540 - Drug Delivery Systems - Exam Iv - Pulmonary Drug Delivery

Front 1

Describe the architecture of the airways (name and generation)

Back 1

Traceha (Gen 0)
Main Bronchi (Gen 1)
Lobar Bronchi (Gen 2)
Segmental (Gen 3)
Bronchi -> Bronchioles -> Term Bronchioles (Gen 16)

Front 2

List four facts pertaining to the architecture of the airways

Back 2

1) Decreasing diameter and length
2) Gemoetrically increasing number (Lg increase in SA)
3) Lungs not identical (left is smaller)
4) Irregular branching patterns

Front 3

What parts make up the respiratory unit?

Back 3

1) Alveolar Ducts
2) Atria
3) ~20 alveoli

Front 4

What is the alveolar region?

Back 4

1) Airway terminates at the "respiratory unit"
2) Tiny round air sacs separated by alveolar septum
3) Surrounded by capillaries which connect to arteries and veins
4) 10^8 alveoli in the lung
5) Sites of gas exchange

Front 5

What are the 3 levels of epithelia in the lung?

Back 5

1) Bronchus
2) Bronchiolus
3) Alveolus

Front 6

What makes up the pulmonary epithelia?

Back 6

Cilaited cubodial cells. Thinner epithelium, less mucus

Front 7

Describe the alveolar epithelium

Back 7

1) Very small (0.2 mm dia)
2) No mucus
3) Flatter epithelium
4) Type-I pneumocytes
5) Type-II pneumocytes

Front 8

Describe Type-I pneumocytes

Back 8

Thin squamous cells with a short airway-to-blood path length for easy exchange of gases. Makes up 93% of alveolar surface.

Front 9

Describe Type-II pneumocytes

Back 9

Cubodial cells secrete pulmonary surfactant, lowers surface tension and maintains morphology and function of the lung

Front 10

Describe ciliated cells in the pulmonary system

Back 10

1) Completely cover the central airways
2) Decrease in abundance as we go deeper into the alveolar region
3) Mucus secreted via Goblet Cells

Front 11

Describe mucus in the pulmonary system and its benefits

Back 11

1) Visocelastic layer in the tracheobroncial region
2) Mainly submucosal glands, from goblet cells
3) Contains glycoproteins, proteins, lipids
4) altered in disease states
5) Traps inhaled foreign particulates
6) Easily transports these out of the lungs via cough and cilary beating

Front 12

What allows for rhythmic ciliary beating?

Back 12

Epithelial serous fluid

Front 13

What secretes lung surfactant?

Back 13

Type II pneumocytes

Front 14

What is the function of lung surfactant?

Back 14

Decreases surface tension while maintaining lung morphology and function; critical for respiration

Front 15

What is respiratory distress syndrome?

Back 15

Surfactant deficiency

Front 16

Describe the pathology of asthma

Back 16

Inflamed airways -> swollen, sensitive to inhaled substances -> react by tigthening muscles -> less air flows in -> more mucus -> shortness of breath -> chain reaction

Front 17

What are the causes and treatments of asthma?

Back 17

Causes: family history, childhood infections, allergic reactions

Treatment: Inhaled steroids, theophylline

Front 18

What is Chronic Obstructive Pulmonary Disease (COPD)?

Back 18

When bronchioles lose their shape and become clogged with mucus. As well as the destruction of the walls of the alveoli

Front 19

Describe the pathology of Emphysema

Back 19

Collapse and destruction of air sacs -> shortness of breath

Front 20

Describe the pathology of Chronic Bronchitis

Back 20

Chronically inflamed airways, increased mucus -> COPD

Front 21

What are the causes and treatments for COPD?

Back 21

Causes: Smoking, pollution, occupational hazards -> Irreversible lung damage

Treatments: Bronchodilators, inhaled steroids, antibiotics

Front 22

Describe the pathology of Bronchitis

Back 22

Mucus membranes inflamed -> excess mucus shuts off bronchioles -> Coughing spells, thick phlegm, breathlessness

Front 23

What is the difference between acute and chronic bronchitis?

Back 23

Acute: <6 weeks; 90% viral, 10% bacterial

Chronic: Frequent reoccurance, especially in smokers

Front 24

What is the treatment for bronchitis?

Back 24

Antibiotics if bacterial, mucolytics

Front 25

What organs are effected by cystic fibrosis?

Back 25

1) Sinuses
2) Lungs
3) Skin
4) Liver
5) Pancreas
6) Intestines
7) Reproductive Organs

Front 26

Describe the pathology of Cystic Fibrosis

Back 26

Thick, sticky mucus -> trap bacteria -> repeated infections -> lung damage

Front 27

What is the rational for pulmonary drug delivery?

Back 27

1) Large surface area of adult human lungs
2) Locally for asthma, COPD, respiratory infections
3) Most direct route of drug entry into the bloodstream
4) Route for systemic drugs

Front 28

What are the goals of pulmonary drug delivery?

Back 28

1) Improve targeting to the site of action
2) Prolong residence time and decrease dosing frequency
3) Improve patient compliance

Front 29

What are the four factors affecting pulmonary drug delivery?

Back 29

1) Physiological factors
2) Physiochemical factors
3) Fate of inhaled particles
4) Metabolism of inhaled particles

Front 30

What are the three factors affecting residence time in the airways

Back 30

1) Mucus barrier
2) Mucocilary clearance
3) Alveolar clearance

Front 31

What are the five factors affecting absorption and metabolism of drugs?

Back 31

1) Surface area
2) Thickness of the absorption barrier
3) Blood supply
4) Permeability and transport routes
5) Enzymatic activity

Front 32

What happens to highly water-soluble drugs when they encounter mucus?

Back 32

They dissolve in the very high relative humidity of the airways, then diffuse into the epithelia lining fluid

Front 33

What effects the diffusion through mucus?

Back 33

1) Thickness and viscosity of the mucus layer
2) Molecular size of the drug
3) Drug-Mucus interactions

Front 34

How do disease states affect mucus in drug delivery?

Back 34

Mucus thickness increases, limiting drug delivery to the site of action

Front 35

Where does the mucocilary escalator end?

Back 35

At the terminal bronchioles

Front 36

How quickly do cilia beat?

Back 36

1000 times per minute

Front 37

Is Oregon going to win the Rose Bowl?

Back 37

Hell Freaking No

Front 38

Describe how alveolar clearance works

Back 38

Marcophages engulf particles -> to mucociliary escalator (slow) -> to lymphatics -> to lymph and blood

Uptake into macrophages is very rapid, while clearance of macrophages can take days or weks

Front 39

Why is the absorption barrier so efficient?

Back 39

1) Large surface area, ~140 m^2
2) Tin barrier leads to rapid gas and small molecule exchange
3) Drug absoprtion through alveolar region more rapid than through any other epithelia

Front 40

Are drugs absorbed in the lungs subject to the first pass effect?

Back 40

No, they pass directly into the heart

Front 41

What is the "pre-systemic first pass effect"?

Back 41

Metabolism by endothelial cells of the lungs

Ex) P450, esterases, peptidases, etc

Front 42

What are some effects of disease states on lung morphology?

Back 42

1) Hypersecretion of mucus
2) Narrowing of the airways

Front 43

What are the regional differences in lung morphology?

Back 43

1) Tracheobroncial (TB) region 10x SA < alveolar region (AR)
2) TB airway-to-blood pathlength 10x > AR
3) TB blood flow 10x < AR
4) Cap network less extensive in TB
5) Mucocilary Cl only in TB
6) AR absorption 2x > TB
7) Systemically acting drugs should be delivered to AR
8) Locally acting drugs - Complex situation depending on area of deposition v. redistribution

Front 44

Describe the Pulmonary Epithelium

Back 44

1) Main barrier to permeability
2) 10-fold lower permeability to hydrophilic drugs than endothelium
3) More permeable than other epithelia
4) Tight junctions between alveolar cells are more permeable than other epithelia

Front 45

What diseases increase membrane permeability in the pulmonary epithelium?

Back 45

1) Adult respiratory distress syndrome
2) Fibrosis
3) Smoking
4) Pollutants

Front 46

Why do newborns have high membrane permeability in the pulmonary epithelium?

Back 46

To absorb proteins from fluid-filled lungs

Front 47

By what route do lipid-soluble drugs transport across the pulmonary system?

Back 47

Transcellular Diffusion

Front 48

By what route do hydrophilic drugs transport across the pulmonary system?

Back 48

Paracellular Diffusion, inverse relation to MW

Front 49

How do large MW drugs cross the pulmonary system?

Back 49

Via transcytosis, phagocytosis, pinocytosis

Front 50

What are the advantages of pulmonary drug delivery?

Back 50

1) Large surface area for absorption
2) Thin alveolar epi -> rapid absorption
3) Highly vascular, direct route to blood
4) No extremes of pH or metabolic activity
5) Bypasses GI absorption and first pass effect
6) Similar or superior therapeutic response at a fraction of the systemic dose

Front 51

What are the disadvantages of pulmonary drug delivery?

Back 51

1) Deposition in mouth or pharynx may cause local side effects
2) Patient compliance -> difficulty correctly using device
3) Mucociliary clerance

Front 52

What are the advantages of using the pulmonary route for systemic diseases?

Back 52

1) Non-invasive
2) Wide range of molecules
3) Large surface area/rapid absorption
4) Less harsh enzymatic environment than liver
5) Reproducible absorption kinetics

Front 53

What are the disadvantages of using the pulmonary route for systemic diseases?

Back 53

1) Lungs not readily accessible surface
2) Patient compliance
3) Toxicity issues for drugs with narrow therapeutic index
4) Mucus layer may limit drub absorption
5) Mucocilary clearance limits residence time of drugs in airways

Front 54

Describe and state the goal of therapeutic aerosols

Back 54

1) It is a two phase colloidal system
2) Drug in a dispersed phase
3) Depends on the formulation and method of aerosol generation

Goal: To transport droplets or particles to correct region of the lung in sufficient quantity

Front 55

Where should drugs be applied in the pulmonary system for local action?

Back 55

In the Tracheobronchial Region

Front 56

Where should drugs be applied in the pulmonary system for systemic action?

Back 56

In the Alveolar Region

Front 57

What drugs are applied to the Tracheobronchial Region and what do they treat?

Back 57

Drugs: Steroids, bronchodilators

Tx: Asthma, bronchitis, COPD

Front 58

What drugs are applied to the Alveolar Region?

Back 58

Insulin, heparin, calcitonin

Front 59

What are the five factors affecting pulmonary drug delivery?

Back 59

1) Pharmaceutical factors affecting deposition
2) Mechanism of particle deposition
3) Physiological factors affecting deposition
4) Fate of particles in the airways
5) Absorption and metabolism of deposited particles

Front 60

What are the four pharmaceutical factors affecting pulmonary drug delivery?

Back 60

1) Particle diameter
2) Particle characteristics
3) Aerosol stability
4) Aerosol velocity

Front 61

What size of particles are deposited in the tracheobronchial region?

Back 61

3-5 µm

Front 62

What size of particles are deposited in the upper airway?

Back 62

10 µm

Front 63

What size of particles are deposited in the alveolar region?

Back 63

< 3 µm

Front 64

What is the optimal particle size?

Back 64

3-5 µm

Front 65

What is the "Respirable Fraction"?

Back 65

The % of drug present in aerosol particles less than 5 µm in size

Front 66

What is the aerodynamic diameter of a particle?

Back 66

The diameter of spherical particle with unit density that settles at same rate as particle in question

Front 67

What is the mass median AD (MMAD)?

Back 67

The aerodynamic diamter at which 50% w/w particles have a lower diameter and 50% w/w have higher diameter

Front 68

What is the geometric standard deviation (GSD)?

Back 68

The ratio of diameters corresponding to 84% and 50% on the cumulative frequency curve

Front 69

At what GSD level are particles considered to be monodisperse?

Back 69

GSD < 1.22

Front 70

At what GSD level are particles considered to be polydisperse?

Back 70

GSD > 1.22

Front 71

Do most commercial aerosol devices produce monodisperse particles?

Back 71

No, there is varied size distribution

Front 72

What three characteristics are used to define aerosols?

Back 72

1) Aerodynamic diameter
2) MMAD
3) GSD

Front 73

What makes aerosols inherently unstable?

Back 73

High concentrations in close proximity lend to repulsion or inter-particulate interactions

Front 74

What can aerosol particles increase or decrease in size?

Back 74

Increase via hygroscopic powders taking up water

Decrease via solvent evaporation

Front 75

What is the main problem with pMDIs?

Back 75

High velocity deposits particles in oropharyngeal region, not ideal

Front 76

What causes particle sedimentation in lungs?

Back 76

Low airstream velocity, particles settle under gravity

Front 77

What causes particle diffusion in lungs?

Back 77

Low airstream velocity, small particles are displaced by random bombardment of gas molecules

Front 78

What is Inertial Impaction?

Back 78

High velocity particles that are unable to change direction impact the tracheobroncial region

Front 79

Describe the physiological factors of lung morphology.

*From Second Lecture*

Back 79

1) Airways of decreasing diameter and length
2) Each branch = high probability for impaction
3) Decreasing Diameter, smaller displacement needed for particle to contact surface
4) Particles must constantly change direction to remain airborne
5) Lobes with the shortest pathlength have the greatest deposition

Front 80

How does increased inspiration flow rate effect drug deposition?

Back 80

An increase in particle momentum & turbulence leads to impaction

Front 81

How do disease states effect drug deposition?

Back 81

Obstructions lead to greater local airflow and turbulence which causes deposition in larger tracheobroncial airways

Front 82

What are the two absorption barriers to pulmonary drug delivery?

Back 82

1) Mucus
2) Pulmonary Epithelium

Front 83

How are particles cleared in the tracheobronchial region?

Back 83

Via mucociliary clearance

Front 84

How are particles cleared in the alveolar region?

Back 84

Via phagocytosis

Front 85

What are the three main devices for pulmonary drug delivery?

Back 85

1) Neutralizers
2) Pressurized Metered Dose Inhalers (pMDIs)
3) Dry Powder Inhalers (DPI)

Front 86

What is atomization?

Back 86

An electric, pneumatic or mechanical process to generate an aerosol

Front 87

What is a jet nebulizer?

Back 87

Compressed gas passes through a narrow oriface

Front 88

What is an ultrasonic nebulizer?

Back 88

Use a piezoelectric crystal vibrating at a high frequency to generate an aerosolized liquid

Front 89

How much of a drug is lost during exhalation or breath-holding while using a nebulizer?

Back 89

2/3rds

Front 90

What is a dosimetric nebulizer?

Back 90

Releases aerosol only during the inhalation phase

Front 91

What is the benefit of using a spacer with a pMDI?

Back 91

Decelerates the aerosol decreasing the chance of it impacting the throat and increasing the chance of reaching its intended site of action

Front 92

What are five facts pertaining to dry powder inhalers?

Back 92

1) Used in place of pMDIs using CFCs
2) Micronized drug w/ or w/o carrier (lactose)
3) Breath actuated; A respirable cloud is produced when a patient inhales
4) Particles travel slowly, less impaction
5) Individual or multi-unit doses

Front 93

What are the four powder characteristics of DPI formulation?

Back 93

1) Particles < 5µm aggregate readily
2) Drug particles are loosely associated w/ larger carrier particles
3) Patient inhales, detaching drug via turbulence
4) Turbulence also increases the resistance of the inhaler to airflow. May be difficult to inhale at flow rate necessary for optimal drug delivery

Front 94

What are the advantages of using a nebulizer?

Back 94

1) No specific technique or patient coordination
2) Delivery of large doses
3) Suitable for infants

Front 95

What are the disadvantages of using a nebulizer?

Back 95

1) Expensive
2) Time consuming
3) Wastage of drug
4) Bulky and non-portable

Front 96

What are the advantages of using a pMDI?

Back 96

1) Compact, portable
2) Easy to use
3) Inexpensive
4) Multiple dosing
5) Reproducible dosing
6) No contamination risk

Front 97

What are the disadvantages of using a pMDI?

Back 97

1) Requires specific technique and coordination
2) High oral deposition
3) Limits size of dose
4) Limited number of drugs
5) Environmentally hazardous propellants

Front 98

What are the advantages of using a DPI?

Back 98

1) Compact and portable
2) Easy to use
3) Breath actuated
4) No propellant
5) Less drug loss because particles travel slowly

Front 99

What are the disadvantages of using a DPI?

Back 99

1) Dose delivered depends on inspiratory flow rate
2) Can trigger coughing reflex
3) Susceptible to humidity
4) Dose loss if patient doesn't inhale during dosing