborah et al. American Association for respiratory care 2011
  50. 50. Dry Powder Inhaler (DPI) Turbuhaler DishkhalerEasyhaler Accuhaler Swinghaler
  51. 51. ADVANTAGE DISADVANTAGE Small and portable  Dependence on pt’s inspiratory flow  Pt less aware of delivered dose Built-in dose counter  Relatively high oropharyngeal Propellant free impaction. Breath-actuated  Vulnerable to ambient humidity or Short preparation and exhaled humidity into mouthpiece administration time  Different DPIs with different drug  Easy for pt to confuse direction Deborah et al. American Association for respiratory care 2011
  52. 52.  Failure to coordinate MDI actuation on inhalation Too short period of breath hold after inhalation Too rapid inspiratory flow rate Inadequate shaking/mixing before use Abrupt discontinuation of inspiration as aerosol hits throat Firing MDI multiple times during single inhalation Firing MDI into mouth but inhaling through nose Exhaling during actuation Putting wrong end of inhaler in mouth Holding canister in wrong position Failing to remove cap before use Excessive use of MDI beyond rated capacity (loss of dose count) Wasting of remaining doses Lack of adequate hand strength or flexibility to activate MDI McFadden ER Jr. JACI 1995;96:278-283.
  53. 53.  Incorrect assembly of add-on device Failure to remove electrostatic charge in many holding chambers/spacers Lengthy delay between MDI actuation and inhalation from holding chamber/spacer Inhaling too rapidly Firing multiple puffs into holding chamber/spacer before inhaling Wildhaber JH et al. Thorax -
  54. 54.  Not holding device correctly while loading dose Exhaling through mouthpiece Not exhaling to residual volume before inhaling Not inhaling forcefully Inadequate or no breath hold Exhaling into mouthpiece after inhaling Use of multi-dose reservoir designs (eg, Turbuhaler) in high ambient humidity which can reduce fine particle dose Melani AS et al. Ann Allergy Asthma Immunol 2004;93:439-446.
  55. 55.  Failure to assemble equipment properly Spillage of dose by tilting some nebulizers Failure to keep mouthpiece in mouth during nebulization Failure to mouth breathe Deborah et al. American Association for respiratory care 2011
  56. 56.  Dysphonia  The most common complaint is of hoarse voice  May occur > 50 % of pts using MDI. Thrush  Mouth should be rinse discarded Cough and throat irritation  accompanied by reflex bronchoconstriction, given via MDIs. rectified by switching to DPI. Unusual local complications: perioral dermatitis, tongue hypertrophy, increased thirst. Roland NJ et al. Chest. 2004;126(1)213
  57. 57.  Growth deceleration  Growth retardation may ccurs with low to medium doses depending on ICS and delivery system.  Velocity reduced in the first 6 mo-1 yr of therapy and then returns to normal.  Effect is generally small (1–2 cm total) and no evidence of ‘catch-up’ growth, predicted adult height is not affectedStuart W. Stoloff et al. Current Opinion in Allergy and Clinical Immunology 2011, 11:000–000
  58. 58. Brian J et al. Arch Intern Med. 1999;159:941-955
  59. 59.  Intraocular pressure  Increase risk of glucoma Cataracts  Risk factor for posterior subcapsular cataract Gonzalez AV et al.Pulm Pharmacol Ther. 2010 Pelkonen A et al. JACI.2008;122(4):832.
  60. 60.  Skin change and bruising  dose dependent at high daily doses Adverse airway effects  No evidence for atrophy of airway epithelium Infection  High dose ICS increase risk activation of TB  No increase risk pneumonia Psychiatric effect  Psychiatric disturbance Pierre Ernst et al. Curr Opin Pulm Med 2012, 18:85–89 Stuart W. Stoloff et al. Current Opinion in Allergy and Clinical Immunology 2011, 11:000–000
  61. 61.  Step down treatment to the lowest possible dose of ICS that maintains symptom control. Increase medication frequency while decreasing daily dose . Optimize compliance Optimize delivery (use spacer in adults, spacer and facemask in children) Evaluate and treat for complicating features of asthma Maximize nonpharmacologic treatment (eg, trigger avoidance)
  62. 62.  Improvement  Symptoms: the first 1–2 wks and max in 4–8 wks.  LFT: 1–2 wk and plateau at 4 wk but may increase slightly thereafter for 6–8 wk.  BHR: 2–3 wk and max in 1–3 mo but may continue to improve over 1 yr  FeNO: max decrease within 1 wk  Decreases Sensitivity to exercise challenge: 4 wksStuart W. Stoloff et al. Current Opinion in Allergy and Clinical Immunology 2011, 11:000–000

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