Drugs in Treatment of COPD

Question 1

outline the pathology of COPD

Answer 1

characterised by airflow reduction during expiration that in some patients is partially reversible (with bronchodilators) but which progressively worsens as assessed by FEV1
exacerbation of symptoms include cough and mucus production
historically divided into bronchitis and emphysema, may overlap

chronic bronchitis;
inflammation of bronchi and bronchioles
cough
clear mucoid sputum
infections with purulent sputum
increasing breathlessness

emphysema;
distension and damage to alveoli
destruction of acinial pouching in alveolar sacs
loss of elastic recoil

Question 2

explain how the activation of muscarinic acetylcholine (M3) receptors causes contraction of airway smooth muscle

Answer 2

reducing parasympathetic neuroeffector transmission with muscarinic receptor antagonists is important treatment
muscarinic receptor antagonists act as pharmacological antagonists of bronchoconstriction caused by smooth muscle, M3, receptor activation in response to ACh released from postganglionic parasympathetic fibres (mediates contraction to ACh, also present on mucus-secretingg cells evoking increased secretion)

Question 3

describe the use of short-acting (SAMAs) and long-acting (LAMAs) muscarinic receptor antagonists in treatment of COPD

Answer 3

SAMAs - ipratropium
LAMAs- tiotropium, glycopyrronium, aclidinium, umeclidinium

inhaled
quaternary ammonium group reduces absorption and systemic exposure avoiding multiple potential adverse effects of generalised parasympathetic block

delayed onset of bonrchodilator action relative to a SAMA
reduces bronchospasm caused by irritant stimuli and also blocks ACh - Mediated basal tone (epithelia also secretes ACh)
decreases mucus secretion
little effect on progression of COPD, their effect is mainly palliative
few adverse effects (little sympathetic absorption due to possession of the quaternary ammonium group)

Question 4

appreciate the potential advantage of M3 selective antagonists in such treatments and explain why this is the case

Answer 4

M3 selective blockers superior to ipratropium

functional selectivity of relatively selective M3 blocks (LAMAs) 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 release of ACh from parasympathetic post-ganglionic neurones is increased by auto receptor antagonism (activation by ACh inhibits further ACh release, non-selective antagonists increase release)
**refer to PP

Question 5

understand the scientific rationale of combining bet2-ADR agonists (LABAs) with LAMAs in treatment of COPD

Answer 5

beta-ADR agonists administered by inhalation include salbutamol (SABA) and salmeterol and formoterol (LABA)
provide bronchodilatation but have no effect on underlying inflammation
indacaterol and olodaterol are ultra-LABAs and are not recommended for relief of acute bronchospasm (once daily dosing is effective)

combination of beta2 agonists and a muscarinic antagonist is superior to either drug alone in increasing FEV1 (available as numerous combination inhalers that ease patient usage, but do not allow adjustment of the dosage of the individual drugs)
LABA/LAMA combinations are scientifically logical - 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 (e.g. muscarinic antagonist / beta2 agonists (MABAs). Such drugs are in development (e.g. batefenterol – phase II) )

Question 6

comment upon other drug classes used to treat COPD, including phosphodiesterase inhibits in combination with other drugs

Answer 6

Phosphodiesterase-4 (PDE4) is the prominent PDE expressed in neutrophils, T cells and macrophages – inhibition of PDE4 may have inhibitory effects upon inflammatory and immune cells
rofumilasta 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 7

comment upon other drug classes used to treat COPD, including glucocorticosteriods inhibits in combination with other drugs

Answer 7

beta-adrenoceptor agonists and/or muscarinic receptor antagonists are co-administered by 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
Glucocorticoid 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. fluticasone/umeclidinium/vilanterol) have very recently been approved as once daily treatment for moderate/severe COPD (but not acute bronchospasm, or asthma)