Inhaled corticosteroids in clinical practice Presented by Sasikarn Suesirisawad, MD.

1. Sasikarn Suesirisawad, MD

2.  Mechanism of action
 Structure of ICS
 PK/PD
 ICS comparison
 Device comparison
 Side effect
 Clinical response

4.  Suppression of inflammation
 Increased expression of beta 2-receptors and
enhanced coupling of beta 2-receptors to G-
proteins

5. Fernando M et al.Am J Respir Crit Care
Med Vol 185, Iss. 1, pp 12–23, Jan 1, 2012

6.  Anti-inflammatory gene activation
 Switching off inflammatory genes
 Inflammatory cell inhibition

7.  2 types of glucocorticoid receptors (GR)
 GR alpha
 GR beta
 Glucocorticoid action facilitated by GR
alpha, but inhibited by GR beta.

10. Clark AR et al.J Endocrinol.

11.  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

13. Melanie Hubner et al. Immunol Allergy Clin N Am ( ) –

14. Melanie Hubner et al. Immunol Allergy Clin N Am ( ) –

16. Johnson M et al. JACI. 1996;97(1 Pt 2):169.

17. Franklin Cerasoli et al. Chest 2006;130;54S-64S

18. Melanie Hubner et al. Immunol Allergy Clin N Am ( ) –

19. Stuart W. Stoloff et al. Current Opinion in Allergy and Clinical Immunology 2011, 11:000–000

20.  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 ( ) –

21.  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 ( ) –

22.  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 ( ) –

23. Stuart W. Stoloff et al. Current Opinion in Allergy and Clinical Immunology 2011, 11:000–000

24. Franklin Cerasoli et al. Chest 2006;130;54S-64S

25. Franklin Cerasoli et al. Chest 2006;130;54S-64S

26. Franklin Cerasoli et al. Chest 2006;130;54S-64S

27. Zia R Tayab et al. Expert opin. Drug Deliv. (2005) 2(3):519-532

29. Budesonide Beclomethasone
Fluticasone

30. Stuart W. Stoloff et al. Current Opinion in Allergy and Clinical Immunology 2011, 11:000–000

31.  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

32. Melanie Hubner et al. Immunol Allergy Clin N Am25 2005 469-488

33. Melanie Hubner et al. Immunol Allergy Clin N Am25 2005 469-488

35. Melanie Hubner et al. Immunol Allergy Clin N Am25 2005 469-488

36.  3 types
 Small volume nebulizer (SVN)
 Metered-dose inhaler (MDI)
 Dry powder inhaler (DPI)
Deborah et al. American Association for respiratory care 2011

37. Deborah et al. American Association for respiratory care 2011

38. Deborah et al. American Association for respiratory care 2011

39. Mestitz H et al. Chest 1989;96:1237-1240

40. Deborah et al. American Association for respiratory care 2011

41. 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

42. Rau JL Jr. Respiratory care pharmacology, 6th ed. St. Louis: Mosby; 2002: 39

43. National Asthma Education and Prevention Program, Expert Panel II: Guidelines for diagnosis and
management of asthma, Bethesda, MD; 1997. National Institutes of Health.

44. 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

45. Deborah et al. American Association for respiratory care 2011

46. Deborah et al. American Association for respiratory care 2011

47. Deborah et al. American Association for respiratory care 2011

48. Deborah et al. American Association for respiratory care 2011

49. Deborah et al. American Association for respiratory care 2011

50. Deborah et al. American Association for respiratory care 2011

51. Deborah et al. American Association for respiratory care 2011

52. 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

53. Deborah et al. American Association for respiratory care 2011

54. Deborah et al. American Association for respiratory care 2011

55. 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

56. Deborah et al. American Association for respiratory care 2011

57. Dry Powder Inhaler (DPI)
Turbuhaler Dishkhaler
Easyhaler Accuhaler Swinghaler

59. 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

61.  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.

62.  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 -

63.  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.

64.  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

66.  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

68.  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 affected
Stuart W. Stoloff et al. Current Opinion in Allergy and Clinical Immunology 2011, 11:000–000

70. Brian J et al. Arch Intern Med. 1999;159:941-955

71.  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.

72.  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

73.  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)

74.  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 wks
Stuart W. Stoloff et al. Current Opinion in Allergy and Clinical Immunology 2011, 11:000–000