Inhaled corticosteroids Presented by Thitima Kantachatvanich, MD. October05, 2018

1. Inhaled Corticosteroids
Thitima Kantachatvanich, M.D.

2. Endogenous GCs
• Peak levels about 8 am
• Lowest levels just after midnight
• Exogenous GC: Mimicking the pulsatile cortisol
• ↓SE & ↑anti-inflammatory properties
Middleton 8th edition

3. Exogenous GCs (Synthetic)
Middleton 8th editionModified for ↑efficacy, ↓SE (e.g.↑binding aff. to GR, ↓binding aff. to MR)

4. Pharmacokinetics: Systemic
Peter J. Barnes: Inhaled Corticosteroids; Pharmaceuticals 2010, 3, 514-540c
• Systemic absorption (GI, lung)
• If water soluble  ↑lung uptake
(rapid onset) e.g. budesonide
• Binding to albumin/transcortin
• First-pass metabolism at liver
• CYP 450 dependent mixed function
oxidases: to inactive
• Glucuronyl transferase: conjugate to
water soluble
• Inactivate & Urinary excretion at
kidney
• 11B-HSD type 2 (11B-dehydrogenase)
1st pass metabolism: Budesonide, FP > BDP

5. Pharmacokinetics: Local
• Esterification (↑lipophilicity)
• Retention in tissue e.g. Budesonide, triamcinolone, ciclesonide, BMP
• Longer duration of action
• Hydrolysis by esterase
• Activate drug and release
• Others
• Beclomethasone dipropionate (BDP)
to beclomethasone 17α-monopropionate (BMP); higher affinity for GR
Middleton 8th edition
Miller-Larsson A. et al. Drug Metab Dispos. 1998;26(7):623-630

6. GR Binding Characteristics
• GR = Nuclear Receptor Subfamily 3, Group C, Member 1; NR3C1
• Affinity, duration, and SE
• Regulator: Degree of occupancy of the binding cleft
https://en.wikipedia.org/wiki/Glucocorticoid_receptor#/media/File:Glucocorticoid_receptor.png

7. SElective Glucocorticosteroid Receptor
Agonists (SEGRA)
• Classic GR activities: GR agonist
• ↓SE from the steroid backbone
• Tissue retention, longevity of
action: ongoing developed
Middleton 8th edition

8. Middleton 8th edition

9. Bioavailability
Dose Device
Particle size
Properties
(PPB, lipophilicity,
metabolism)
↓Oral bioavailability, ↓particle size, rapid metabolism,
↑clearance, ↑plasma protein binding, ↓systemic T1/2

10. Properties of Drugs: Receptor Binding, Tissue
Deposition, Vd
• Lipophilic property α lung retention, GR binding affinity, duration of
action
• FF >> MF ≥ FP > TAA >> BUD ≥ des-CIC > FLU ≥ BMP
• Soluble intracellular esters (esterification): Budesonide, triamcinolone,
ciclesonide, BMP
• Lipophilicity α Vd, plasma T1/2
• But ↓SE from fluticasone
• Almost complete 1st pass metabolism in the liver
• PC of GCs: vary greatly (up to tenfold)
• After oral intake of the same dose to normal volunteers
Middleton 8th edition
Clark TJH. Effect of beclomethasone dipropionate delivered
by aerosol in patients with asthma. Lancet 1972; 1: 1361–4.

11. ICS vs oral GCs
• ↓4X effect on HPA axis ICS
(same degree of antiasthma efficacy)
FF = longest lung retention, highest potency
- OD dose
Therapeutic Index Values
• <1 for mid/high doses of BDP, BUD and TAA
• 1 for FLU
• >1 for CIC, FP, MF and FF
Peter T. Daley-Yates, corticosteroids potency
and therapeutic index, BJCP 2015

12. Modern ICS
• High receptor affinity, retained in AW  ↑efficacy
• Rapidly metabolized after absorption from the GI tract  ↓SE
Middleton 8th edition

13. Mechanism of Actions
↓Inflammatory gene expression
↑Anti-inflammatory gene expression
Inhibit inflammatory cells
Structural cell change
Genomic
Non-genomic

14. Mechanism of Actions
Middleton 8th edition

15. Inflammatory Signal
Peter J. Barnes: Inhaled Corticosteroids; Pharmaceuticals 2010, 3, 514-540c
• GC bind to coactivators to inhibit HAT activity directly
• GC recruit histone deacetylase-2 (HDAC2)
 reverses histone acetylation

16. Middleton 8th edition
Peter J. Barnes: Inhaled Corticosteroids; Pharmaceuticals 2010, 3, 514-540

17. Effects on Cells
Peter J. Barnes: Inhaled Corticosteroids; Pharmaceuticals 2010, 3, 514-540

18. Mechanism of Actions
• Hours to days
• Cytoplasmic GR-α
• Gene switch on & off, mRNA degrade,
co-activator binding
Genomic
• Seconds to minutes
• mGR, cGR, direct interaction
• Vascular permeability, AW perfusion,
remodeling
Non-
genomic
Hossny E et al, The use of inhaled corticosteroids in pediatric asthma: update, World Allergy Organ J 2016 Aug 12;9:26.

19. Interaction with Beta-2 Adrenoceptor
Peter J. Barnes: Inhaled Corticosteroids; Pharmaceuticals 2010, 3, 514-540

20. From Bench to Clinic

21. How to Start?

22. © Global Initiative for Asthma www.ginasthma.org
Stepwise management - pharmacotherapy
*Not for children <12 years
**For children 6-11 years, the
preferred Step 3 treatment is
medium dose ICS
#For patients prescribed
BDP/formoterol or BUD/
formoterol maintenance and
reliever therapy
 Tiotropium by mist inhaler is
an add-on treatment for
patients ≥12 years with a
history of exacerbations
Diagnosis
Symptom control & risk factors
(including lung function)
Inhaler technique & adherence
Patient preference
Asthma medications
Non-pharmacological strategies
Treat modifiable risk factors
Symptoms
Exacerbations
Side-effects
Patient satisfaction
Lung function
Other
controller
options
RELIEVER
STEP 1 STEP 2
STEP 3
STEP 4
STEP 5
Low dose ICS
Considerlow
doseICS
Leukotriene receptor antagonists (LTRA)
Low dose theophylline*
Med/high dose ICS
Low dose ICS + LTRA
(or + theoph*)
As-needed short-acting beta2-agonist (SABA) As-needed SABA or
low dose ICS/formoterol#
Low dose
ICS/LABA**
Med/high
ICS/LABA
PREFERRED
CONTROLLER
CHOICE
Add tiotropium*
Med/high dose
ICS + LTRA
(or + theoph*)
Add low
dose OCS
Refer for
add-on
treatment
e.g.
tiotropium,*
anti-IgE,
anti-IL5*
GINA 2018, Box 3-5 (2/8) (upper part)

23. © Global Initiative for Asthma www.ginasthma.org
Initial Controller Treatment in Adults and Adolescents (≥ 6 year-old)

24. © Global Initiative for Asthma www.ginasthma.org
Assessment of risk factors for poor asthma outcomes
GINA 2018, Box 2-2B (4/4)
Risk factors for exacerbations include:
• Uncontrolled asthma symptoms
Additional risk factors, even if the patient has few symptoms:
• High SABA use (≥1x 200 dose canister/month)
• Having ≥1 severe exacerbation in last 12 months
• Low FEV1(<60%) ; higher bronchodilator reversibility
• Incorrect inhaler technique and/or poor adherence
• Smoking
• Obesity, chronic rhinosinusitis, pregnancy, sputum/blood eosinophilia
• Major psychological or socioeconomic problems
• Elevated FeNO in adults with allergic asthma taking ICS
• Ever intubated or ICU care for asthma
Risk factors for fixed airflow limitation include:
• No ICS treatment, smoking, occupational exposure, mucus
hypersecretion, sputum/blood eosinophilia; pre-term birth, low birth weight
Risk factors for medication side-effects include:
• Frequent oral steroids, high dose/potent ICS, P450 inhibitors
Start low dose ICS
in step2
Start low dose
ICS/LABA
or med/high ICS
in step3

25. Stepwise approach – pharmacotherapy
(children ≤5 years)
GINA 2018, Box 6-5 (3/8)
Infrequent
viral wheezing
and no or
few interval
symptoms
Symptom pattern consistent with asthma
and asthma symptoms not well-controlled, or
≥3 exacerbations per year
Symptom pattern not consistent with asthma but
wheezing episodes occur frequently, e.g. every
6–8 weeks.
Give diagnostic trial for 3 months.
Asthma diagnosis, and
not well-controlled on
low dose ICS
Not well-
controlled
on double
ICS
First check diagnosis, inhaler skills,
adherence, exposures
CONSIDER
THIS STEP FOR
CHILDREN WITH:
RELIEVER
Other
controller
options
PREFERRED
CONTROLLER
CHOICE
As-needed short-acting beta2-agonist (all children)
Leukotriene receptor antagonist (LTRA)
Intermittent ICS
Low dose ICS + LTRA Add LTRA
Inc. ICS
frequency
Add intermitt ICS
Daily low dose ICS
Double
‘low dose’
ICS
Continue
controller
& refer for
specialist
assessment
STEP 1 STEP 2
STEP 3
STEP 4

26. © Global Initiative for Asthma www.ginasthma.org
ICS Dosage

27. © Global Initiative for Asthma www.ginasthma.org
ICS Dosage

28. © Global Initiative for Asthma www.ginasthma.org
 This is not a table of equivalence
 A low daily dose is defined as the lowest approved dose for which safety
and effectiveness have been adequately studied in this age group
‘Low dose’ inhaled corticosteroids (mcg/day)
for children ≤5 years – updated 2018
GINA 2018, Box 6-6
Inhaled corticosteroid
Low daily dose, mcg
(with lower limit of age-group studied)
Beclometasone dipropionate (HFA) 100 (ages ≥5 years)
Budesonide (nebulized) 500 (ages ≥1 year)
Fluticasone propionate (HFA) 100 (ages ≥4 years)
Mometasone furoate 110 (ages ≥4 years)
Budesonide (pMDI + spacer) Not sufficiently studied in this age group
Ciclesonide Not sufficiently studied in this age group
Triamcinolone acetonide Not sufficiently studied in this age group
GINA 2018, Box 6-6

29. The Inhaled Steroid Treatment
As Regular Therapy in Early Asthma (START Study)
• Population
: Recent onset (< 2 yr)
Mild asthma
Aged 5-66 years
• N = 7241 (5155 completed 3 year-study)
• Duration
: 3 + 2 = 5 years
• Visit: q 3 mo (+/-14 days)
• Primary outcome
• Db blind phase: time to 1st SARE
• All 5 years: post BD FEV1 change
William W. et al, The Inhaled Steroid Treatment As Regular Therapy in Early Asthma (START) study 5-year follow-up:
Effectiveness of early intervention with budesonide in mild persistent asthma; J Allergy Clin Immunol 2008;121:1167-74.

30. The Inhaled Steroid Treatment As Regular Therapy
in Early Asthma (START Study) X 3 Years
Helen K Reddel et al., Should recommendations about starting inhaled corticosteroid treatment for mild asthma
be based on symptom frequency: a post-hoc efficacy analysis of the START study, Lancet 2017; 389: 157–66

31. The Inhaled Steroid Treatment As Regular Therapy
in Early Asthma (START Study) X 5 Years
William W. et al, The Inhaled Steroid Treatment As Regular Therapy in Early Asthma (START) study 5-year follow-up:
Effectiveness of early intervention with budesonide in mild persistent asthma; J Allergy Clin Immunol 2008;121:1167-74.
PostBD
PreBD
OR = 0.61; (P <.001)

32. The Inhaled Steroid Treatment As Regular Therapy
in Early Asthma (START Study) X 5 Years
William W. et al, The Inhaled Steroid Treatment As Regular Therapy in Early Asthma (START) study 5-year follow-up:
Effectiveness of early intervention with budesonide in mild persistent asthma; J Allergy Clin Immunol 2008;121:1167-74.

33. Implications from START Trial
• Low dose ICS in recent onset mild
asthma
• ↑Time to 1st SARE (severe asthma-
related event)
• ↓Risk of SARE
• ↓Systemic GCs, additional med use
• ↑pre & postBD FEV1 change from
baseline
• ↑Symptom free days
• Low dose ICS in
+ve risk of AE
GINA
2018

34. The Symbicort Given as Needed
in Mild Asthma (SYGMA) 1 trial
• Population
: Aged 12 years or older
mild asthma at GINA step 2
• N = 3849
• Duration
: 52 weeks
• Primary outcome
• Weeks with well controlled
(Hypothesis: Symbicort was superior to SABA)

35. OR = 1.14 (P = 0.046)
14% higher in the budesonide–formoterol group than in the terbutaline group.
OR = 0.64; (95% CI = 0.57 to 0.73)
36% higher in the budesonide maintenance group than in the budesonide –
formoterol group.
57 vs 340 mcg (17% of that in the budesonide maintenance group)
SE: terbutaline>budesonide maintenance> budesonide–formoterol) but not notably
SE led to stop: terbutaline>budesonide maintenance> budesonide–formoterol

36. The Symbicort Given as Needed
in Mild Asthma (SYGMA) 2 trial
• Population
: Aged 12 years or older
mild asthma at GINA step 2
• N = 4215
• Duration
: 52 weeks
• Primary outcome
: Annualized rate of severe
asthma exacerbations
(Hypothesis: Symbicort was non-inferior to
Budesonide maintenance)
• No electronic reminder (real life)

37. Median daily dose of ICS: Bud/for was 75% lower than Bud maintenance
Same median No. of days with systemic GCs

38. Implications from SYGMA Trial: Personalized
Goal (Symptom control or ↓AE)
Adherence
Preference (SE concern, regular/prn)
Asthma
Socioeconomic,
Concern,
Behavior
Comorbid
Symptom
Risk of AE
QoL
Lung function

39. How to Adjust?

40. © Global Initiative for Asthma www.ginasthma.org
Step Up
• Sustained step up (for at least 2–3 months)
• Short-term step up (for 1–2 weeks)
• Day-to-day adjustment
*Check inhaler technique, adherence, modifiable risks first

41. © Global Initiative for Asthma www.ginasthma.org
Step Down
OCS
• ↑ICS/LABA
• Tape OCS (AD)
ICS/LABA
• ↓ICS 50%,
then OD
• Maintain
LABA/2nd
Controller
ICS/For
(regular+prn)
• ↓ICS then OD in
regular dose
Low dose
ICS
↓to OD
Add LTRA
• Controlled and plateau lung function for 3 or more months
• Appropriate time (no respiratory infection, not travelling, not pregnant)
• Assess risk factors for exacerbations or fixed airflow limitation
• ↓ICS doses by 25-50% at 3 month intervals
• Ensure to have sufficient medication to resume
Symptom
PEF
Sputum Eo
FENO

42. © Global Initiative for Asthma www.ginasthma.org
Consider Stopping Controller
• No symptom for 6-12 months
• No any risk for poor asthma outcome
(Evidence D)
*Complete cessation of ICS in adults is not advised (↑Risk of AE)
(Evidence A)

43. Pregnancy &
Breastfeeding

44. © Global Initiative for Asthma www.ginasthma.org
Pregnancy (GINA 2018)
• ICS reduce the risk of AE during pregnancy (Evidence A)
• Cessation of ICS during pregnancy = significant risk factor for
exacerbations(Evidence A)
• Use of ICS, beta2-agonists, montelukast or theophylline
• Not ↑incidence of fetal abnormalities
• Advise that poorly controlled asthma, and AE
• Greater risk to their baby than do current asthma treatments
• Not step down Tx until delivery

45. Pregnancy
• Budesonide (Pulmicort®) is recommended as ICS of choice during
pregnancy
• large amount of reassuring human gestational safety data
• Others (such as beclomethasone [Qvar®], fluticasone [Flovent®],
flunisolide [Aerobid®], mometasome [Asmanex®], and triamcinolone
[Azmacort®]
• Not been proven to be unsafe during pregnancy
• Can be continued in patients well-controlled prior to pregnancy
https://acaai.org/asthma/who-has-asthma/pregnancy

46. Lactation
• Amount of medicine in the breast milk = low
• e.g. BDP, BUD, FP, combination FP/salmeterol
• Some asthma medicines (e.g. formoterol, omalizumab, montelukast)
• Not known whether or not the active ingredient is excreted into breast milk
• Feeding the baby just before each daily dose and avoiding feeding
until 4 hours after the dose
http://www.asthmahandbook.org.au/populations/pregnant-women/breastfeeding

47. Link for The US National Library of Medicine’s
Drugs and Lactation Database (LactMed)
https://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm

48. Adverse Effects of ICS

49. Local
• HPA axis suppression
• Adrenal insufficiency
• Growth velocity suppression
• ↓BMD
• Immunity disturb
• Diabetes
• Skin thinning
• Cataract
• Glaucoma
• Pharyngitis
• Dysphonia
• Reflex cough
• Bronchospasm
• Oropharyngeal candidiasis
• Xerostomia
• Halitosis, caries, gingivitis, taste
perception change
Systemic
Hossny E et al, The use of inhaled corticosteroids in pediatric asthma: update, World Allergy Organ J 2016 Aug 12;9:26.
Prevention: Rinse after use

50. Adrenal Insufficiency
• Dose and duration dependent
• Rare in low to medium dose of ICS in short period of time
• Concomitant use of other GCs route
Hossny E et al, The use of inhaled corticosteroids in pediatric asthma: update, World Allergy Organ J 2016 Aug 12;9:26.

51. Recommend: FP ≥ 400 mcg/d (high dose)
in preadolescent: test HPA axis quarterly

52. the Canadian asthma guidelines
S&S of AI (High index of suspicious)
≥ 6 months ICS in
• High dose
• Medium dose + Risk factors1
Risk factors1
• Higher end of the range
• Prolonged duration
• Concomitant use of nasal and topical GCs
• Recent/frequent short courses oral steroids
• High level of adherence
• Smaller body mass for age
Issa-El-Khoury K et al., CSACI position statement: systemic effect of inhaled corticosteroids on adrenal
suppression in the management of pediatric asthma. Allergy, Asthma Clin Immunol. 2015;11:9.
the Canadian Society of Allergy and Clinical Immunology
:CSACI Position Statement: AI Screening

53. • By asthma itself
• Growth velocity & final adult height*
• Variable results in studies
• Unknown if permanent or temporary slowing growth velocity
• Should monitor periodically
• A Cochrane review1
• Intermittent vs daily ICSs in 532 asthma patients
• Modest suppression in growth (0.41 cm) in daily compared with intermittent
treatment
Growth Delay
Hossny E et al, The use of inhaled corticosteroids in pediatric asthma: update, World Allergy Organ J 2016 Aug 12;9:26.
1Chauhan BF, Chartrand C, Ducharme FM. Intermittent versus daily inhaled corticosteroids for
persistent asthma in children and adults. Cochrane Database Syst Rev 2013;(2):CD009611.

54. Low
Low-Med
Med
Low
Low-high
High
High

55. Kelly HW et al., CAMP Research Group. Effect of inhaled glucocorticoids
in childhood on adult height. N Engl J Med. 2012;367:904–12
The decrease was not progressive or cumulative
The CAMP Study

56. Bone Mineral Density
• By asthma itself
• Variable results in meta-analysis, studies
• Trend toward ↓BMD and ↑fracture risk for long-term mod- to high-dose ICS
• Caution if risk for osteoporosis and fractures
Buehring B, Viswanathan R, Binkley N, Busse W. Glucocorticoid-induced osteoporosis:
an update on effects and management. J Allergy Clin Immunol. 2013;132:1019–30.

57. Effect on Immunity
• ↑Pneumonia in adult COPD
• Nested case control study from Korea
• ↑risk of TB in long-term high dose ICS users
• Disseminated varicella infection, HZV in systemic GCs
• A retrospective cohort
• Chicken pox outbreaks was associated with oral GCs use
Hossny E et al, The use of inhaled corticosteroids in pediatric asthma: update, World Allergy Organ J 2016 Aug 12;9:26.

58. Diabetes
• Variable results
• Trend toward ↑progression of diabetes in adult
• Paucity of study in children
• Should monitor in diabetic patient
• A large cohort Canadian study: Adult patients with COPD treated with
ICS (esp. high dose)
• ↑Risk of development and progression of diabetes
• A cross-sectional study: non diabetic children with asthma
• ↑Mean HbA1c (5.44 ± 0.75 %) among non-diabetic children with asthma
compared to the healthy control (5.14 ± 0.41 %)
• Not correlate with the cumulative dose or time of usage
Hossny E et al, The use of inhaled corticosteroids in pediatric asthma: update, World Allergy Organ J 2016 Aug 12;9:26.

59. Ocular Complication
• Subcapsular, nuclear cataract
• Greater in older > children
• The CAMP study: 1 child after 6 years ICS use  suspected PSC
• No evidence of ↑glaucoma risk
• Monitor IOP esp. in elderly on prolonged ICS use
Hossny E et al, The use of inhaled corticosteroids in pediatric asthma: update, World Allergy Organ J 2016 Aug 12;9:26.

60. Skin Complication (from case report)
• Skin thinning, bruising/purpura (more common in adults)
• Reported in patients on high dose ICS
• Acne
• Hypertrichosis (onset 1 month – 3 years)
• Hair depigmentation
Hossny E et al, The use of inhaled corticosteroids in pediatric asthma: update, World Allergy Organ J 2016 Aug 12;9:26.

61. Psychiatric Morbidity
• A study conducted in the Netherlands
• Alterations in behavior in the pediatric population
• The CAMP study:
• Greater improvement in the total score on the Children’s Depression
Inventory in the budesonide vs placebo (a decline of 3.2 vs. 2.2, P = 0.01)
• A cross-sectional study
• High dose ICS is negatively associated with mental well being
Hossny E et al, The use of inhaled corticosteroids in pediatric asthma: update, World Allergy Organ J 2016 Aug 12;9:26.

62. Recommend
Lowest Effective
Dose of ICS

63. KCMH ICS
Drug Tradename Dose Amount Cost Welfare
Beclomethasone dipropionate/Formoterol Foster MDI 100/6 120 931.- ยานอกบัญชี
Budesonide Aeronide MDI 200 200 106.- บัญชี ก
Budecort MDI 200 200 105.- บัญชี ก
Giona Easyhaler 200 200 626.- บัญชี ค
Obucort Swinghaler 200 200 626.- บัญชี ค
Pulmicort MDI 200 100 366.- บัญชี ก
Pulmicort MDI 50 200 257.- บัญชี ก
Pulmicort Turbuhaler 100 200 552.- บัญชี ก
Pulmicort Turbuhaler 200 100 482.- บัญชี ก
Budesonide/Formoterol Symbicort Forte Turbuhaler 320/9 60 737.- บัญชี ค
Symbicort Rapihaler 160/4.5 120 700.- ยานอกบัญชี
Symbicort Turbuhaler 160/4.5 120 1008.- บัญชี ค
Symbicort Turbuhaler 80/4.5 60 503.- บัญชี ค

64. KCMH ICS
Drug Tradename Dose Amount Cost Welfare
Fluticasone propionate Flixotide Evohaler 125 120 268.- บัญชี ค
Fluticasone propionate/Vilanterol Relvar Ellipta 100/25 30 853.- ยานอกบัญชี
Relvar Ellipta 200/25 30 1088.- ยานอกบัญชี
Fluticasone propionate/Salmeterol Seretide Accuhaler 100/50 60 454.- บัญชี ค
Seretide Accuhaler 250/50 60 549.- บัญชี ค
Seretide Accuhaler 500/50 60 698.- บัญชี ก
Seretide Evohaler 50/25 120 443.- บัญชี ค
Seretide Evohaler 250/25 120 663.- บัญชี ค