COPD & Emphysema

Question 1

Summarise chronic obstructive pulmonary disease (COPD).

Answer 1

A global problem - predicted to be the third most common cause of death worldwide by 2020 - largely caused by smoking, pollution as well but to a lesser extent.

Characterised by airflow reduction that is in some patients partially reversible (with bronchodilators) but which progressively worsens as assessed by FEV1 and exacerbation of symptoms including cough and mucus production.

Historically divided into bronchitis and emphysema, but these may overlap.

Question 2

Compare chronic bronchitis and emphysema.

Answer 2

Chronic bronchitis
- inflammation of bronchi and bronchioles
- cough
- clear mucoid sputum
- infections with purulent sputum
- increasing breathlessness

Emphysema
(differs in detail according to site of damage)
- distension and damage to alveoli
- destruction of acinial pouching in alveolar sacs
- loss of elastic recoil

Question 3

What are the characteristics of COPD?

Answer 3

COPD is characterised by increased resistance to air flow during expiration.
In severe COPD:
- inhalation phase near normal
- exhalation phase fail; much greater resistance to air flow during exhalation
-> breathing out is hard work in COPD

Question 4

Describe muscarinic acetylcholine receptors in the airways.

Answer 4

Reducing parasympathetic neuroeffector transmission with muscarinic receptor antagonists is an important treatment of COPD.
Muscarinic receptor antagonists of bronchoconstriction caused by smooth muscle M3 receptor activation in response to ACh released from postganglionic parasympathetic fibres (and epithelial cells).

Question 5

Describe molecular mechanisms of airway smooth muscle (ASM) contraction by M3 receptors.

Answer 5

Neurotransmitter binds to M3 receptor.
The receptor activated Gq/11 to stimulate phospholipase C to produce IP3 (and DAG) from PIP2.
IP3 stimulates Ca2+ release from sarcoplasmic reticulum.
Ca2+ goes through intermediate steps including calmodulin and myosin light chain kinase (MLCK).
This produces contraction.

Question 6

Describe the M1 receptor in relation to the airways.

Answer 6

M1 - ganglia
Facilitate fast neurotransmission mediated by ACh acting on nicotinic receptors (nAChR).
M1 receptors mediate a slow EPSP (excitatory postsynaptic potential) that increases action potential frequency resulting from nicotinic receptor stimulation.

Question 7

Describe the M2 receptor in relation to the airways.

Answer 7

M2 - postganglionic neuron terminals
Act as inhibitory auto-receptors reducing the release of ACh.
Their blockade thus increases the release of ACh and are therefore not a good target to treat COPD.

Question 8

Describe the M3 receptor in relation to the airways.

Answer 8

M3 - airway smooth muscle
Mediate contraction to ACh.
(also present on mucus secretory cells evoking increased secretion)

Question 9

List the muscarinic receptor antagonists currently used to treat COPD and their administration route.

Answer 9

Competitive mAChR antagonists currently licensed are:
- Ipratropium (short acting muscarinic antagonists SAMA)
- Tiotropium
- Glycopyrronium
- Aclidinium
- Umeclidinium
These are long acting muscarinic antagonists, LAMAs.

All administered by inhalation to reduce systemic side effects.

Question 10

State the effects of muscarinic receptor antagonists in the treatment of COPD.

Answer 10

Reduce bronchospasm caused by irritant stimuli and also block ACh-mediated basal tone.
Decrease mucus secretion.
Have little effect on the progression of COPD, their effect is mainly palliative.

Have few adverse effects, little systemic absorption due to the drugs possessing the quaternary ammonium group.

Question 11

Why are M3 selective blockers superior to Ipratropium?

Answer 11

Ipratropium is a non-selective blocker of M1, M2 and M3 receptors.

The functional selectivity of relatively selective M3 blockers over Ipratropium is achieved by differences in rates of association and dissociation from the M3 receptor.

Block of M3 (and M1) is desirable, but block of M2 is not because it inhibits the release of ACh from parasympathetic post-ganglionic neurons. Therefore blocking this receptor increases ACh release as it is blocking the negative feedback.

Question 12

Describe in detail muscarinic antagonists and beta2 agonist combinations in the treatment of COPD.

Answer 12

Beta-adrenoreceptor agonists administered by inhalation include salbutamol (short acting, administered every 4-6 hours) and salmeterol, formoterol (long acting, administered twice daily).
Provide bronchodilation, but have no effect on underlying inflammation.

Indacaterol and olodaterol are ‘ultra-LABAs’ and are not recommended for relief of acute (once daily dosing is effective).

LABA/LAMA combinations are scientifically logical as the drugs work by different, but complementary, mechanisms to cause smooth muscle relaxation.

LABA/LAMA combinations are likely to be most effective when both drugs are deposited in the same location in the airways.

One approach is to develop ligands that possess both LABA and LAMA activity within the same molecule, i.e. muscarinic antagonists / beta2 agonist (MABAs).
Such drugs are in development e.g. betafenoterol is currently in phase 2 of drug development.

Question 13

Explain the basic logic behind Beta2 agonist muscarinic antagonist combinations.

Answer 13

Muscarinic antagonists block activation by ACh.
Activation of beta2 receptor by beta2 agonists.
Synergism by cross-talk in signalling pathways.
Blocking of muscarinic receptor prevents contraction.
Activation of beta2 receptor causes relaxation.

Question 14

List beta2 agonist / muscarinic antagonist combinations.

Answer 14

Salbutamol (SABA) - Ipratropium (SAMA)

Formoterol (LABA) - Aclinidinium bromide (LAMA)

Indaceterol (LABA) - Glycopyrronium (LAMA)

Olodaterol (LABA) - Tiotropium (LAMA)

Vilanterol (LABA) - Umeclidinium (LAMA)

Question 15

Describe the use of drugs which inhibit phosphodiesterase-4 in the treatment of COPD.

Answer 15

Phosphodiesterase-4 (PDE-4) is the prominent PDE expressed in neutrophils, T cells and macrophages.
Inhibition of PDE may have inhibitory effects upon inflammatory and immune cells.

Rofumilast, a selective PDE4 inhibitor, suppresses inflammation and emphysema in animal models of COPD. Approved as oral treatment for severe COPD accompanied by chronic bronchitis, but has limiting adverse gastrointestinal effects.

Question 16

Describe the use of glucocorticoids in the treatment of COPD.

Answer 16

Beta-adrenoreceptor agonists and / or muscarinic receptor antagonists are co-administered with glucocorticoids in combination inhalers.
The benefit of the routine inclusion of a glucocorticoid in some COPD patients has been debated since even high dose glucocorticoids alone do not suppress inflammation.

Glucocorticoids are of benefit in patients who develop frequent and severe exacerbations when given with a LABA.

Glucocorticoids unresponsiveness in COPD patients may be due to oxidative / nitrative stress (associated with chronic inhalation of tobacco smoke) - HDAC2 is reduced in COPD.

Triple inhalers (e.g. flucticasone / umeclidinium / vilanterol) have recently been approved as once daily treatment for moderate / severe COPD but not acute bronchospasm or asthma.

Question 17

Summarise the importance of the British Doctors Study (1951-2001).

Answer 17

40, 000 participants all of which were doctors in the UK.
It produced an accurate projection of smoker life span.
Conclusively proved link between smoking, vascular illness and cancer.
Conclusively proved cessation of smoking at any age improves all health outcomes and lifespan.