CODP Pharmacology

Question 1

What is COPD ?

Answer 1

Progressive airflow obstruction and lung hyperinflation that is, in some patients, partially reversible
-Characterised by dyspnoea, chesty cough (with mucus), wheezing, chest tightness
-Diagnosed through spirometry: Post bronchodilator FEV1/FVC ratio 0.7
-Increased frequency and severity of exacerbations
-Systemic manifestations include deconditioning and muscle weakness

Question 2

What causes COPD ?

Answer 2

Damage to airways leading to inflammation and lung destruction; Emphysema and Chronic Bronchitis
-Increased Resistance to Air Flow During Expiration

Release of metalloprotein….causes remodelling

Question 3

What is chronic bronchitis ?

Answer 3

Inflammation of bronchi and bronchioles
-cough
-clear mucoid sputum
-infections with purulent sputum
-increasing breathlessness

Question 4

What is emphysema ?

Answer 4

Distension and damage to alveoli
Destruction of acinial pouching in alveolal sacs
Loss of elastic recoil

(differs in detail according to site of damage)

Question 5

How does COPD affect airflow into lung ?

Answer 5

Increased Resistance to Air Flow During Expiration

Moderate COPD makes it a struggle to get air out of lungs

Severe; remodelling and loss of elastic recoil and damage etc causes exhalation phase failure which can lead to air trapping

Question 6

What is Resistive Pressure Drop (Pfr) ?

Answer 6

Resistive Pressure Drop (Pfr): Pressure difference required to move a specific amount of air through the lung

Question 7

How does COPD affect resistive pressures during breathing ?

Answer 7

Resistive prssure = pressure required to overcome airway resistance during airflow
-opposes airflow, not lung expansion itself

Airway resistance increases → resistive pressure increases → breathing (especially expiration) becomes difficult.

Dotted line = elastic lung recoil; severe COPD reduced elasticity

Question 8

What are the different types of musarinic receptors ?

Answer 8

Human airways express M1, M2 and M3 muscarinic receptors at different locations

Question 9

What are M1 muscarinic receptors ?

Answer 9

M1 Muscarinic Acetylcholine Receptors
-Present on postganglionic neurone
-Facilitate faster neurotransmission mediated by ACh acting on nicotinic receptors (nAChR)

Pregangolionic is nicotinic

Question 10

How do M1 receptors increase action potential frequency ?

Answer 10

M1 receptors mediate a slow EPSP that increases action potential frequency resulting from nicotinic receptor stimulation
-EPSP = excitatory post synaptic potential; provides a boost which brings closer to action potential

Question 11

What is an ESPS ?

Answer 11

Excitatory Postsynaptic Potentials
-A local depolarization of the postsynaptic membrane
-Makes the neuron more likely to fire an action potential

Question 12

What are M2 receptors and what do they do ?

Answer 12

M2 Muscarinic Acetylcholine Receptors
-Present on postganglionic neurone presynaptic terminals
-Act as inhibitory autoreceptor reducing release of ACh
-Their blockade thus increases the release of ACh, excaccerbating COPD

Question 13

What are M3 receptors ?

Answer 13

M3 Muscarinic Acetylcholine Receptors
-Present on ASM
-Mediate contraction in response to ACh
-M3 also present on mucus-secreting cells causing increased secretion

Question 14

Explain the Molecular mechanism of airway smooth muscle (ASM) contraction by M3 receptors

Answer 14

PLC: Phospholipase C
PIP2: Phosphatidylinositol (4,5) bisphosphate
IP3: Inositol (1,4,5) trisphosphate
SR: Sarcoplasmic reticulum

Question 15

What do Muscarinic receptor antagonists do ?

Answer 15

Muscarinic receptor antagonists act as pharmacological antagonists of bronchoconstriction
-Reducing parasympathetic neuroeffector transmission is an important treatment of COPD

Question 16

Give an Example of a vago-vagal reflex

Answer 16

Vasgo-vasal reflex would cause bronchoconstriction

This is how M3 antagonists work

Question 17

Discuss the use of Muscarinic Receptor Antagonists in the Treatment of COPD

Answer 17

Reduce bronchospasm caused by irritant stimuli
Impact ACh-mediated basal tone (note epithelium also secretes ACh)
Decrease mucus secretion
Little effect on COPD progression; effect mainly palliative
LAMAs have delayed onset of bronchodilator action relative to SAMA

Question 18

Give examples of currently licenesed SAMAs and LAMAs

Answer 18

Short acting muscarinic antagonist (SAMA)
-Ipratropium

Long acting muscarinic antagonists (LAMAs)
-Tiotropium
-Glycopyrronium
-Aclidinium
-Umeclidinium

Many are atropine derivatives

All administered by inhalation

Question 19

How do Muscarinic Receptor Antagonists avoid systemic exposure

Answer 19

Quaternary ammonium group (c.f. atropine) reduces systemic absorption and systemic exposure
-avoids multiple potential adverse effects of a generalized parasympathetic block.

Tiotropium selective for m1 and 3

Question 20

On which receptor does Ipratropium act ?

Answer 20

Ipratropium is a non-selective blocker of M1, M2 and M3 receptors
-preferred agents with some selectivity for M3 are available

Question 21

How do some drugs achieved greater specificity for M3 than ipratropium ?

Answer 21

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

Question 22

Why are M3 Selective Blockers Superior to Ipratropium ?

Answer 22

Question 23

What are β2-Adrenoceptor Agonists ?

Answer 23

Bronchodilators which act as physiological antagonists of all spasmogens to relax bronchial smooth muscle
-Provide bronchodilatation, but have no effect on underlying inflammation
-Classified as (i) short-acting (SABA), (ii) long-acting (LABA) and (iii) ultra long-acting (ultra-LABA)

Question 24

Give examples of B-adrenoceptor agonists administered by inhalation

Answer 24

B-adrenoceptor agonists administered by inhalation include:
-salbutamol (short acting, administered every 4-6 hrs, first line treatments for mild asthma, taken as ‘relievers’)
-salmeterol and formoterol (long acting, administered twice daily eg for nocturnal asthma).

Question 25

Give examples of 'ultra-LABAs'

Answer 25

Indacaterol and olodaterol are ‘ultra-LABAs’ -not recommended for relief of acute bronchospasm -once daily dosing is effective | preventers

Question 26

What is a logical treatment for COPD ?

Answer 26

Muscarinic Antagonist and β2 Agonists Combinations -β2 agonist and a muscarinic antagonist is superior to either drug alone in increasing FEV1. -LABA/LAMA combinations are scientifically logical - the drugs work by different, but complementary, mechanisms to cause smooth muscle relaxation. Available as numerous combination inhalers: -Ease of patient usage -Do not allow adjustment of the dosage of the individual drugs

Question 27

When are LABA/LAMA combinations likely to be most effective ?

Answer 27

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 antagonist / B2 agonists (MABAs). -Such drugs are in development (e.g. batefenterol)

Question 28

What are triple inhalers ?

Answer 28

B-adrenoceptor agonists and/or muscarinic receptor antagonists can be co-administered with glucocorticoids in combination inhalers -e.g. fluticasone/umeclidinium/vilanterol as once daily treatment for moderate/severe COPD (but not acute bronchospasm, or asthma; Glucocorticoids are much more effective in eosinophilic inflammation (like asthma) than in neutrophilic inflammation (like COPD) | glucocorticoids also used in COPD treatment

Question 29

What is Roflumilast ?

Answer 29

Phosphodiesterase-4 (PDE4) is the prominent PDE expressed in neutrophils, T cells and macrophages -Inhibition of PDE4 has inhibitory effects upon inflammatory and immune cells Roflumilast, 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 | Another drug used to treat COPD

Question 30

What consdierations should be made for a COPD patient with frequent exaccerbations ?

Answer 30

Frequent exacerbations: ≥ 2 moderate or 1 severe exacerbation a year

Question 31

Which increases pneumonia risk in COPD patients on ICSs ?

Answer 31

COPD patients with low baseline blood eosinophil count seem at increased risk of pneumonia -Blood eosinophil count predicts response to ICS -There is a reduced response in patients with low blood eosinophil counts | Here, response = reduction in exaccerbations