Cholinergic Pathways and the limitations of inhaled therapeutics

Reinoud Gosens, PhD 06 Sept 2016

Department of Molecular Pharmacology University of Groningen

Groningen Research Institute for Asthma and COPD

•  Anatomy of the airway cholinergic system.

•  Role in bronchoconstriction.

•  Pro-inflammatory nature of acetylcholine.

•  Contribution to lung function impairment and exacerbations in COPD and asthma.

Goals

Sensory and motor units in the vagal nerve

Kistemaker et al

Sensory nerve

Motor nerve

0

20

40

60

80

100

0,5 1 2 4 8 16 31 62,5

Con

trac

tile

Res

pons

es

EFS (Hz)

Largeairways

Smallairways

Cholinergic neurons are expressed in large and small airways

Time

Sopi et al

Airway

Muscarinic Nicotinic

Acetylcholine

ChAT

Acetyl CoA + Choline

Acetylcholine: synthesis and mode of action

The airway cholinergic system

The output of the airway cholinergic system is increased by inflammation

Sensory nerve

Motor nerve

The airway cholinergic system may contribute to inflammation

Kistemaker and Gosens, Trends Pharmacol Sci (2015)

Tiotropium Aclidinium

Glycopyrronium

Umeclidinium

Long-acting muscarinic antagonists (LAMA)

Compound Dose Frequency Tiotropium 5 µg Once daily Aclidinium 400 µg Twice daily Glycopyrronium 50 µg Once daily Umeclidinium 125 µg Once daily

The Ideal Bronchodilator

Airflow

Quality of life

Exercise endurance

Immediate onset Long duration of action Safe

Exacerbations

Tashkin et al., NEJM (2004) 55:289-294

Long-term impact of tiotropium on lung function

Impact of LAMAs on COPD exacerbations

*p≤0.05; **p≤0.01; ***p≤0.001 Novartis, data on file

Kerwin et al., Eur Respir J (2012)

Impact of LAMAs on Asthma (lung function, exacerbations)

*p≤0.05; **p≤0.01; ***p≤0.001 Novartis, data on file

Severe asthma; on top of corticosteroids+ β2-agonists

Kerstjens, et al. NEJM (2012)

0

5

10

15

20

25

30

35

FEV

1 (%

rela

tive

chan

ge)

Bronchodilator treatment: reality vs. the ideal situation

•  The airway cholinergic system is expressed in both large and small airways.

•  Neuronal acetylcholine regulates bronchoconstriction with a predominant role for the M3 receptor.

•  Inflammation can increase acetylcholine release which in turn may contribute to inflammation.

•  Acetylcholine contributes to lung function impairment and exacerbations in COPD and asthma.

Summary - Conclusions