drug delivery in pediatric asthma

Definition of AsthmaDefinition of Asthma

1950s, 1950s, ClinicalClinical - Widespread airway - Widespread airway narrowing which changes in severity narrowing which changes in severity over short periods of time, either over short periods of time, either spontaneously or in response to spontaneously or in response to treatmenttreatment

1960s, 1960s, PhysiologicalPhysiological - Bronchial - Bronchial HyperresponsivenessHyperresponsiveness

1990s, 1990s, PathologicalPathological - Airway - Airway inflammationinflammation

Definition of AsthmaDefinition of Asthma

A chronic inflammatory disorder of the airways

Many cells and cellular elements play a role

Chronic inflammation is associated with airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing

Widespread, variable, and often reversible airflow limitation

A chronic inflammatory disorder of the airways

Many cells and cellular elements play a role

Chronic inflammation is associated with airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing

Widespread, variable, and often reversible airflow limitation

Classification of SeverityClassification of Severity

CLASSIFY SEVERITYClinical Features Before Treatment

SymptomsSymptoms NocturnalNocturnalSymptomsSymptoms

FEVFEV1 1 or PEFor PEF

STEP 4STEP 4

Severe Severe PersistentPersistent

STEP 3STEP 3

Moderate Moderate PersistentPersistent

STEP 2STEP 2

Mild Mild PersistentPersistent

STEP 1STEP 1

IntermittentIntermittent

ContinuousContinuous

Limited physical Limited physical activityactivity

DailyDailyAttacks affect activityAttacks affect activity

> 1 time a week > 1 time a week but < 1 time a day but < 1 time a day

< 1 time a week< 1 time a week

Asymptomatic Asymptomatic and normal PEF and normal PEF between attacksbetween attacks

FrequentFrequent

> 1 time week> 1 time week

> 2 times a month> 2 times a month

2 times a 2 times a monthmonth2 times a 2 times a monthmonth

60% predicted60% predicted

Variability > 30%Variability > 30%

60 - 80% predicted 60 - 80% predicted

Variability > 30%Variability > 30%


Variability 20 - 30%Variability 20 - 30%


Variability < 20%Variability < 20%

The presence of one feature of severity is sufficient to place patient in that category.The presence of one feature of severity is sufficient to place patient in that category.

Levels of Asthma Control

CharacteristicCharacteristicControlledControlled

((All of the All of the followingfollowing))

Partly controlledPartly controlled(Any present in any (Any present in any

week)week)

UncontrollUncontrolleded

Daytime Daytime symptomssymptoms

None (2 or None (2 or less / week)less / week)

More than More than twice / weektwice / week

33 or more or more features of features of

partly partly controlled controlled

asthma asthma present in present in any weekany week

Limitations of Limitations of activitiesactivitiesNoneNoneAnyAny

Nocturnal Nocturnal symptoms / symptoms / awakeningawakening

NoneNoneAnyAny

Need for rescue / Need for rescue / ““relieverreliever”” treatmenttreatment

None (2 or None (2 or less / week)less / week)

More than More than twice / weektwice / week

Lung function Lung function (PEF or FEV(PEF or FEV11))

NormalNormal

< <80%80% predicted or predicted or personal best (if personal best (if known) on any known) on any

dayday

ExacerbationExacerbationNoneNone One or more / year 1 in any One or more / year 1 in any weekweek

controlled

partly controlled

uncontrolled

exacerbation

LEVEL OF CONTROLLEVEL OF CONTROL

maintain and find lowest controlling step

consider stepping up to gain control

step up until controlled

treat as exacerbation

TREATMENT OF ACTIONTREATMENT OF ACTION

TREATMENT STEPSREDUCE INCREASE

STEP

1STEP

2STEP

3STEP

4STEP

5

RE

DU

CE

INC

RE

AS

E

Step 1 – As-needed reliever medication

Patients with occasional daytime symptoms of short duration

A rapid-acting inhaled β2-agonist is the recommended reliever treatment (Evidence A)

When symptoms are more frequent, and/or worsen periodically, patients require regular controller treatment (step 2 or higher)

Treating to Achieve Asthma Control

Step 2 – Reliever medication plus a single controller

A low-dose inhaled glucocorticosteroid is recommended as the initial controller treatment for patients of all ages (Evidence A)

Alternative controller medications include leukotriene modifiers (Evidence A) appropriate for patients unable/unwilling to use inhaled glucocorticosteroids

Treating to Achieve Asthma Control

Treating to Maintain Asthma Control

Stepping down treatment when asthma is controlled

When controlled on medium- to high-dose inhaled glucocorticosteroids: 50% dose reduction at 3 month intervals (Evidence B)

When controlled on low-dose inhaled glucocorticosteroids: switch to once-daily dosing (Evidence A)

Component 3: Assess, Treat and Monitor Asthma – Children 5 Years and Younger


Childhood and adult asthma share the same underlying mechanisms. However, because of processes of growth and development, effects of asthma treatments in children differ from those in adults.

Childhood and adult asthma share the same underlying mechanisms. However, because of processes of growth and development, effects of asthma treatments in children differ from those in adults.

Asthma Management and Prevention Program




Many asthma medications (e.g. glucocorticosteroids, β2- agonists, theophylline) are metabolized faster in children than in adults, and younger children tend to metabolize medications faster than older children

Many asthma medications (e.g. glucocorticosteroids, β2- agonists, theophylline) are metabolized faster in children than in adults, and younger children tend to metabolize medications faster than older children





Long-term treatment with inhaled glucocorticosteroids has not been shown to be associated with any increase in osteoporosis or bone fracture

Studies including a total of over 3,500 children treated for periods of 1 – 13 years have found no sustained adverse effect of inhaled glucocorticosteroids on growth

Long-term treatment with inhaled glucocorticosteroids has not been shown to be associated with any increase in osteoporosis or bone fracture

Studies including a total of over 3,500 children treated for periods of 1 – 13 years have found no sustained adverse effect of inhaled glucocorticosteroids on growth





Rapid-acting inhaled β2-agonists are the most effective reliever therapy for children

These medications are the most effective bronchodilators available and are the treatment of choice for acute asthma symptoms

Rapid-acting inhaled β2-agonists are the most effective reliever therapy for children

These medications are the most effective bronchodilators available and are the treatment of choice for acute asthma symptoms

Drugs are delivered to a pediatric asthmatic patient through four routes

Orally Rectally By Injections By Inhalations

Inhalation therapy has revolutionized asthma management

Rapid onset of action Less Side Effects In Egypt misbelieves from parents

and doctors as well, make inhalations therapy less popular than it should be

Inhalation therapy is delivered by Pressurized metered dose

inhaler (pMDI) Pressurized metered dose

inhaler (pMDI) with spacer Nebulizer Dry powder inhalers

For an aerosol device to deliver medications efficiently to lower respiratory tract

Aerosol particle should be in the respirable range

Patient should inhale the aerosol with slow deep inspiration followed by a breath hold to allow sedimentation of medication particles

An aerosol is a group of particles that remain suspended in air for a relatively long time because of low terminal settling velocity (the velocity at which particle will fall in air because of gravity(

This terminal settling velocity is related to the size and density of the particle which is expressed as the mass median aerodynamic diameter MMAD

Respirable fraction between 0.5-5 um

Larger particles tend to deposit in the device or upper airway

Very small particles do not settle in the airway and can be exhaled

Mechanisms of aerosol deposition in lower airways (Inertial Impaction, Gravitational Sedimentation & Diffusion

Inertial Impaction For particles > 3 um

#smaller diameter of upper airway in infants and children, preferential nose breathing

#Inertial impaction is highly flow dependant

Gravitational Sedimentation for particles smaller than 2 um and larger particles under low-flow conditions

#The longer particles remain in the lungs,

the greater is their rate of deposition

# Breath holding for 5-10 sec is recommended after inhalation of an aerosol

# Low tidal volume and small vital capacity of infants decrease gravitational sedimentation

Diffusion affect particles so small that Brownian motion has greater influence on particle movement than gravity

Random Brownian movement result in coalescence of particles with airway structures and with other particles

The earliest aerosol device used abulb atomizer similar to those used for some perfume spray which is quite inefficient

In 1945, the daughter of an executive of the Ricker company complained to her father that her asthma atomizer kept breaking

Pressurized metered dose inhaler pMDI Advantages : small size , portable inexpensive,

deliver medication in the respirable range , most asthma medications are available as pMDI

Disadvantages : # Need co-ordinations between actuation and

inhalations # Use of too rapid inspiratory flow # Damaging effect of CFC propellants on ozone # Alternative propellants hydrofluoroalkans (HFA)

may have impact on global warming. With HFA beclomethazone lung deposition increase by 3 to 4 folds while with fluticasone & budesonide remain the same

# Cold freon effect # Patient does not know exactly when canister is

empty

pMDI disadvantages (Continued)#Paradoxical Broncho-constriction even when the

drug is bronchodilator#It is difficult to asses how much drug remain in

the pMDI#Delivered dose may vary, particularly if pMDI is

not properly shaken# Pressurized MDI have a high initial velocity and

the droplets have high initial MMAD (30 um)

Pressurized metered-dose inhalers with spacer Disadvantages: # Large size and lack of portability # Much of the first 10-20 doses of

aerosol fired into a new plastic spacer is deposited on its wall because of its electrostatic charges. Frequent washing may restore the charges.

# Multiple actuations into a spacer before inhalation may reduce delivered dose to the patient because of expansion of CFC within the spacer

pMDI with spacer (Continued)

Advantages : # Overcome the problem of co-ordination

between actuation and inhalations # Overcome the problem of high initial

velocity & high initial MMAD of pMDI (30um) The velocity of the aerosol decreases

within the spacer, the large particles either deposit within the spacer or reduced in size by evaporation to MMAD < 5 um

Nebulizers

Two main types : jet & ultrasonic nebulizer

Jet nebulizer effective for all types of medications including particulate suspension such as inhaled steroids

Ultrasonic Nebulizers

Use high frequency sound waves produced from piezoelectric crystal, which bounce on the surface of the liquid to generate aerosol

Less efficient than jet nebulizer, can not nebulize particulate suspension

The heat of crystal can denature some medications (particularly proteins)

Crystal can develop coating or cracking that can be difficult to detect

Have medication volumes of up to 1.2 ml remaining in the reservoir after nebulization

Jet nebulizer therapy for hospitalized patients

Administered using compressed air or O2 at 50 pound/square inch to generate a flow of 6-8L/minute. This produce acceptable particle size and acceptable nebulization time of 5-10 minute for a 4 ml

fill volume The greater the pressure of O2, the

smaller the particle size

Factors affecting nebulizer performance Type of nebulizer Residual volume remaining in

nebulizer cup (0.5-2ml) is unavailable to the patient

Increasing the fill volume by adding saline allow nebulization of greater proportion of medication at the coast of increased time

The longer the nebulization time, the less likely the patient will consistently take deep breath allowing maximal drug delivery to lower airways

Factors affecting nebulizer performance ( Continued)

Infant crying markedly decrease medication delivery to lower airways since crying is a very long expiration followed by a rapid & brief inspiration. During rapid inspiration the nebulized particles will be deposited in the upper airway by inertial impaction

Patient agitation makes achieving a good seal on either face mask or mouth piece almost impossible

Face mask should be of appropriate size comfortable and fit tightly on the face

Advantages & Disadvantages of Nebulizers

#Advantages The ability to deliver high dose of drugs

particularly bronchodilator Allow patient to receive treatment who are

otherwise unable to inhale drugs (infants) #Disadvantages Complex, time consuming less portable and less

convenient to the patient More coasty than dry powder inhaler or pMDI If they are not perfectly cleaned, nebulizer can become

colonized by microorganisms Even with good care nebulizer performance can decline

overtime

Dry powder inhalers (DPIs)

Dry powder inhalers use the patient inspiratory force to generate drug aerosol from dry powder

Because significant surface force can cause small particles to clump together, medications are hold medications in humidity-protected blisters or mixed with a carrier agent such as lactose to aid dispersion

Two main types of DPIs are available for pediatric use in Egypt ; Turbhaler (Astra-Zenica) & Diskus (GSK)

A moderate to high resistance inhaler device (60-90 L/M) , suitable for children >5 y

Affected by humidity especially if the child exhales into the device

However, when used appropriately it deliver aerosol more effectively than nebulizrsas & as effective as pMDI with spacer

Diskus is a lower resistance multi-dose DPI (30 ml/m)

Medication is contained in individual blister packs better protected from humidity, but still exhalation into the devise will aggregate the preloaded dose

Drug Delivery to the lung from different inhalers

Can be assessed in vitro using scintigraphy, where the aerosol is prelabelled with particle containing a radio-isotope

Systemic availability of inhaled drugs

The relationship between clinical efficacy, local side effects & systemic side effects is more complex with inhaled steroids

Beclomethasone have lower first pass metabolism than fluticasone and budesonide

drug delivery in pediatric asthma

Health & Medicine