Physical properties of the lung/Physics of particle inhalation Flashcards
Which part of the lung is drug deposition to be avoided and why?
- The upper respiratory tract (trachea/oropharynx)
- Deposition here results in drug just being swallowed into the GIT
Why do we deliver drugs to the lung/via the respiratory tract?
- Local effect; bronchodilators/corticosteroids/antibiotics/mucolytics
- Systemic effect; volatile anaesthetics (halothane), ergotamine tartarate (migraine), peptide drugs (insulin avoiding first pass effect normally broken down in stomach)
- Rapid onset of action (huge SA w/strong blood supply)
- Smaller doses than oral formulations
- Less systemic and GI adverse effects
- Relatively comfortable
What are the advantages of local action?
- Direct access to the site of disease
- Rapid onset of action
- Avoids GI tract and first-pass hepatic metabolism
- Lower doses
- Fewer side-effects
What are the advantages for systemic action?
- Avoids GI tract (acidic ph/enzymes)
- Avoids first-pass hepatic metabolism
- Non-invasive, needle-free
- High bioavailability as compared to other non-invasive routes
- Rapid absorption, rapid onset of action (insulin, opioids)
What is the purpose of the airways via a physical perspective?
- Heat and humidify the inhaled air (conditioning)
- Remove particles from inhaled air via deposition (like a filter)
- Clear away deposited particles efficiently into GI tract (clearance via mucociliary escalator)
- Particles should NOT reach the alveoli where gas exchange occurs
- Particles of diameter > 10µm do not reach the alveoli.
How are deposited particles cleared from the upper airway?
- Upper airways covered with mucus (salts/lactate/glycoproteins)
- Via mucociliary escalator; ciliary action moves mucus (w/particles) towards pharynx where it is swallowed to GIT
- Clearance within hours
How are deposited particles cleared from the alveolar region?
- Do not possess mucus layer or cilia
- Thus deposited insoluble particles cleared v. slowly (up to months or years)
- Soluble particles; cleared by dissolving and entry to blood stream
- Insoluble particles; cleared by macrophages via phagocytosis or via surface tension effects pushing them up to the mucociliary escalator
How must pulmonary drugs be delivered?
- Aerosol form; suspension of liquid or solid particles in a gas, sufficiently small to remain airborne for a considerable time
What are the 5 main mechanisms of particle deposition in the lung?
- Inertial impaction
- Sedimentation (settling)
- Diffusion
- Interception
- Electrostatic precipitation
What is inertial impaction?
Where is it most prevalent and why?
- Air flows easily round bends of bronchiole
- Particles in air leave this flow due to their inertia and may thus impact on airway walls
- Heavier the particle, the more the inertia (proportional to diameter)
- Most important in large airways (large velocities, bifurcations (when branches split off)
- Inertial trapping good for impact at desired site; small particle follows air flow, larger particle is trapped.
What is sedimentation?
Where is it most prevalent and why?
- Particles settle by gravitation onto airway wall
- Most important in smaller airways and the alveoli (low flow velocities, small airway dimensions) and horizontally orientated airways
- Settling velocity proportional to diameter
What parameter governs deposition by sedimentation and inertial impaction?
- Aerodynamic diameter; via Stoke’s law taking into account a particle’s density and size; aerodynamically a particle with greater density/small size is less favourable than a less dense/greater size particle
What is Brownian diffusion?
Where is it most prevalent and why?
- Small particles leave original air flow lines by diffusion and deposit onto airway walls
- Most important deposition mechanism for particles
What is interception?
Where is it most prevalent?
- Without deviating from OG flow lines, particles contact airway surface because of their physical size/shape (get stuck on bifurcations etc even tho following flow)
- Long fibres easily intercepted; small aerodynamic particle diameter, large in one dimension.
- Not important for inhaled drugs although drug particles are not usually perfectly spherical
What is electrostatic deposition?
Where is it most prevalent?
- Charged particles attracted towards airway walls by electrostatic charges
- Aerosols with high charge and concentration can repel each other and drive particles toward airway walls
- Not important other than for freshly generated (and charged) aerosols like in nebulisers
What is the respirable fraction?
The percentage of drug present in aerosol particles less than 5 µm in size and thus likely to be deposited
How can the respirable fraction be determined?
By particle sizing techniques or devices which simulate the inhalation process such as the Anderson Cascade Impacter and the Next Generation Impinger.
What particle deposition mechanism is most prevalent at the pharynx/mouth and at what size?
Impaction, when particles > 5µm.
What particle deposition mechanism is most prevalent at the trachea, primary/secondary/terminal bronchi and at what size?
Sedimentation; 1 - 5µm.
What particle deposition mechanism is most prevalent at the alveoli and at what size?
Diffusion, when particles
Name 3 types of particle sizing techniques.
Microscopy (optical and electron), laser diffraction and aerosizer.
Briefly describe microscopy for particle sizing
- Spray onto microscope slides or other sample stub and image
- Labour intensive
- But gives info on particle shape, surface texture as well as size
Briefly describe laser diffraction for particle sizing
- Aerosol passes through laser beam, light is diffracted (changes direction)
- Amount of diffraction is related to particle size
- Smaller particles diffract light through a larger angle, large particles diffract light through a small angle
Briefly describe aerosizer for particle sizing
- Time of flight of particles between two laser beams
- Measurement of the aerodynamic diameter
- Smaller particles accelerated at a greater rate in constant airflow than larger particles
