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