Inhaled corticosteroids in clinical practice

Sasikarn Suesirisawad, MD

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

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

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

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

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

Clark AR et al.J Endocrinol.

 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

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

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

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

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

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

 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 ( ) –

 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 ( ) –

 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 ( ) –

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

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

Budesonide BeclomethasoneFluticasone

 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

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

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

Deborah et al. American Association for respiratory care 2011

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

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

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.

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

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

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

Dry Powder Inhaler (DPI) Turbuhaler DishkhalerEasyhaler Accuhaler Swinghaler

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

 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.

 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 -

 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.

 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

 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

 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

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

 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.

 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

 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)

 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

Inhaled corticosteroids in clinical practice

by Division of Allergy and Clinical Immunology, Department of Medicine, Faculty of Medicine, Chulalongkorn University on Mar 23, 2012

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