1
Q
Do you want a drug to stay in the oropharynx? Why or why not?
A
- No
- Drug deposited in oropharynx is swallowed and absorbed, leading to systemic exposure and potential systemic adverse effects
- Can also cause local adverse effects (ex: candidiasis, hoarseness)
2
Q
Who may benefit from using a spacer?
A
Px w/ poor coordination, poor lung function, or arthritic joints
3
Q
What type of propellants were previously used and what type are now used? Why was this changed?
A
- Used to use chlorofluorohydrocarbons (CFCs)
- Now use hydrofluoroalkanes (HFA)
- CFCs cause atmospheric damage to ozone layer
4
Q
Which dosage routes can aerosols be used for?
A
- Pulmonary
- Sublingual
- Dermal
- Rectal
- Vaginal
5
Q
Aerosols are ____ phase systems consisting of _____ and depend on _____ to expel contents
A
- 2 phase systems
- Consist of droplets or particulates dispersed in air
- Depend on compressed or liquefied gas
6
Q
How can aerosols be dispensed?
A
Fine wet spray, foam, semisolid stream, or dry particles
7
Q
How are drugs added to aerosols?
A
Dissolved, suspended, or emulsified in propellant or mixture of solvent and propellant
8
Q
What is the epithelium like in the respiratory tract?
A
Varies in thickness and permeability (thick trachea; more permeable alveoli)
9
Q
How are different types of drugs absorbed in the respiratory tract?
A
- Hydrophobic molecules absorbed through transcellular pathway of lipid bilayer around cells
- Hydrophilic molecules subject to paracellular absorption through aqueous pores in intercellular tight junctions
- Some molecules subject to active transport
- Absorption profile of an inhaled molecule is culmination of all these routes of absorption
10
Q
Pulmonary drug delivery is determined by….
A
- Nature of active ingredient
- Formulation
- Device
- Functional performance in aerosolization
11
Q
Important feature of inhaled drugs is ______. Why?
A
- Particle size of dose components
- Large particles won’t reach deep lung tissue; small particles risk being exhaled
12
Q
What is the function of respiratory epithelial cells?
A
- Regulate respiration
- Produce airway lining fluid
13
Q
What is the surface area of the respiratory mucosa?
A
70-140 m^2 in adults
14
Q
What are the divisions in the respiratory tract?
A
- Bronchi
- Bronchioles
- Terminal bronchioles
- Respiratory bronchioles
- Alveolar ducts
15
Q
The deeper the passageways of the respiratory tract go, _____ decreases and _____ increases
A
- Diameter decreases
- Surface area increases
16
Q
What happens when inhaled particulate substances enter the airways?
A
Once deposited in airways, particles are carried by mucociliary system and degraded or absorbed into systemic circulation or lymph ducts
17
Q
What is found on airway surfaces from trachea to terminal bronchioles?
A
- Ciliated epithelium covered by mucous
- Mucous is biphasic (2 layers) – low-viscosity periciliary layer and thicker gel layer on top
18
Q
What is the purpose of the biphasic mucous layer of the respiratory tract?
A
- Protects epithelium from dehydration
- Helps humidify air
- Protective mechanism to trap inhaled particles
19
Q
What happens to insoluble particles in the respiratory tract?
A
- Trapped and moved toward larynx where they are either coughed up or swallowed
- Consumed and eliminated by alveolar macrophages
20
Q
What determines the clearance speed of the respiratory tract?
A
- Number and beat frequency of ciliated cells
- So factors that influence function of cilia or quantity or quality of mucous affects rate
21
Q
What happens to soluble particles in the respiratory tract?
A
Eliminated by absorptive mechanisms into systemic circulation, bronchial circulation, or lymphatic system
22
Q
Where is the rate of absorption the fastest in the respiratory tract?
A
Alveolus
23
Q
Where is the greatest membrane permeability in the respiratory tract?
A
Alveolus
24
Q
What are advantages to pulmonary administration?
A
- Avoids first-pass effects in GI tract and liver
- Used for local effect, so dose is smaller and potential SE are avoided
- Large surface area, excellent blood supply, and permeable mucosa make route an alternative to parenteral
- Rapid onset especially for local effect
- Convenient delivery systems
25
What are disadvantages to pulmonary administration?
- Some systems (ex: pMDI) require coordination by patient to time actuation of device and inhalation
- Dry powder inhalers require px to generate aerosol using inspiratory flow, so not suitable for very young and very old
- Dose of drug must be small
26
What determines the fate of inhaled particles?
- Physicochemical characteristics
- Deposition site
- Biological defences like mucociliary transport and airway macrophages
27
Which drug factors affect absorption through airway epithelium?
- Molecular weight
- Hydrophobicity
- pH
- Charge factors
28
What is the goal of pulmonary drug delivery?
Achieve high lung deposition in target region for either local or systemic effect
29
Is airflow direction and velocity the same throughout the respiratory tract?
No, decrease from laminar to stagnant in alveolar region
30
What are the processes of particle deposition in airways?
- Inertial impaction
- Gravitational sedimentation
- Brownian diffusion
- Interception
- Electostatic attraction
31
What is the normal size of particles of aerosolized drugs? How does this affect deposition?
- Greater than 1 um
| - Main mechanisms of deposition are impaction and sedimentation
32
How does size of particles affect location of deposition?
- Larger than 10 um deposited in oropharynx
- 5-10 um deposited in central airways
- 0.5-5 um deposited in small airways and alveoli
33
What size of particles is best for topical respiratory treatment? What is this called?
- 0.5-5 um
| - Breathable fraction of an aerosol
34
What is mass median aerodynamic diameter (MMAD)?
Diameter at which 50% of particles by mass are larger than 50% are smaller
35
What is geometric standard deviation (GSD)? How is it calculated?
- Measure of spread of an aerodynamic particle size distribution
- GSD = (d84/d16) ^1/2
- d84 and d16 represent diameters at which 84% and 16% of aerosol mass are contained, respectively, in diameters less than these diameters
36
When does inertial impaction occur?
- Particles w/ high momentum collide w/ airway wall
- Happens in first 10 bronchial generations
- Associated w/ rapid speed and diameter equal to or larger than 10 um
37
Which devices tend to cause drugs to be retained in oropharyngeal region?
- Dry powder inhalers
| - Pressurized metered-dose inhalers
38
When does interception occur?
- When particles are fiber shaped
| - Due to their elongated shape, deposited as soon as they come in contact w/ airway wall
39
When does electrostatic deposition occur?
Charged particles
40
What is gravitational sedimentation? Where is it most likely to occur
- Particles w/ sufficient mass are deposited due to force of gravity
- Predominates in last 5 bronchial generations, where air speed is slow and residence time is longer
41
What is Brownian diffusion? What particles does it affect? What happens to these particles?
- Particles move erratically due to Brownian diffusion
- Affects particles smaller than 0.5 um when they reach alveolar spaces where air speed is practically zero
- Particles are expelled on exhalation and not deposited
42
What determines air flow in the lungs?
Tidal volume and respiratory rate
43
What is the effect of airflow velocity in the first four generations of the respiratory tract? What happens below these generations?
- Deposition for any size particle increases as inspiratory flow increases
- Beyond this, airflow is reduced and no longer laminar
44
When does particle deposition by impaction increase?
- Larger particles
- Inspiratory airflow is greater
- Angle separating two branches is wider
- Airway is narrower
45
How does chronic bronchitis or asthma affect deposition of aerosolized drugs?
- Bronchoconstriction
- Inflammation
- Secretion accumulation
- Smaller caliber of airway increases air speed and produces turbulence where flow is usually laminar
46
What does airway obstruction cause?
Causes air to be displaced toward unobstructed areas, therefore drug will tend to deposited in healthy areas of the lung
47
What happens when particles are hygroscopic?
- Absorb humidity, so get larger upon entering the airway
- Diameter that a particle reaches after hygroscopic growth depends on initial diameter, intrinsic properties of particle, and environmental conditions in airways
48
What is the property of hygroscopicity used for?
To try to manage deposition pattern of inhaled drugs
49
Where are beta 2 receptors located in the lungs?
Majority in alveolar walls; large amount in airway between main bronchi and terminal bronchioles
50
Where are the majority of M3 muscarinic receptors located?
- Alveolar walls
- Submucosal glands and lung lymph nodes
- Lower proportion in smooth muscle of airways
51
Where should muscarinic receptor antagonists (ipratropium bromide), beta 2 agonists (salbutamol), antibiotics and corticosteroids be deposited?
- Muscarinic antagonists = conducting airways
- Beta 2 agonists = middle and small airways
- Antibiotics = depends on disease being treated
- Corticosteroids = throughout the lungs
52
What are the devices currently used for administration of inhaled drugs?
- Pressurized metered-dose inhalers
- Dry powder inhalers
- Nebulizers
53
What are advantages to metered-dose inhalers?
- Release a fixed dose of medication w/ each pulse
- Small size, easy to handle, inexpensive
- Possibility to fit spacer chambers
54
Do metered-dose inhalers contain a suspension or a solution of drug?
Either or
55
What size and what speed do metered-dose inhalers release drugs?
- High speed, over 30 m/s
| - Particles or droplets w/ a diameter between 1-5 um
56
What are disadvantages to metered-dose inhalers?
- Difficulty in synchronizing activation and inhalation
- Low dose reaches lungs; over 80% of dose undergoes intertial impaction and largely retained in oropharyngeal region
- Possible variation in dose if formulation is a suspension and device isn't shaken
57
What is the optimal technique to use a metered-dose inhaler? Why is this method optimal?
- Exhale
- Activate inhaler
- Inhale slowly and deeply
- Hold breath for 5 seconds
- Increases deposition by sedimentation in more peripheral areas of airway
58
What can be used to help when coordination is an issue?
Spacer
59
What are advantages to spacers?
- Aerosol goes into chamber and remain suspended until inhaled by px
- Allows aerosol to lose speed thereby reducing impaction against oropharynx and reducing local adverse effects
60
What were dry powder inhalers designed to do?
Eliminate inherent coordination difficulties of pMDIs
61
DPI administer doses in a powder form contained in....
- Capsules broken prior to administration
- Blisters broken open before administration (unidose systems)
- Powder reservoirs (multidose systems)
62
Do DPIs contain propellants?
No
63
Do pMDIs or DPIs allow more drug to reach the lungs?
Both about the same; less than 20% of initial dose actually reaches lungs
64
How is aerosol generated w/ a DPI?
By the inhalation effort of the patient
65
What is the normal diameter of particles from a DPI?
1-5 um
66
What are the 2 types of nebulizers? What is the difference between them?
- Jet
- Ultrasonic
- Differ in mechanism used to generate aerosol
67
What is the normal size of droplets from a nebulizer?
1-5 um
68
What px are nebulizers used for and why?
- Don't require px coordination between inhalation and actuation
- Used for pediatric, elderly, ventilated, non-conscious px; those unable to use pMDIs or DPIs
69
What is an advantage to nebulizers?
Deliver larger doses compared to other aerosol devices, but require longer administration times
70
What occurs in jet nebulizers? What do they require?
- Airstream moves through small capillary tube at high velocity creating a low pressure that drives liquid up capillary tube
- Require a compressor
71
What occurs in ultrasonic nebulizers? What do they require?
- Sound waves created due to vibration of piezoelectric crystals at high frequency, creating crests that break liquid into small droplets
- Require electricity
72
What are disadvantages of nebulizers?
- Have to be assembled and loaded prior to use and then disassembled and cleaned
- May be difficult for elderly
73
What are the contents of a pMDI?
Propellant and therapeutic agent
74
What happens following actuation of a pMDI?
- Droplets about 40 um are released; volume released is usually 25-100 uL
- Propellant evaporates quickly, leaving solid particles which are deposited into respiratory tract when px inhales slowly and deeply
75
What happens if a pMDI is a suspension?
Particle size of drug will have been reduced by milling size necessary for delivery to appropriate part of respiratory system
76
What is the purpose of propellants?
To drive medication out of device then evaporate quickly to allow particle to be inhaled and deposited in correct location
77
What are propellants made of and why?
Typically a blend of 2 hydrofluoroalkanes (HFAs) to ensure pressure is sufficient to expel material and rate of evaporation is suitable
78
What is added if excipients are needed for pMDIs?
Sometimes alcohol is added to ensure solubility of excipient
79
Why are excipients needed for suspensions?
Prevent caking and agglomeration
80
What is the purpose of excipients for pulmonary suspensions?
Decrease electrostatic charges between particles, preventing agglomeration and adhesion to container or valve
81
What are some examples of non-ionic surfactants for pulmonary use?
- Sorbitan trioleate (span 85) and sorbitan tristearate (span 65)
- Lecithin and oleic acid also used but need some ethanol to solubilize them
82
What is a disadvantage to HFA propellants? How can this be overcome?
- Many drugs have limited solubility in HFA propellants
| - Alcohol may be added as a cosolvent
83
How can ethanol concentration influence pulmonary drug delivery?
- Changes formulation density and thus total mass atomized
- Changes size of atomized droplets
- Changes evaporation rate of droplets
84
What else can be used to enhance solubility in pMDIs?
Spans, tweens, and PEGs
85
What excipient is commonly used in DPIs?
Bulking agent (lactose commonly used, mannitol is also an option)
86
What is the common size of lactose used in DPIs? Why?
30-60 um to ensure it doesn't enter lower airways
87
How are drug particles detached from the surface of carrier particles?
By energy of inspired flow that overcomes adhesion force between drug and carrier
88
What is the vehicle for nebulizers? Why?
Water for injection b/c nebulizers are sterile
89
What is the ideal pH for nebulizers? What is needed if this pH isn't achieved?
- Over pH 5
| - 5 or under requires buffering since can cause bronchoconstriction
90
Solutions for nebulizers must be ___tonic b/c ____
Isotonic b/c hyper or hypotonic can cause bronchoconstriction
91
What are some tonicity adjusting agents?
Sodium chloride, mannitol, dextrose
92
What is an example of an antioxidant?
Sodium bisulfite
93
Which non-invasive dosage route provides the best bioavailability?
Pulmonary
94
Which non-invasive dosage route provides the fastest onset of action?
Pulmonary
