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Respiratory: Pharmacology > Drugs used in the Treatment of COPD > Flashcards

Drugs used in the Treatment of COPD Flashcards

1
Q

What are the causes of COPD?

A
  • Smoking

* Air pollution (not as important)

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2
Q

What are the effects of COPD?

A
  • Airflow reduction that is partially reversible with bronchodilators in some patients (lowered FEV1, FVC) *cough
  • mucus production
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3
Q

What is COPD divided into?

A

Chronic bronchitis and emphysema

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4
Q

Explain the process of how smoking causes COPD

A
  • 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
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5
Q

What are the signs and symptoms of chronic bronchitis?

A
  • inflammation of bronchi and bronchioles
  • cough
  • clear mucoid sputum
  • infections with purulent sputum
  • increasing breathlessness
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6
Q

What is emphysema?

A
  • loss of elastic recoil

* distension and damage to alveoli

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7
Q

What is an important treatment to reduce parasympathetic neuroeffector transmission in COPD?

A

Muscarinic receptor antagonists

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8
Q

What are muscarinic receptor antagonists?

A
  • Competitive antagonists of bronchoconstriction caused by smooth muscle M3 receptor activation
  • M3 receptor activated in response to ACh released from postganglionic parasympathetic fibres
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9
Q

What are the different types of muscarinic ACh receptors expressed in human airways?

A

M1, M2 and M3

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10
Q

Where are airway M1, M2 and M3 receptors found?

A
  • M1 - cell bodies of post-ganglionic neurones
  • M2 - post-ganglionic neurones terminals
  • M3 - airway smooth muscle cells
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11
Q

What is the function of M1 receptors in the airway?

A
  • 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
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12
Q

What is the function of M2 receptors in the airway?

A

Inhibitory autoreceptors reducing release of ACh (their blockade thus increases the release of ACh)

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13
Q

What is the function of M3 receptors in the airway?

A
  • Control contraction in response to ACh

* Also present on mucus-secreting cells causing increased secretion

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14
Q

Why is Ipratropium (SAMA) no longer used in the treatment of COPD?

A

It is a non-selective muscarinic antagonist, meaning it blocks M1, M2 and M3 indiscriminately

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15
Q

Why are non-selective muscarinic antagonists not useful in the treatment of COPD?

A

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
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16
Q

Which muscarinic receptor is the most important to target in COPD?

A

M3 - muscarinic receptor antagonist will cause relaxation of bronchial smooth muscle

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17
Q

What are examples of muscaranic receptor antagonists used in the treatment of COPD?

A
  • Ipratropium (SAMA - not really used anymore)
  • Tiotropium (LAMA)
  • Glycopyronium (LAMA)
  • Aclidinium (LAMA)
  • Umeclidinium (LAMA)
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18
Q

How are muscaranic receptor antagonists administered in COPD?

A

All administered by inhalation

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19
Q

What is the advantage of using Tiotropium (etc) as opposed to Atropine?

A
  • 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)
20
Q

Why is it important that ‘-iums’ don’t enter systemic circulation?

A

Would effectively block all activities of parasympathetic NS

21
Q

What are the effects of muscaranic receptor antagonists?

A
  • 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)
22
Q

What is Ipratropium?

A

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

23
Q

Why is bronchospasm caused by irritant stimuli known as a vago-vagal reflex?

A

Both sensory and motor components of reflex are in same nerve (CN X – vagus)

24
Q

How do modern muscaranic receptor antagonists work?

A

They are selective M3 blockers - block transmission by ACh acting on ASM M3 receptors

25
Q

How is functional selectivity of M3 blockers over Ipratropium achieved?

A

Different binding kinetics - differences in rates of association and dissociation from the M3 receptor (occupy M3 receptors for longer than M1 and M2)

26
Q

Why is blockage of M2 receptors not desirable?

A

Release of ACh from parasympathetic post-ganglionic neurones is increased by autoreceptor antagonism (increased by non-selective antagonists)

27
Q

What B-adrenoceptor agonists are administered by inhalation in COPD?

A
  • SABAs (administered every 4-6 hrs) - salbutamol

* LABAs (administered twice daily) - salmeterol and formoterol

28
Q

What is the effect of B-adrenoceptor agonists in COPD?

A

Provide bronchodilatation, but have no effect on underlying inflammation

29
Q

What are ultra-LABA’s used in the treatment of COPD?

A

Indacaterol and olodaterol

30
Q

Why are ultra-LABAs not used in relief of acute bronchospasm?

A

They have a delayed onset of action

31
Q

What is the advantage of Ultra-LABAs?

A

Once daily administration

32
Q

Why are B-adrenoceptor agonists and muscaranic receptor antagonists used in combination therapies for COPD?

A
  • 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
33
Q

What is an advantage and disadvantage of combination inhalers containing both LABA and LAMA?

A
  • 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
34
Q

When are LABA/LAMA combinations likely to be most effective? How is this achieved?

A

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)

35
Q

What is an example of a MABA?

A

Batefenterol (phase II)

36
Q

Explain the complementary pathways of LAMAs and LABAs

A
  • Muscarinic antagonists block activation by ACh – prevent contraction
  • Activation by β2 agonists - cause relaxation
  • When activated together, have a synergistic effect
37
Q

What is the effect of inhibition of PDE4?

A

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

38
Q

What is an example of a selective PDE4 inhibitor?

A

Rofumilast

39
Q

What is the effect of Rofumilast?

A

Suppresses inflammation and emphysema in animal models of COPD

40
Q

When is Rofumilast used?

A

Approved as oral treatment for severe COPD accompanied by chronic bronchitis

41
Q

What are the drawbacks of Rofumilast?

A

Has limiting adverse gastrointestinal effects as it is given orally rather than by inhalation

42
Q

What is administered alongside LABA’s and LAMA’s in combination inhalers for COPD?

A

Glucocorticoids

43
Q

Why are glucocorticoids administered via combination inhalers?

A

Even high doses of glucocorticoids /alone/ do not suppress inflammation

44
Q

What is the benefit of delivering glucocorticoids in combination with LABA/LAMAs in COPD?

A

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

45
Q

Why are glucocorticoids ineffective when delivered on their own in COPD?

A

Due to oxidative/nitrative stress (associated with chronic inhalation of tobacco smoke) – histone de-acetylase (HDAC2) is reduced in COPD

46
Q

What are triple inhalers?

A

e. g. fluticasone/umeclidinium/vilanterol

* Once daily treatment for moderate/severe COPD (but not for acute bronchospasm or asthma)

Respiratory: Pharmacology (4 decks)

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