inhaled corticosteroids in clinical practice
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Inhaled corticosteroid in clinical practice
Sasikarn Suesirisawad, MD
Outline
Mechanism of action Structure of ICS PK/PD ICS comparison Device comparison Side effect Clinical response
Mechanism of action
Molecular effects of inhaled glucocorticoid therapy in asthma
Suppression of inflammation
Increased expression of beta 2-receptors and enhanced coupling of beta 2-receptors to G-proteins
Anti-inflammatory mechanism of glucocorticoid
Fernando M et al.Am J Respir Crit Care Med Vol 185, Iss. 1, pp 12–23, Jan 1, 2012
SUPPRESSION OF INFLAMMATION
Anti-inflammatory gene activation
Switching off inflammatory genes
Inflammatory cell inhibition
Anti-inflammatory gene activation
2 types of glucocorticoid receptors (GR) GR alpha GR beta
Glucocorticoid action facilitated by GR alpha, but inhibited by GR beta.
Steroid effects gene expression
Corticosteroids suppression of activated inflammatory genes
Clark AR et al.J Endocrinol.2003;178(1)
BETA 2-RECEPTOR EFFECTS
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. JACI2010;125(5):1020.
Structure of ICS
Melanie Hubner et al. Immunol Allergy Clin N Am25 (2005) 469– 488
Melanie Hubner et al. Immunol Allergy Clin N Am25 (2005) 469– 488
PK/PD
Pharmacokinetics of ICS
Johnson M et al. JACI. 1996;97(1 Pt 2):169.
Franklin Cerasoli et al. Chest 2006;130;54S-64S
Combination of PK/PD to evaluate effect drug over time
Melanie Hubner et al. Immunol Allergy Clin N Am25 (2005) 469– 488
Stuart W. Stoloff et al. Current Opinion in Allergy and Clinical Immunology 2011, 11:000–000
Pharmacokinetics of Inhaled Glucocorticosteroids
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 Am25 (2005) 469– 488
Receptor potency
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: 12Melanie Hubner et al. Immunol Allergy Clin N Am25 (2005) 469– 488
Oral bioavailability
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 Am25 (2005) 469– 488
PK/PD of ICS
Stuart W. Stoloff et al. Current Opinion in Allergy and Clinical Immunology 2011, 11:000–000
Franklin Cerasoli et al. Chest 2006;130;54S-64S
Franklin Cerasoli et al. Chest 2006;130;54S-64S
Franklin Cerasoli et al. Chest 2006;130;54S-64S
Zia R Tayab et al. Expert opin. Drug Deliv. (2005) 2(3):519-532
ICS comparison
Fluticasone
Budesonide Beclomethasone
Inhaled corticosteroids
Comparative daily dosages(μg) of ICS
Stuart W. Stoloff et al. Current Opinion in Allergy and Clinical Immunology 2011, 11:000–000
Lung deposition
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
Lung deposit of different ICS
Melanie Hubner et al. Immunol Allergy Clin N Am25 (2005) 469-488
Comparison of protein binding of ICS
Melanie Hubner et al. Immunol Allergy Clin N Am25 (2005) 469-488
Device comparison
Pulmonary deposition of different inhaler
Melanie Hubner et al. Immunol Allergy Clin N Am25 (2005) 469-488
Types of Aerosol Inhalers
3 types
Small volume nebulizer (SVN) Metered-dose inhaler (MDI) Dry powder inhaler (DPI)
Deborah et al. American Association for respiratory care 2011
Drug deposition with aerosol inhaler
Deborah et al. American Association for respiratory care 2011
Deborah et al. American Association for respiratory care 2011
Mean change in FEV1 versus cumulative dose from MDI and SVN.
Mestitz H et al. Chest 1989;96:1237-1240
Changes in FEV1 for 3 different routes of administration with terbutaline.
Deborah et al. American Association for respiratory care 2011
Inhalation route of aerosolized drugs
ADVANTAGES
Aerosol doses are generally smaller than systemic doses.
Onset of effect is faster than oral.
Drug delivered directly to lung, minimal systemic exposure.
Systemic side effects are less frequent and severe.
Less painful and comfortable.
DISADVANTAGES
Lung deposition is relatively low fraction of total dose.
Correct breathing pattern & use of device can affect lung deposition.
Difficulty coordinating hand action and inhalation with MDIs.
Lack of knowledge of use of devices.
Number and variability of device types confuses pts and clinicians.
Deborah et al. American Association for respiratory care 2011
The effect of aerosol particle size on site of preferential deposition in airways
Rau JL Jr. Respiratory care pharmacology, 6th ed. St. Louis: Mosby; 2002: 39
National Asthma Education and Prevention Program, Expert Panel II: Guidelines for diagnosis and management of asthma, Bethesda, MD; 1997. National Institutes of
Health.
Small volume nebulizer (SVN)
ADVANTAGE
Aerosolize many drug solution.
Aerosolize drug mixture (>1 drug)
Minimal pt cooperation
Useful in very young, very old,
distressed pt
Drug concentration and dose can be
modified.
Normal breathing pattern can be
used and breath-hold is not required
for efficacy
DISADVANTAGE
Treatment may range from 5-25
min.
Equipment required may be large
and cumbersome.
Need for power source.
Potential drug delivery into eye with
face mask.
Variability in performance
characteristics among different
types, brand and model.
Assembly and cleaning are
required.
Contamination is possible.
Deborah et al. American Association for respiratory care 2011
Pneumatic Jet Nebulizers
Deborah et al. American Association for respiratory care 2011
Jet nebulizer with reservoir tube
Deborah et al. American Association for respiratory care 2011
Nebulizer with aerosol collection bag
Deborah et al. American Association for respiratory care 2011
Breath-enhanced nebulizer
Deborah et al. American Association for respiratory care 2011
Breath-actuated nebulizer
Deborah et al. American Association for respiratory care 2011
Ultrasonic Nebulizers
Deborah et al. American Association for respiratory care 2011
Mesh Nebulizers
Deborah et al. American Association for respiratory care 2011
Metered-dose inhalers(MDI)ADVANTAGE
Portable, light, compact
Multiple dose convenience
Short treatment time
Reproducible emitted
doses
No drug preparation
required
Difficult to contamination
DISADVANTAGE
Hand-breath coordination
required
Fixed drug concentration and
doses
Reaction to propellant
FB aspiration from debris-
filled mouthpiece
High oropharyngeal
deposition
Difficult to determine dose
remaining in canister without
dose counter
Deborah et al. American Association for respiratory care 2011
HFA VS CFC
Deborah et al. American Association for respiratory care 2011
Deborah et al. American Association for respiratory care 2011
Holding chamber used with pMDI
ADVANTAGE
Reduce mouth/throat drug
impaction and loss
Increase inhaled drug by 2-4
times than pMDI alone
Allow use pMDI when pt is
short of breath
No drug preparation
Simplifies coordination pMDI
actuation and inhalantion
DISADVANTAGE
Large and cumbersome
compared to pMDI alone
More expensive and bulky
Some assembly may be needed
Pt error in firing multiple puffs
into chamber prior to inhaling or
delay between actuation and
inhalation
Possible contamination with
inadequate cleaning
Deborah et al. American Association for respiratory care 2011
Valve holding chamber and spacer
Deborah et al. American Association for respiratory care 2011
Dry Powder Inhaler (DPI)
Turbuhaler
Easyhaler
Dishkhaler
Accuhaler
Swinghaler
Dry-powder inhalers(DPI)
ADVANTAGE
Small and portable
Built-in dose counter
Propellant free
Breath-actuated
Short preparation and
administration time
DISADVANTAGE
Dependence on pt’s inspiratory
flow
Pt less aware of delivered dose
Relatively high oropharyngeal
impaction.
Vulnerable to ambient humidity
or exhaled humidity into
mouthpiece
Different DPIs with different drug
Easy for pt to confuse directionDeborah et al. American Association for respiratory care 2011
Common problems, disadvantages and errors
Metered-dose inhalers 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 MDIMcFadden ER Jr. JACI 1995;96:278-283.
Holding Chambers/Spacers
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 inhalingWildhaber JH et al. Thorax1996;51:985-988.
Dry Powder Inhalers
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.
Nebulizers
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
Side effect
Local side effect
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
Systemic side effect
Skeletal effect
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
Effect of ICS on BMD
Meta-analysis of adrenal suppression
Brian J et al. Arch Intern Med. 1999;159:941-955
Ocular side effect
Intraocular pressure Increase risk of glucoma
Cataracts Risk factor for posterior subcapsular
cataract
Gonzalez AV et al.Pulm Pharmacol Ther. 2010Pelkonen A et al. JACI.2008;122(4):832.
Systemic side effect
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 disturbancePierre 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
MEASURES TO MINIMIZE SYSTEMIC SIDE EFFECTS
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)
Clinical response
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
THANK YOU
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