Pulmonary Drug Delivery

Question 1

What are 2 limitations of using adrenaline for the treatment of asthma?

Answer 1

Short duration of action

Lack of selectivity for the B2 adrenoceptors so can result in cardiovascular side effects as could bind to B1 also

Question 2

Identify structural features that have enhanced the selectivity between Beta and alpha receptors using adrenaline and isoprenaline?

Answer 2

The addition of a bulky N-alkyl substituent on isoprenaline affords Beta selectivity over alpha

Question 3

Identify structural features that have enhanced the selectivity between Beta1 and B2 receptors using isoprenaline and isoetharine?

Answer 3

The addition of an alkyl group to the side chain linking the aromatic ring and the amine - added an ethyl group which has afforded selectivity to Beta2

Question 4

Isoetharine is selective for B2 receptors so why isnt it used?

Answer 4

It has a short duration of action as the catechol group is metabolised by COMT

Question 5

Draw the structure of (R)-salbutamol

Answer 5

..

Question 6

What is 2 advantages of chiral switching in consideration of salbutamol

Answer 6

Better therapeutic properties e.g R salbutamol more active than S

New patent so a new business opportunity

Question 7

Comparing structures of salbutamol and salmeterol - why does salmeterol have a longer duration of action?

Answer 7

Salmeterol has increased lipophilicity and thus can bind more strongly to the tissue in the vicinity of the adrenoceptor (it is hydrophobic) - so it can act for a longer period of time.
This is a result of the increased length of the N-substituent with a further hydrocarbon chain and aromatic ring in comparison to salbutamol

Question 8

Why is decreasing the half life of drugs in the blood system that are designed for delivery to the lungs?

Answer 8

Often a portion of the drug is swallowed by mistake and it could be absorbed in the blood supply from the GIT and target other aspects of the body resulting in side effects in other areas e.g Cardiovascular side effects e.g tachycardia, disrhythmias

Question 9

How can the half life of pulmonary drugs in the blood system be decreased?

Answer 9

By addition of metabolically labile groups such as esters - esterases in the blood can metabolise it into an inactive carboxylic acid - metabolism makes the drugs easier to eiminate from the body

Question 10

What class of drugs does salbutamol belong to?

Answer 10

Beta2-adrenoceptor agonists - targets receptors so they can relax the bronchial smoothmuscle – bronchodilation during asthma attacks (reliever)

Question 11

How do beta-2 agonists inteact with the Beta2 receptor?

Answer 11

Catechol hydrogen bonds with Serine residues in receptor
Benzene ring has VDW with the phenylalanine
Secondary hydroxyl group hydrogen bonds with asparagine
Amine group has ionic interactions with aspartic acid

Question 12

What part of salbutamol structure prevents it being metabolised by COMT?

Answer 12

The primary hydroxyl group on the left side of the ring - where the catechol was (extended)

Question 13

What are the requirements of chiral switching?

Answer 13

Must demonstrate that there is a significant clinical advantage in having the pure entantiomer instead of racemic

Demonstrate that this could not have been easily predicted at the time of patenting the racemic mixture

Question 14

What domain of the B2 receptor does salbutamol bind to?

Answer 14

extracellular domain

Question 15

Describe the MoA of salbutamol?

Answer 15

B2 receptors are GPCRs - Salbutamol binds to the G alpha S subunit, causing a conformational change to interact with the G protein, facilitating the conversion of GDP to GTP.
Alpha subunits dissociate and travel, activate adenylate cyclase which leads to production of cAMP - stimulating a kinase phosphorylation cascade and activation of PKA.

Question 16

What is an advantage of having salbutamol in a metered dose inhaler?

Answer 16

straight into lungs rather than systemic circulation - cannot produce any unwanted side effects eg CV.

Question 17

What are the 3 mechanisms responsible for particulate deposition in the lung?

Answer 17

Impaction
Gravitational sedimentation
Brownian diffusion

Question 18

What is gravitational sedimentation?

Answer 18

How quickly particles will sediment in the airways gravitationally.
This depends on - particle size, particle density, residence time in airways, air viscosity (more viscous- lower the settling velocity)
Important deposition mechanism for particles 0.5-3 micrometer in alveoli, for particles that have escaped deposition by impaction

Question 19

What is inertial impaction

Answer 19

Dominant deposition mechanism for particles >1 micrometer in the upper tracheobronchial regions

Question 20

Where the particles deposit in the airways depends on what?

Answer 20

Their aerodynamic diameter and their velocity

Question 21

What is brownian diffusion

Answer 21

very small particles - under 1 micrometer. - they collide with air molecules and collide with the airway walls. The probability of particle deposition by diffusion increases with decreasing particle size. (smallest particles are breathed out as not heavy enough)

Question 22

If a particle is larger than 10 micrometer what happens to it in the airways?

Answer 22

It impacts the upper airways and rapidly removed by coughing, swallowing, mucociliary processes - we want them to go into the lower airways

Question 23

What size particles do we need for lower resp impaction?

Answer 23

0.5-5 micrometer escape impaction in upper airways and deposit by impaction and sedimentation in the lower respiratory regions so better change of being delivered down to the alevoli - BUT dont want them too small as they would be affected by exhalation.

Question 24

Outline physiological factors affecting particle deposition in the airways

Answer 24

1. Lung morphology - must pass through branching tubes of decreasing size
2. Oral and Nasal breathing - aerosols must be inhaled by mouth otherwise they would stay in nose if breathed via nose.
3. Inspiratory flow rate - if breath in faster it enhances deposition by impacting in larger airways and wouldnt reach alveoli - we need slower Insp flow rate.
4. Breath holding - need to hold breath after inhalation to enhance the deposition of particles by sedimentation and diffusion - smaller particles get to alveoli and stay there.

Question 25

How do we achieve optimal aerosol deposition?

Answer 25

Slow, deep inhalations to total lung capacity, followed by breath holding prior to exhalation

Question 26

Pharmaceutical factors affecting particle deposition?

Answer 26

Aerosol velocity - can be controlled
Size / size distribution 
shape of particles e.g sphere - faster 
Density - how well particles are deposited due to aerodynamic diameter
Physical stability

Question 27

What physiological mechanisms affect particles in airways?

Answer 27

Mucus barrier

Mucocilliary clearance

Question 28

advantages of pulmonary drug delivery for locally acting drugs?

Answer 28

Dose needed to produce an effect is reduced in comparison to oral.
Low [drug] in systemic circulation - less s/e
Rapid onset
Avoid GI upset
Avoid first pass metabolism

Question 29

What are 3 classes of devices for pulmonary drug delivery?

Answer 29

pressurised metered dose inhaler
Dry powder inhaler
Nebulisers

Question 30

What is a pMDI?

Answer 30

Most common - Drug either dissolved or suspended in liquid propellant with excipients, and preserved in a pressurised canister with a metering valve - pre determined dose is released as a spray on actuation of the metering valve - USES GASES TO PUSH MEDICINE INTO MOUTH - contains propellents e.g CFCs :(

Question 31

What is a dry powder inhaler ?

Answer 31

Drug pre loaded into device or filled into hard gel capsules/foil blister discs loaded into device prior to use - DPI is breath actuated - patient must inhale e.g Diskhaler, Spinhaler

Question 32

What is a nebuliser

Answer 32

Drug exists as particles which are made up of many molecules - convert aqueous solutions into an aerosol for inhalation - deliver large volumes of drug but not very portable

Question 33

What is a specific technique to control aerosol particle size?

Answer 33

Cascade impactor - NOT used for drug delivery - purely for size characterisation (mimics the lung)

Question 34

give 2 advantages and 2 disadvantages of pMDI

Answer 34

Good = Unit dosing, cheap
Bad = Use of CFCs are propellants
Co-ordination difficulties as click and breath, must also shake first

Question 35

give 2 advantages and 2 disadvantages of DPI

Answer 35

Good = No co-ordination problems, no drug closs by impaction as patient is inhaling

Bad = High inspiratory effort needed, less convenient

Question 36

give 2 advantages and 2 disadvantages of Nebuliser

Answer 36

Good = No co-ordination problems, can generate small particles with higher delivery capacity (and delivery high volume of drug)

Bad = Inconvenient, expensive, poor dose control