JB 9/2001 SF.ppt Conflict of Interest Disclosure Neonatal and - - PDF document

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Neonatal and Childhood Pulmonary and Vascular Disease Conference , UCSF

Relationships Between Inhaled Aerosol Deposition in the Lungs and Human Lung Physiology in Children and Adults

Joseph D. Brain Harvard University Saturday, March 11, 2017

Conflict of Interest Disclosure

 Aerogen, Inc  Current Support: NHLBI, NIEHS, NSF, NIOSH, Hoffman Foundation, BASF

Neonates & Children vs. Teenagers & Adults

 > O2/kg, > surface area/kg, >metabolism, and > activity.  Smaller airways and alveoli  Surface forces contribute more to ”elastic” properties  More permeable air-blood barrier  Maturation of the lungs continues both biochemical and anatomical

Structural alveolation Lung volume ↑ Birth

smooth- walled saccular airspace; little alveolar septation rapid alveolation by the formation of new septa (secondary septa) from primary septa Primary septa Secondary septa

Dramatic changes occur in the acinar structure during postnatal lung development

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Semmler-Behnke et al., PNAS 2012 human rat

b.

birth

4d 7d 14d 21d 35d adult

1.5~2y ~8years

> 90 days

What is an Aerosol?

 A suspension of small solid or liquid particles in a gas (usually air)  Unit of size measurement for respirable aerosols is the micrometer (µm) = micron (µ) = 10-6m  Size ranges: Coarse 2.5–10.0 µm Fine < 2.5 µm Ultrafine < 0.1 µm

Aerosols

Monodisperse Same size – unusual Polydisperse A continuous spectrum of sizes Particle size determines how aerosols move through air and where and how they interact with the surfaces they encounter. Breathing pattern and lung anatomy also determine deposition of aerosols in the respiratory tract. Environmental and pharmacologic aerosols are composed of a range of particle sizes.

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Aerosols:

 Are ubiquitous indoors and outdoors  Cause and aggravate lung disease  Can be an important therapeutic tool

Aerosols Can Hurt Neonates and Children

 Particulate Matter – Indoors, Outdoors, Occupational  Mold, E.G. Stachybotrys chartarum  Passive Tobacco Smoke  Airborne Infection: Measles, Tb, Influenza  Neonate and child lungs not only collect toxic particles, they also capture therapeutic aerosols

Aerosols Can Heal Neonates and Children

 Pulmonary Surfactants  Antivirals, Antibiotics, e.g. Tobramycin  Steroids  Bronchodilators  Mucolytic, e.g. Pulmozyme  Anti-proteases, inhibitors of fibrosis or abnormal repair

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Drug Delivery Directly to the Lungs

 Rapid delivery to the site of action; the lungs are < 1% of body weight, why waste it.  High local concentrations where the drug is needed  Minimize dosing of extra-pulmonary sites and thus minimize side effects  Avoids hepatic uptake and processing.  Injections, IV administration, not needed. Moreover if the drug is needed on alveolar suraces, the tight epithelial is avoided

Routes of Exposure and Anatomic Barriers

Route Organ Barrier Surface Area (m2) Thickness from Environment to Blood (m) Typical Daily Exposure Dermal Skin Epidermis 1.8 100-1000 Variable, easily reduced Oral Ingestion GI Tract Intestinal Epithelium 1,200 15-40 1.5 kg food 2 kg water Some particles from respiratory tract Inhalation Lungs Alveolar Epithelium 140 0.64 10-20 m3 (10,000 – 20,000 L)

• r 15 - 25 kg air

Two notable characteristics of the lung:

• high daily exposure
• thin barrier

Drug Delivery Through the Lungs Is Possible

Large surface area—about 150 m2 Thin barrier—< 1 µm Few proteases Avoids first-pass liver clearance Rapid and efficient transport Avoids unpleasant injections

Advantages of pulmonary delivery of proteins to systemic circulation:

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Niven RW. Crit Rev Ther Drug Carrier Syst. 1995;12:151-231. Wolff RK, Dorato MA. Crit Rev Toxicol. 1993;23:343-369.

Even Peptide and Protein Hormones Can Be Administered Via the Lungs

 Insulin  Calcitonin  Parathyroid hormone  Human growth hormone  Somatostatin  Thyroid stimulating hormone  α-1-antitrypsin

Pharmacologic Aerosols:

The dose of an inhaled aerosolized drug and its anatomic distribution depend on: aerosol size & concentration, physics breathing pattern lung anatomy, e.g. acute and chronic changes (asthma, ARDS, PAH) equipment between the device producing the aerosol and the patient’s airway

Deposition of Particles

(IMPACTION)

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Classification of Particles by Size

 Inhalable Coarse Particles, PM >10 m

• Can deposit in the nose or mouth
• Deposited primarily by impaction

 Thoracic Coarse Particles, PM 2.5 to 10 m

• Can deposit in airways of the lungs
• Deposited primarily by impaction and sedimentation

 Respirable Particles (fine fraction) PM <2.5 m

• Most penetrate beyond the terminal bronchioles and reach the gas

exchange region

• Deposit there primarily by sedimentation and diffusion

 Ultrafine Particles are <0.1 m (also called nanoparticles)

• Small fraction by mass but not by number or surface area.
• Deposit primarily by diffusion throughout the respiratory tract

(IMPACTION)

Aerodynamic particle diameter is a determinant of how much and where particles are deposited in the respiratory tract

Primary mechanism

• f deposition

Diffusion Inertial Impaction Sedimentation

Effect of Breathing Pattern on Particle Deposition

 Increased linear velocity of airflow promotes inertial impaction of particles in more proximal airways. When inspiratory flow rates are excessive, there may be significant losses in the device and oral phatynx.  An increase in tidal volume leads to deeper penetration by particles, more alveolar deposition.  Lower inspiratory flow rates and increased end tidal breath holds provide more time for diffusion and sedimentation and thus more alveolar deposition.

23

Now let us review:

Lung anatomy Clearance mechanisms that determine drug retention

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Air is filtered, humidified and brought to body Temperature in the conducting airways.

Gas exchange

• ccurs here.

Each clump

• f alveoli

& ducts is called an acinus.

CONDUCTING AIRWAYS

NASOPHARYNX (upper airways)

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Anatomic Region Clearance Mechanism Approximate Clearance Half- time Nasopharynx Mucociliary Transport Minutes Tracheobronchial Mucociliary Transport Minutes to Hours Alveolar Macrophage Phagocytosis Hours Alveolar Macrophage Dissolution Hours to Months to ?

Alveolar Macrophage

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Iron Oxide Particles on Respiratory Surfaces of the Lung 3 hours after a 1 hour exposure Arrows indicate macrophages that have taken up iron oxide particles.

Austin et al. AJRCCM 195(1):23-31, 2017 Feb. 1 Austin et al. AJRCCM 195(1):23-31, 2017 Feb. 1

Conclusions:

 Give neonates and children clean air. Take advantage of therapeutic aerosols Modify devices and delivery strategies as needed. Early events have long term, life time consequences.