Drug  Delivery  In Pediatric Asthma
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  • 1.  
  • 2. Definition of Asthma
    • 1950s, Clinical - Widespread airway narrowing which changes in severity over short periods of time, either spontaneously or in response to treatment
    • 1960s, Physiological - Bronchial Hyperresponsiveness
    • 1990s, Pathological - Airway inflammation
  • 3. Definition 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
  • 4.  
  • 5.  
  • 6. Classification of Severity CLASSIFY SEVERITY Clinical Features Before Treatment Symptoms Nocturnal Symptoms FEV 1 or PEF STEP 4 Severe Persistent STEP 3 Moderate Persistent STEP 2 Mild Persistent STEP 1 Intermittent Continuous Limited physical activity Daily Attacks affect activity > 1 time a week but < 1 time a day < 1 time a week Asymptomatic and normal PEF between attacks Frequent > 1 time week > 2 times a month  2 times a month  60% predicted Variability > 30% 60 - 80% predicted Variability > 30%  80% predicted Variability 20 - 30%  80% predicted Variability < 20% The presence of one feature of severity is sufficient to place patient in that category.
  • 7. Levels of Asthma Control Characteristic Controlled (All of the following) Partly controlled (Any present in any week) Uncontrolled Daytime symptoms None (2 or less / week) More than twice / week 3 or more features of partly controlled asthma present in any week Limitations of activities None Any Nocturnal symptoms / awakening None Any Need for rescue / “ reliever ” treatment None (2 or less / week) More than twice / week Lung function (PEF or FEV 1 ) Normal < 80% predicted or personal best (if known) on any day Exacerbation None One or more / year 1 in any week
  • 8. controlled partly controlled uncontrolled exacerbation LEVEL OF CONTROL maintain and find lowest controlling step consider stepping up to gain control step up until controlled treat as exacerbation TREATMENT OF ACTION TREATMENT STEPS REDUCE INCREASE STEP 1 STEP 2 STEP 3 STEP 4 STEP 5 REDUCE INCREASE
  • 9.  
  • 10.  
  • 11.
    • Step 1 – As-needed reliever medication
    • Patients with occasional daytime symptoms of short duration
    • A rapid-acting inhaled β 2 -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
  • 12.  
  • 13.
    • 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
  • 14.  
  • 15.  
  • 16.  
  • 17. 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)
  • 18. 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.
  • 19. Asthma Management and Prevention Program Component 3: Assess, Treat and Monitor Asthma – Children 5 Years and Younger
    • Many asthma medications ( e.g. glucocorticosteroids, β 2 - agonists, theophylline) are metabolized faster in children than in adults, and younger children tend to metabolize medications faster than older children
  • 20. Asthma Management and Prevention Program Component 3: Assess, Treat and Monitor Asthma – Children 5 Years and Younger
    • 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
  • 21. Asthma Management and Prevention Program Component 3: Assess, Treat and Monitor Asthma – Children 5 Years and Younger
    • Rapid-acting inhaled β 2 -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
  • 22. Drugs are delivered to a pediatric asthmatic patient through four routes
    • Orally
    • Rectally
    • By Injections
    • By Inhalations
  • 23. 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
  • 24. Inhalation therapy is delivered by
    • Pressurized metered dose inhaler (pMDI)
    • Pressurized metered dose inhaler (pMDI) with spacer
    • Nebulizer
    • Dry powder inhalers
  • 25. 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
  • 26.
    • 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
  • 27.
    • 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
  • 28.  
  • 29. 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
  • 30.
    • 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
  • 31.
    • 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
  • 32.
    • 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
  • 33. 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
  • 34. 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)
  • 35.  
  • 36. 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
  • 37. 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
  • 38.  
  • 39. Nebulizers
    • Two main types : jet & ultrasonic nebulizer
    • Jet nebulizer effective for all types of medications including particulate suspension such as inhaled steroids
  • 40. 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
  • 41.  
  • 42. 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
  • 43. 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
  • 44. 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
  • 45. 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
  • 46. 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)
  • 47.
    • 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
  • 48.
    • 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
  • 49. 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
  • 50. 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
  • 51.  
  • 52.