Inhaled drug delivery

Question 1

Types of bronchodilators - B2 adrenergic

Answer 1

Selective short acting:
- salbutamol
- fenoterol
- terbutaline sulphate ( and pro-drug bambuterol)

Selective long acting
- salmeterol
- formoterol
- indacaterol and olodaterol (COPD)

Question 2

Anticholinergics (Antimuscarinics)

Answer 2

• ipratropium bromide
• aclidinium bromide (COPD)
• glycopyrronium bromide (COPD)
• umeclinidium (COPD)
• tiotropium

Question 3

Anti-inflammatories - Corticosteroids

Answer 3

• beclometasone dipropionate
• fluticasone propionate
• mometasone furoate
• budesonide
• ciclesonide

Question 4

Non - steroidal antiinflammatories

Answer 4

• sodium cromoglycate
• nedocromil sodium

Question 5

Monoclonal antibodies

Answer 5

• omalizumab (injection)
• orally administered steroids for severe exacerbations

Question 6

Leukotriene antagonists (LTRA)

Answer 6

• montelukast
• zafirlukast
  tablet, not inhaler
• theophylline and aminophylline tablets

Question 7

lung deposition - nasal pharyngeal

Answer 7

• (compartment)- nose to larynx
• (deposition) - impaction, diffusion/Brownian motion, interception, electrostatic
• (clearance) - mucociliary (mins), sneezing, blowing
• (pathology) - inflammation, ulceration, cancer

Question 8

Tracheobronchial

Answer 8

• (compartment) - trachea, ciliated bronchi & bronchioles
• (deposition) - impaction, diffusion/Brownian motion, interception, electrostatic, sedimentation
• (clearance) - mucociliary (hours), coughing
• (pathology) - bronchospasm, obstruction, cancer

Question 9

Pulmonary

Answer 9

• (compartment) - non-ciliated respiratory bronchioles, alveolar ducts and alveoli
• (deposition) - sedimentation, diffusion/Brownian motion, interception, electrostatic
• (clearance) - solubilisation, phagocytosis (hours to years)
• (pathology) - inflammation, oedema, emphysema, fibrosis, cancer

Question 10

what is lung clearance?

Answer 10

• dissolution of soluble materials - absorption into systemic circulation
• phagocytosis - macrophages which translocate to ciliated airways or lymphatic system
• direct passage of particles into the blood

Question 11

Particle properties

Answer 11

• size (diameter) - given as ‘mass median aerodynamic diameter’ (MMAD)
• for deep lung deposition, (5um) needed to penetrate bronchioles - target to bronchodilators.
• inertial impaction
• interception
• gravitational settling
• electrostatic interactions
• brownian diffusion

Question 12

inertial impaction

Answer 12

• when airflow changes direction, particles will continue in original direction due to inertia
• product of mass x velocity (momentum)
• small fraction of particles will get past bend in throat
• branching airways means airflow reduced in lower airways and inertial impaction becomes less important.

Question 13

Sedimentation

Answer 13

• gravitational force
• Stokes’ law to calculate sedimentation velocity and factors affecting

Question 14

Brownian motion

Answer 14

• very small particles, aerodynamic diameter.
• hitting of colloidal particles by molecules /atoms of surrounding medium - random motion.
• net result is migration of particles from high to low colloid concentration (diffusion).

Question 15

Interception

Answer 15

• if dimensions of particle similar to the anatomical dimensions of the lung tubes.
• important for elongated particles such as fibres

Question 16

Electrostatic precipitation

Answer 16

• aerosol particles will be charged and hence will be attracted to surfaces of opposite charge.
• charge may also influence direction of flow

Question 17

Aerosol properties

Answer 17

• velocity of particles - particles move with velocity of gas flow. If high, inertial impaction will occur at bends.
• particle size range - polydisperse or mono disperse. Usually log normal distribution
• Particle concentration - (high) higher chances of particle interactions - MMAD increases as conc increases - related to decreased propellant fraction and agglomeration.
• evaporation of propellants - residual propellant may increase effective particle size, increase likelihood of interactions and lead to cough reflex.

Question 18

physiological properties

Answer 18

• complex nature of lung system - airways undergo a number of bifurcations (successive splitting)
• drug particles continually forced to change direction
• mechanism present to keep particles out - mucociliary escalators, cough
• lungs are often diseased - asthma (narrow, swollen tubes and mucus - airways obstructuion
• humidity - hygroscopic growth and agglomeration

Question 19

Patient handling

Answer 19

• shaking inhaler - most are suspension systems
• holding breath - allow time for deposition mechanisms to occur
• some inhaler devices are sophisticated and require training before use - inhaler technique should be reinforced by pharmacists
• is inhalation therapy efficient ?
• from a pMDI, often get 10-20% w/w dose reaching deep lung area good compared to oral route for treating asthma.