Drugs used in the Treatment of COPD Flashcards
What are the causes of COPD?
- Smoking
* Air pollution (not as important)
What are the effects of COPD?
- Airflow reduction that is partially reversible with bronchodilators in some patients (lowered FEV1, FVC) *cough
- mucus production
What is COPD divided into?
Chronic bronchitis and emphysema
Explain the process of how smoking causes COPD
- Smoking (air pollution)
- Stimulation of resident alveolar macrophages
- Cytokine production
- Activation of neutrophils, CD8+T cells
- Increased macrophage numbers
- Release of matrix metalloproteinases (e.g. elastase) and free radicals
What are the signs and symptoms of chronic bronchitis?
- inflammation of bronchi and bronchioles
- cough
- clear mucoid sputum
- infections with purulent sputum
- increasing breathlessness
What is emphysema?
- loss of elastic recoil
* distension and damage to alveoli
What is an important treatment to reduce parasympathetic neuroeffector transmission in COPD?
Muscarinic receptor antagonists
What are muscarinic receptor antagonists?
- Competitive antagonists of bronchoconstriction caused by smooth muscle M3 receptor activation
- M3 receptor activated in response to ACh released from postganglionic parasympathetic fibres
What are the different types of muscarinic ACh receptors expressed in human airways?
M1, M2 and M3
Where are airway M1, M2 and M3 receptors found?
- M1 - cell bodies of post-ganglionic neurones
- M2 - post-ganglionic neurones terminals
- M3 - airway smooth muscle cells
What is the function of M1 receptors in the airway?
- Controls fast neurotransmission by ACh acting on nicotinic receptors (nAChR)
- Controls slow e.p.s.p. that increases action potential frequency from nicotinic receptor stimulation
What is the function of M2 receptors in the airway?
Inhibitory autoreceptors reducing release of ACh (their blockade thus increases the release of ACh)
What is the function of M3 receptors in the airway?
- Control contraction in response to ACh
* Also present on mucus-secreting cells causing increased secretion
Why is Ipratropium (SAMA) no longer used in the treatment of COPD?
It is a non-selective muscarinic antagonist, meaning it blocks M1, M2 and M3 indiscriminately
Why are non-selective muscarinic antagonists not useful in the treatment of COPD?
Blockage of M1 and M3 is beneficial, but blockade of M2 is counter-active
- When block M1 receptor, reduces amount of AcH released onto airway SM cell – blockage is beneficial
- M2 receptors act in a negative feedback to reduce release of AcH – when stimulated, reduce the volume of AcH transmitted to SM
- If block M2 receptor – block inhibition of Ach and results in increase in concentration of AcH in junction between neuron and muscle
Which muscarinic receptor is the most important to target in COPD?
M3 - muscarinic receptor antagonist will cause relaxation of bronchial smooth muscle
What are examples of muscaranic receptor antagonists used in the treatment of COPD?
- Ipratropium (SAMA - not really used anymore)
- Tiotropium (LAMA)
- Glycopyronium (LAMA)
- Aclidinium (LAMA)
- Umeclidinium (LAMA)
How are muscaranic receptor antagonists administered in COPD?
All administered by inhalation
What is the advantage of using Tiotropium (etc) as opposed to Atropine?
- Atropine is a tertiary amine (nitrogen is not always positively charged) so when it is not positively charged, it can pass across biological membranes in airways and enter into systemic circulation
- Tiotropium (etc) is a quaternary ammonium so is always positively charged and cannot enter systemic circulation (restricted to airways)
Why is it important that ‘-iums’ don’t enter systemic circulation?
Would effectively block all activities of parasympathetic NS
What are the effects of muscaranic receptor antagonists?
- Reduce bronchospasm caused by irritant stimuli and also block ACh-mediated basal tone
- Decrease mucous secretion
- Have little effect on the progression of COPD as their effect is mainly palliative
- Have few adverse effects (little systemic absorption due to quaternary ammonium group)
What is Ipratropium?
A non-selective blocker of M1, M2 and M3 receptors - preferred agents with some selectivity for M3 are available
Why is bronchospasm caused by irritant stimuli known as a vago-vagal reflex?
Both sensory and motor components of reflex are in same nerve (CN X – vagus)
How do modern muscaranic receptor antagonists work?
They are selective M3 blockers - block transmission by ACh acting on ASM M3 receptors
How is functional selectivity of M3 blockers over Ipratropium achieved?
Different binding kinetics - differences in rates of association and dissociation from the M3 receptor (occupy M3 receptors for longer than M1 and M2)
Why is blockage of M2 receptors not desirable?
Release of ACh from parasympathetic post-ganglionic neurones is increased by autoreceptor antagonism (increased by non-selective antagonists)
What B-adrenoceptor agonists are administered by inhalation in COPD?
- SABAs (administered every 4-6 hrs) - salbutamol
* LABAs (administered twice daily) - salmeterol and formoterol
What is the effect of B-adrenoceptor agonists in COPD?
Provide bronchodilatation, but have no effect on underlying inflammation
What are ultra-LABA’s used in the treatment of COPD?
Indacaterol and olodaterol
Why are ultra-LABAs not used in relief of acute bronchospasm?
They have a delayed onset of action
What is the advantage of Ultra-LABAs?
Once daily administration
Why are B-adrenoceptor agonists and muscaranic receptor antagonists used in combination therapies for COPD?
- Combination of drugs is superior to either drug alone in increasing FEV1
- The drugs work by different but complementary mechanisms to cause smooth muscle relaxation
What is an advantage and disadvantage of combination inhalers containing both LABA and LAMA?
- A - Greater patient compliance as only 1 administration rather than 2 separate administrations for both drugs
- D - does not allow adjustment of the dosage of individual drugs
When are LABA/LAMA combinations likely to be most effective? How is this achieved?
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)
What is an example of a MABA?
Batefenterol (phase II)
Explain the complementary pathways of LAMAs and LABAs
- Muscarinic antagonists block activation by ACh – prevent contraction
- Activation by β2 agonists - cause relaxation
- When activated together, have a synergistic effect
What is the effect of inhibition of PDE4?
Phosphodiesterase-4 (PDE4) is the prominent PDE expressed in neutrophils, T cells and macrophages - so inhibition of PDE4 may have inhibitory effects upon inflammatory and immune cells
What is an example of a selective PDE4 inhibitor?
Rofumilast
What is the effect of Rofumilast?
Suppresses inflammation and emphysema in animal models of COPD
When is Rofumilast used?
Approved as oral treatment for severe COPD accompanied by chronic bronchitis
What are the drawbacks of Rofumilast?
Has limiting adverse gastrointestinal effects as it is given orally rather than by inhalation
What is administered alongside LABA’s and LAMA’s in combination inhalers for COPD?
Glucocorticoids
Why are glucocorticoids administered via combination inhalers?
Even high doses of glucocorticoids /alone/ do not suppress inflammation
What is the benefit of delivering glucocorticoids in combination with LABA/LAMAs in COPD?
Glucocorticoids are of benefit in patients who develop frequent and severe exacerbations when given with a LABA
Why are glucocorticoids ineffective when delivered on their own in COPD?
Due to oxidative/nitrative stress (associated with chronic inhalation of tobacco smoke) – histone de-acetylase (HDAC2) is reduced in COPD
What are triple inhalers?
e. g. fluticasone/umeclidinium/vilanterol
* Once daily treatment for moderate/severe COPD (but not for acute bronchospasm or asthma)
