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Obstructive airway disease Flashcards

1
Q

Give examples of obstructive airway syndromes.

A

Asthma, chronic bronchitis, emphysema

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2
Q

What is the dynamic evolution of asthma?

A

Bronchoconstriction - brief symptoms
Airway inflammation - exacerbations, airway hyperresponsiveness
Airway remodelling - fixed airway obstruction

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3
Q

What are the histological hallmarks of asthma?

A

Basement membrane thickening
Collagen deposition in the submucosa
Hypertrophy of the smooth muscle

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4
Q

What are the different types of inflammation (mediated by which cells) in asthma and COPD?

A

asthma - eosinophilic inflammation

COPD - neutrophilic inflammation

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5
Q

What is airway remodelling?

A

Formation of collagen (scar tissue) in the airways which is not reversible.

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6
Q

What is the genetic influence of asthma?

A

Asthma has a high genetic loading - if you have a first degree family member with asthma, you are likely to get it.

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7
Q

Briefly describe the inflammatory cascade involved in asthma and how to treat each stage.

A
  1. Genetic predisposition and trigger factor (eg allergen, virus, chemicals)
    - avoidance
  2. Airway inflammation
    - anti-inflammatory: corticosteroids
  3. Mediators (eg histamine, leukotrienes)
    - anti-histamines, anti-leukotrienes
  4. Twitchy smooth muscle (hyper-reactivity)
    - bronchodilators: beta 2-agonists

Should treat as high up the cascade as possible - corticosteroids

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8
Q

How do you determine airway inflammation?

A

Do bronchoscopy under sedation and take a biopsy.

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9
Q

Describe the airway inflammation in asthma.

A

Infiltration of eosinophils and desquamation (destruction) of basal membrane.

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10
Q

What are the only drugs that will normalise bronchial structure in asthma?

A

corticosteroids

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11
Q

Why does asthma get worse at night?

A

We release most of our inflammatory mediators and cytokines at night - this is why symptoms are worse in the morning and there is diurnal variation in peak flow.

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12
Q

Which drugs can act as triggers for asthma?

A

beta-blockers, NSAIDs

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13
Q

Describe the clinical syndrome of asthma.

A

Episodic symptoms and signs
Diurnal variation - nocturnal/early morning
Non-productive (dry) cough, wheeze
Triggers
Associated atopy (rhinitis, conjunctivitis, eczema)
Family history of asthma

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14
Q

What is wheeze?

A

expiratory noise due to turbulent airflow

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15
Q

How is asthma diagnosed?

A 
History and examination
diurnal variation in symptoms
Reduced FVC/FEV1 ratio
Reversibility with inhaled salbutamol
Bronchial provocation (challenge) testing - bronchospasm: eg allergen/histamine inhilation, exercises
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16
Q

How does COPD develop?

A

Inhilation of noxious fumes eg smoking
Inflammation leading to impaired mucocilliary function and tissue.
Leads to development of obstruction and worsening of the disease
Characterised by: exacerbations, reduced lung function
Symptoms include SOB, reduced quality of life

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17
Q

What are the histological features of COPD?

A

Goblet cell hyperplasia (more goblet cells produced), mucous hypersecretion, smooth muscle hypertrophy- leads to luminal obstruction
Disrupted alveolar attachments = emphysema
Chronic inflammation of airways = bronchitis
emphysema and bronchitis go hand in hand
Chronic bronchitis is only partially reversible (unlike asthma) and emphysema is irreversible

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18
Q

Describe the disease process in COPD.

A

Cigarette smoking
Infiltration of CD8+ lymphocytes and alveolar macrophages
Accumulation of neutrophils due to release of neutrophil cha=emotactic mediators eg cytokines (IL-8), mediators eg LTB4 and oxygen radicals
Leads to reduced protease inhibition and increased protease action
destruction of alveolar walls (emphysema) and mucous hypersecretion (chronic bronchitis)
Progressive airflow obstruction

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19
Q

What are the different characteristics of chronic bronchitis and emphysema?

A 
Chronic Bronchitis:
- chronic neutrophilic inflammation
- mucous hypersecretion
- bronchial smooth muscle spasm and hypertrophy
- partially reversible
Emphysema:
- alveolar wall destruction
- impaired gas exchange
- loss of bronchial support
- Irreversible
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20
Q

How do you assess COPD?

A

assess:
Symptoms
Airflow using spirometery
Risk of exacerbations (using history of exacerbations and spirometery)

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21
Q

What is the clinical syndrome of COPD?

A 
Chronic symptoms - not episodic like asthma
Smoking
Non-atopic
Progressive breathlessness
Daily productive cough
Prone to infective exacerbations
bronchiectasis - wheezing
emphysema - reduced breath sounds
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22
Q

What is the chronic progression of COPD?

A 
Progressive fixed airflow obstruction
Impaired gas exhange
pulmonary hypertension
right sided heart failure/hypertrophy - cor pulmonale
death
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23
Q

What are the treatments of COPD?

A 
Non-pharmacological: smoking cessation
influenza/pneumococcal vaccination
physical activity
domiciliary oxygen
venesection
lung volume reduction surgery
Pharmacological:
SAMA/LAMA
SABA/SAMA
LABA/LAMA combo
LABA + ICS
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24
Q

What is the dominant neuronal control of bronchial smooth muscle?

A

Parasympathetic

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25
Q

What is the overall effect of parasympathetic stimulation on airway and how is this effect caused?

A

Parasympathetic stimulation causes increased airway resistance
stimulation of M3 receptors by ACh causes bronchial smooth muscle contraction and increased mucous production.

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26
Q

Where are the post-ganglionic fibers of the parasympathetic division in the lungs?

A

bronchial smooth muscle and submucosal glands

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27
Q

What is the overall effect of sympathetic stimulation on airway resistance and how is this effect caused?

A

Sympathetic stimulation causes decreased airway resistance
There is little or no sympathetic innervation of bronchial smooth muscle, the post-ganglionic fibres are in blood vessel smooth muscle and sub-mucosal glands.
Stimulation causes activation of ACh nicotinic receptors on chromaffin cells of the adrenal gland which stimulates release or adrenaline into the blood. Adrenaline activates beta 2-adrenoceptors in bronchial smooth muscle causing relaxation of bronchial smooth muscle
Also causes decreased mucous secretion and increased mucociliary clearance

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28
Q

How is asthma defined?

A

Inflammatory disease characterised by recurrent, reversible attacks of bronchoconstriction (causing dyspnoea, wheeze and cough) caused a stimulus that wouldn’t normally cause the same reaction in a non-asthmatic individual.

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29
Q

Give examples of some asthma tiggers.

A

allergens in atopic individuals (eg animal dander)
exercise, cold
respiratory infections eg viral
chemicals, pollutants, dust

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30
Q

What symptoms are experienced during intermittent attacks of bronchoconstriction?

A

wheeze, non-productive cough, dyspnoea

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31
Q

What are the pathological changes to the bronchioles due to long standing inflammation?

A
  1. smooth muscle hypertrophy and hyperplasia
  2. oedema
  3. increased mucous secretion
  4. epithelial damage - exposes sensory nerve endings
32
Q

Why is there a wheeze in asthma?

A

Sound on expiration - produced when trying to force air out through narrowed lumen and increased mucous lining the airways.

33
Q

What are the two components of hyper-responsiveness?

A

Hypersensitivity and hyper-reactivity

34
Q

How can hyper-responsiveness be measured?

A

By measuring FEV1 after giving an inhaled bronchoconstrictor (spasmogen eg histamine, methacholine)
A shift to the left = reaction at a lower concentration of spasmogen = hypersensitivity
Maximal elevation = greater degree of reaction = hyper-reactivity

35
Q

What type of inflammation is caused by epithelial damage exposing sensory nerve endings (C-fibres - irritant receptors) and why is it caused?

A

Neurogenic inflammation -caused by release of certain peptides

36
Q

What are the tow phases of an asthma attack?

A

Immediate - bronchoconstriction

Delayed - inflammation (after about 6 hours)

37
Q

Compare the immune responses involved in an atopic and non-atopic individual on exposure to an allergen

A

Non-atopic: Phagocytosis by antigen presenting (dendritic) cell; low level TH1 cell-mediated response; involves IgG and macrophages
ATOPIC: phagocytosis by antigen-presenting (dendritic) cell; strong TH2 response; antibody mediated; involves IgE antibodies

38
Q

How does desensitisation of beta 2-adrenoceptors occur?

A

As with many G-protein coupled receptors, repeated stimulation can lead to desensitisation tehn loss of function and endocytosis
there are kinases involved: protein kinase A (PKA) and G-protein receptor kinases (GRK)
PKA causes phosphorylation of the beta 2 receptor, preventing agonist binding resulting in loss of function
GRK causes phosphorylation of beta 2 receptor allowing the binding of beta-arrestin protein to the receptor. This causes loss of function and the causes the receptor to be endocytosed and either broken down in a lysosome or recycled back onto the membrane.
PKA can phosphorylate the receptor whether the agonist is already bound or not. GRK can only phosphorylate the receptor if the agonist is bound.

39
Q

Describe short acting beta 2 agonists and give examples.

A

salbutamol, albuterol
relievers
first line treatment fir miled, intermittent asthma
taken by inhaled route through metered dose inhaler usually (or oral in children, IV in emergency)
rapid onset of action to relax bronchial smooth muscle (5 mins, maximal effecta at 30 mins) with relaxation effect lasting for 4-6 hours
cause decreased mucous secretion and decreased mediator release from mast cells and neutrophils
can be taken prophylactically
few adverse side effects - any side effects come from unwanted systemic absorption: fine tremor, tachycardia/arrhythmia

40
Q

Describe LABAs and give example.

A

salmeterol
NOT recommended for relief of bronchospasm - too long to act
For nocturnal asthma - long half life
NOT used as a monotherapy - can be used as an add-on therapy for asthma which is not adequately controlled with another drug eg glucocorticoids

41
Q

How do cysteinyl leukotriene receptor antagonists work?

A

The following pathway causes bronchial smooth muscle contraction, mucous secretion and oedem. It is blocked by cysLT1 receptor antagonists to cause relaxation of bronchial smooth muscle.
Mast cell activation causes intracellular release of arachadonic acid by phospholipase A. This stimulates mast cell production of 5-lipoxygenase by FLAP. 5-lopoxygenase LTA4 which is mtabolised to LTB4 and LTC4 which cross the mast cell membrane through transporters to leave the cell. LTB4 causes infiltration of inflammatory cells releasing cysLTs. LTC4 is further metabolised to LTD4 and LTE4. CysLT, LTD4 and LTE4 stimulate the cysLT receptor causing bronchoconstriciton in the early phase and inflammation in the late phase.
CysLT receptor antagonists prevent this by blocking the CysLt receptor.

42
Q

Describe CysLT receptor antagonists and give examples.

A

montelukast, zafirlukast
effective add-on therapy in mild persistent asthma and in combo with other medications in more severe asthma
delivered by oral route
bronchodilators - relax bronchial smooth muscle in response to cysLTs
effective in allergen-induced and exercise induced asthma
not recommended in acute severe asthma (status asthmaticus) as their bronchodilator effect < salbutamol
generally well tolerated - few side effects

43
Q

Describe xanthines and give examples.

A

theophylline, aminophylline
bronchodilator and anti-inflammatory effects (relaxation of bronchial smooth muscle, prevent release of inflammatory mediators from mast cells, increased mucocilliary clearance)
second line drugs used in combination with beta 2 agonists and corticosteroids
method of action uncertain but may be due to inhibition of phosphodiesterase enzymes (PDE) which inactivate cAMP and cGMP (second messengers which cause smooth muscle relaxation)
given via oral route
Several side effects including nausea, vomiting, abdominal discomfort and headaches - have a narrow therapeutic index and have various drug interactions

44
Q

Describe chronic bronchitis and emphysema.

A

Chronic bronchitis: inflammation of bronchi and bronchioles, cough, clear mucoid sputum, exacerbations with purulent sputum, increasing breathlessness
Emphysema: distension and damage to alveoli, destruciton of acinal pouching in alveolar sacs

45
Q

Give examples of SAMAs and LAMAs

A

SAMA - ipratropium, oxitropium

LAMA - tiotropium, aclidinium

46
Q

Describe muscarinic antagonists and give examples.

A

Can be relatively short acting (ipratropium) or relatively long acting (tiotropium)
delivered by inhilational route
relax bronchoconstriction caused by activation of irritant receptors and block basal tone of bronchial smooth muscle by parasympathetic stimulation which is exaggerated in COPD
Palliative - do not affect development of COPD
Ipratropium not selective - blocks M1, M2 and M3
Tiotropium more selective - M3 only - and has a much longer half life

47
Q

What drug combination is recommended for moderate COPD and why?

A

LABA + LAMA - greater improvement in FEV1 than either drug alone as they act my different but complimentary mechanisms

48
Q

How do phosphodieseterase inhibitors help in COPD? Give an example of a PDE inhibitor

A

Rofumilast
Supresses inflammation by inhibiting phosphodiesterase-4 which is expressed in neutrophils, T lymphocytes and macrophages.

49
Q

What is rhinitis?

A

Acute or chronic inflammation of the nasal mucosa characterised by rhinitis, sneezing, itching and nasal congestion or obstruction due to swelling of the nasal mucosa due to dilated blood vessels. Can be allergic, non-allergic or mixed. Can be debilitating.
Allergic rhinitis can be seasonal (SAR) or perennial (PAR)

50
Q

What is the mechanism involved in allergic rhinits?

A

similar to atopic asthma
Inhilation of allergen increases specific IgE antibodies
IgE binds to receptor on mast cells and basophils
Re-exposure to allergen causes mast cell and basophil degranulation
Release of inflammatory mediators - histamine, cysLT, prostaglandins, tryptase causing acute itching, sneezing, rhinorrhoea and nasal congestion
Delayed response caused by recruitment of lymphocytes and eosinophils to nasal mucosa contributes to nasal congestion and obstruction

51
Q

What is non-allergic rhinitis?

A 
Any episode of rhinitis (acute or chronic) that does not involve IgE. Can have many causes:
infection
hormonal imbalance
non-allergic eosinophilia
vasomotor disturbances
medication

occupational rhinitis can be allergic or non-allergic

52
Q

How do rhinitis and rhinorrhoea cause difficulty breathing?

A

Increased mucosal blood flow and increased blood vessel permeability which causes increased mucosal volume leading to difficulty breathing.

53
Q

How do you treat rhinitis and rhinorrhoea?

A

Glucocorticoids - anti-inflammatory
H1 and CysLT1 receptor antagonists - mediator receptor blockers
Vasoconstrictors - nasal blood flow
Sodium chromoglycate - anti allergic

54
Q

What drugs are used as the mainstay of treatment of allergic rhinitis and what is their mechanism of action?

A

Glucocorticoids
reduced inflammation by reducing vascular permeability, recruitment and activity of inflammatory cells and release of mediators and cytokines
usually delivered topically to the nasal mucosa as a soray
after a period of weeks, the symptoms of rhinitis have usually reduced
can be given in combination with an anti-histamine for moderaste to severe rhinitis
can be given orally short term in very severe intractable cases

55
Q

How are antihistamines used in rhinitis and what is their mecahism of action?

A

Mechanism: competitive antagonists of H1 histamine receptors which prevent the effects of histamine release from mast cells, which include: vasodilatin and increased capillary permeability, activation of sensory nerve fibres and increased secretion of mucous from submucosal glands

56
Q

Why are muscarinic antagonists used in rhinitis?

A

Parasympathetic post-ganglionic fibres activate muscarinic receptors on submucosal glands causing lots of watery secretions contributing to rhinorrhoea - blocking ACh prevents this.
Good for rhinorrhoea but no other symptoms eg itching, sneexing, congesiton
Always delivered by nasal route
May cause dry nasal membranes

57
Q

Why are CysLT receptor antagonists used in rhinitis?

A

block the effects of CysLT on nasal mucosa
may be used as add-on therpay with anti-histamines
given orally
should be especially considered in patients with asthma and rhinitis
montelukast is the only drug on this class that is used

58
Q

Why are vasoconstrictors used in rhinitis?

A

Mimic noradrenaline and activate alpha-1 receptors in blood vessels to cause vasoconstriction to reduce swelling
Should not be given for more than a few days - get rebound congestion once therapy has stopped
eg oxymetazoline

59
Q

What 3 pathological changes can occur in the lungs in COPD?

A 
Chronic bronchitis (large airways)
Emphysema
Respiratory bronchiolitis (small airways)
60
Q

What are the key points in pathology of COPD?

A
  1. Consists of chronic bronchitis, emphysema and bronchiolitis (small airway disease)
  2. Produces irreversible airway obsruction
  3. Submucous glands become hyperplastic causing mucous hypersecretion
  4. The basis of hypoxic pulmonary hypertension is muscularization of pulmonary arteries
  5. Death is from bronchopneumonia, respiratory or cardiac failure or other cigarette-induced disease eg MI, lung cancer
61
Q

What is the clinical definition of chronic bronchitis?

A

A cough productive of sputum most days for 3 months of at least 2 successive years.

62
Q

What is the pathology associated with chronic bronchitis?

A

chronic irritation (by cigarette smoking) leads to a defensive increase in number of epithelial cells, especially goblet cells, in bronchi and increased mucous secretion due to increased number of serous and mucous glands. This hypersecretion probably doesn’t contribute to the pathological basis of fixed airway obstruction in COPD.
Non-reversible
Can lead to recurrent chest infections, particularly with H.influenza and S.pneumoniae.

63
Q

What is the pathology of small airway disease (respiratory bronchiolitis)?

A

Goblet cell metaplasia, macrophage accumulation and fibrosis around terminal and small bronchioles. May cause functional airway obstruction.

64
Q

What is the definition of emphysema?

A

Permanent increase beyond normal in size of air spaces distal to the terminal bronchioles, either by dilatation of by destruction of their walls

65
Q

What are the different types of emphysema?

A 
centriacinar
panacinar
bullous
paraseptal
around a scar
66
Q

How do you diagnose emphysema?

A

Difficult to diagnose in life - can be seen as changes in lung density on CT but often it is an assumed diagnosis in life. Diagnosed in post-mortem

67
Q

How does emphysema impair lung function?

A

Reduced alveolar surface area available for gas exchange

Loss of elastic recoil and support for small airways leading to tendency to collapse with obstruction

68
Q

What are the differences between centriacinar and panacinar emphysema?

A

Centriacinar - dilatation of bronchioles and some of the surrounding alveoli; usually have black pigment (carbon) in their walls
Panacinar - characterised by persistent enlargement and fusion of air spaces involving the entire acinus (functional unit of lung). Usually shows upper lobe distribution - if patient has panacinar emphysema of lower lobe, should consider an alpha-1 anti-tripsin definciency

69
Q

What does COPD cause as the disease advances?

A

Decreased PO2 which leads to:

  • Breathlessness and increased respiratory rate
  • chronic vasoconstriciton which can lead to pulmonary hypertension
70
Q

What is the epidemiology of COPD?

A

Smoking
environmental pollution
genetic factors

71
Q

What is the protease/anti-protease hypothesis?

A

elastic tissue on alveolar walls is sensitive to damage by elastases (proteases produced by macrophages and neutrophils). Alpha 1 anti-tripsin acts as an anti-elastase
An imbalance in either of these arms predisposes to destruction of elastic alveolar walls (emphysema).

72
Q

How does tobacco smoke predispose to emphysema?

A

Increases numbers of macrophages and neutrophils to the lungs (so increase amount of elastases)
Slows transit of these cells
Promotes neutrophil degranulation (release of elastases)
Inhibits alpha 1 antitrypsin

73
Q

Differentiate between extrinsic and intrinsic asthma.

A

Extrinsic - response to inhaled allergen

Intrinsic - non-immune mechanism (eg cold, exercise, aspirin)

74
Q

Briefly describe the immunological mechanism of asthma.

A

Type I hypersensitivity reaction - allergen binds to IgE on mast cell surface, causing degranulation - histamine release causing muscle spasm, inflammatory cell influx (eosinophils) and mucosal inflammation/oedema

75
Q

What is the pathology of asthma?

A

Narrowed oedematuos airways
Mucous plugs
Inflammatory cells (lymphocytes, eosinophils, plasma cells)
Epithelial damage

Respiratory (5 decks)

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