Asthma

Question 1

What are the characteristic symptoms of an asthma attack?

Answer 1

• Dyspnoea (shortness of breath)
• Wheezing
• Coughing
• Chest tightness
• The unexpected and sudden nature of the attacks can promote anxiety, which exacerbates the symptoms.

Question 2

^{How is asthma diagnosed?}

Answer 2

1. Medical history
2. Physical examination
3. Objective measures of lung function by spirometry.
   
   • Spirometry is used to measure the FEV₁ (forced expiratory volume in 1 second) and PEFR (peak expiratory flow rate) – reductions in these values indicate airway obstruction.
   • The reversibility of obstruction is diagnosed by rapid improvement in lung function after inhalation of a short-acting bronchodilator.

Question 3

How can the severity of an asthma attack be determined?

Answer 3

1. Clinical history

• First is the clinical history.
• A recent hospital admission or previous life-threatening attack suggests greater severity

1. Intensity of symptoms
   
   • Symptom intensity can be assessed by a clinical examination.
   • Measurements include the general appearance of the patient and difficulty in speaking
2. Lung function
   
   • Thirdly, lung function can be assessed with spirometry.
   • Spirometry is used to measure the:
     
     1. FEV₁ (forced expiratory volume in one second)
     2. PEFR (peak expiratory flow rate).
     3. In addition, the FEV₁/PEFR ratio can be calculated.
   • Reductions in these values indicate airway obstruction, with the magnitude of reduction correlating with severity.
   • The magnitude of the improvement in lung function following bronchodilator administration also indicates severity.
   • Can be explained in terms of Poiseuille’s Law
3. Blood gases
   
   • Fourthly, arterial blood gas measurements are obtained as indicators of pulmonary ventilation
   • These include P_aO_2, P_aCO_2, S_aO_2, and plasma pH

Question 4

Outline the different grades of severity

Answer 4

• Moderate attack
  
  • A moderate attack is indicated by:
    
    • Worsening symptoms
      
      • FEV > 50% of predicted
• Status asthmaticus
  
  • An acute, severe attack, also known as status asthmaticus (SA), is indicated by:
    
    • Dyspnoea severe enough to impair speech
    • Accessory respiratory muscle activity (sternocleidomastoid, scalenes, abdominal muscles)
    • Paradoxical pulse > 12 mmHg
    • Heart rate > 120 bpm
    • Breathing rate > 30 per minute
    • FEV₁ < 50% of predicted
    • S_aO₂ < 91%
      
      • The patient is hypocapnic (low P_aCO₂) and alkalotic (high blood pH) because of hyperventilation, which is a result of juxtacapillary receptor activation in response to lung oedema.
• Life-threatening attack
  
  • In life-threatening SA, fatigue of the respiratory muscles due to prolonged effort leads to hypoventilation and CO₂ retention resulting in:
    
    • A rise in P_aCO₂ to normal.
    • A fall in blood pH to normal.
  • Other indicators include
    
    • FEV₁ < 30% of predicted
      
      • Silent chest
• Near fatal asthma
  
  • In near fatal asthma, respiratory failure leads to a rise in P_aCO₂ and fall in plasma pH.

Question 5

Outline the steps for the pathogenesis of asthma

Answer 5

1. Triggers
2. Sensitisation
3. Inflammatory response on re-exposure
4. Pathological consequences
5. Late asthmatic response
6. Airway Remodelling – long term consequence

Question 6

Outline the triggers for asthma

Answer 6

• Extrinsic asthma (atopic)
  
  • Thought to be mediated by a genetic predisposition
    
    • to produce immunoglobulin E (IgE) against common environmental aeroallergens resulting in a type I hypersensitivity reaction
      
      • Type 1 hypersensitivity reaction increases the number of T helper 2 (Th2) cells and immunoglobulin E (IgE) in the airway mucosa.
  • Atopy is defined as a genetic predisposition to produce immunoglobulin E (IgE) against common environmental aeroallergens such as dust mites, moulds, pollens and animal dander. About 80% of patients with asthma are atopic compared with 30% of the general population.
• Intrinsic asthma
  
  • Unknown aetiology and is poorly understood.
  • Triggering stimuli:
    
    • Exercise
    • Stress
    • Cold air
    • Infections

Answer 7

1. Activation of the airway epithelium by pollutants / microbial infection leads to the release of IL-33, IL-25 and thymic stromal lympho-protein
2. Cytokines activate dendritic cells that bind the allergens and present them to CD4+ T cells.
   
   • DERP 1 produced by house dust mites cleaves occluding junctions and can be presented by CD4 T cells as well allowing access to adjuvants, stimulating an immune response
3. This stimulates a TH₂ cell response and increases cytokine secretion
   
   • IL-4 and IL-13, which stimulate B cell IgE production
   • IL-5, which stimulates locally recruited eosinophils
4. This contributes to the inflammatory soup
5. B-cells produce allergen specific IgE that binds to FcE receptors
6. This leads to mast cell sensitisation

Question 8

How is histamine released? What is its effect?

Answer 8

• Histamine released rapidly from pre-packaged granules
• Effect
  
  • ​Vasodilation
  • Mucus secretion

Question 9

How are leukotrienes/prostaglandins released? What are their effects?

Answer 9

• Formed from arachidonic acid by COX enzyme activation
• Effect
  
  • Bronchoconstriction
  • Prostoglandins result in vasodilation

Question 10

What are cytokines released in response to? What are their effect?

Answer 10

• TNF alpha & IL-4
• Local infalmmation

Question 11

Discuss the pathological consequences of asthma

Answer 11

• Airway obstruction (decreased lumen diameter) is a consequence of:

1. Bronchoconstriction
2. Mucus accumulation
3. Oedema
4. Eosinophil recruitment

Question 12

Explain bronchoconstriction

Answer 12

• Bronchoconstriction is generated by the action of inflammatory mediators on bronchial smooth muscle.
• Histamine
  
  • Histamine binds to G_q-linked H₁ receptors on smooth myocytes, stimulating contraction via an IP₃-mediated increase in [Ca²⁺]_i.
• Other mediators
  
  • Prostaglandins and leukotrienes also stimulate contraction via action on smooth muscle GPCRs.
  • Leukotrienes also promote an increase smooth muscle mass that contributes to obstruction.
• Hyperreactivity is also mediated by IL-13
• Shifts the dose response curve of the smooth muscle to the left, so a smaller stimulus is needed for contraction

Question 13

Explain mucus hypersecretion

Answer 13

• Mediator action on goblet cells leads to mucus hypersecretion and blockage of the small airways with mucus.
• The mucus is initially aqueous, but increases in viscosity as the disease progresses, making it harder for the mucociliary escalator to remove.
• Viscosity increases due to an increased sympathetic drive that increases mucin and a decreased parasympathetic drive that decreases water movement into the lumen
• IL-13, IL-5 and IL-9 from B cells stimulate goblet cell hyperplasia increasing production.

Question 14

Describe mucolytics

Answer 14

• Mucolytics:
  
  • Reduce the viscosity of the mucus, making clearance from the airway easier
  • e.g. N-acetyl-cystine
  • It acts by:
    
    • Breaking down disulphide bones in mucoprotein complexes
    • Antioxidant effect that reduces oxidative stress and mucus secretion

Question 15

Explain oedema

Answer 15

• Oedema of the airway wall is a consequence of increased capillary permeability and vasodilation.
• It leads to swelling of the tissue that obstructs the airway.
• Dyspnoea
  
  • Oedema also activates juxtacapillary receptors in the lung parenchyma, which feed in to the respiratory control system and evoke rapid and shallow breathing that gives the sensation of dyspnoea.
  • Dyspnoea can result in a decreased PaO₂ which is then countered by tachypnoea (exacerbated by anxiety and increased sympathetic nervous control)
  • This results in a reduced PaCO₂ and respiratory alkalosis (no CO₂ retention at this early stage)

Question 16

When does eosinophil recruitment occur?

Answer 16

• This acute pathology (referred to as the early asthmatic response) is followed by a late asthmatic response.
• It occurs 3-12 hours later
• Caused by the inflammatory processes activated during the acute phase

Question 17

• Explain the mechanism of eosinophil recruitment.
  
  • What secretes IL-13?
  • What do eosinophils release?

Answer 17

• IL-13 is secreted by activated mast cells, TH₂ cells and B cells to drive recruitment of eosinophils.
• Eosinophils release:
  
  • Major basic protein
    
    • Induce epithelial apoptosis and epithelial damage
  • Cationic protein
    
    • Stimulates histamine release from mast cells
    • Thus acts as a positive feedback loop – mast cells secrete cytokines that activate eosinophils, which secrete protein that degranulates mast cells

Question 18

Describe evidence for airway remodelling as a long-term pathological consequence of asthma

Answer 18

• Cadaver analysis: Houston et al, 1953
  
  • Selected patients who had died in asthma attacks with no other underlying cause of death
  • Analysed their lungs with sections that were stained with H&E
  • Showed that there was:
    
    • Thickening of the airway wall
      
      • Increased collagen and mucus
        
        • Goblet cell metaplasia and hyperplasia
    • Sub-mucosal fibrosis
    • Cellular spirals of leukocytes
  • This all pointed to the inflammatory nature of asthma, but the mediators for it were not yet known.

Question 19

Describe epithelial desquamation - how it occurs and what it can contribute to

Answer 19

• Desquamation = skin peeling
  
  • Shedding of outermost membrane of tissue
• Another important change is desquamation of the bronchial epithelium by the actions of:
  
  • Major basic protein (MBP)
  • Eosinophil cationic protein (ECP)
    
    • From eosinophils
• Bronchial hyper-responsiveness
  
  • Removal of overlying epithelial cells exposes subepithelial irritant receptors, C fibres and immune cells to irritants in the lumen, contributing to the bronchial hyper-responsiveness that is characteristic of asthma
  • Loss of cilia
    
    • It also increases the risk of infection that can exacerbate the asthma due to the loss of cilia to move mucus

Question 20

Explain an experiment which shows that major basic protein contributes to bronchial hyper-responsiveness

Answer 20

• Experiment by Flavahan et al.
• Method
  
  • Rings of guinea pig trachea were suspended between two steel wires connected to strain gauges to record tension.
  • Indomethacin (cyclo-oxygenase inhibitor) was administered
    
    • Prevent the generation of prostaglandins and leukotrienes during the experiment that could interfere with tension
  • Incubation of the trachea in solution containing MBP was associated with an increase in the tension generated by smooth muscle contraction in response to acetylcholine and histamine application.
  • Mechanical removal of the epithelium produced a similar increase in tension, suggesting that the effects of MBP are mediated by epithelial damage

Question 21

What is the consequence of remodelling? What does this highlight?

Answer 21

• Chronic remodelling presents a poor prognosis for asthma patients
  
  • Studies show declines in FEV₁ throughout life
    
    • even in patients with asthma considered ‘well-managed’ by corticosteroid therapy [Copenhagen Heart Study]
• This highlights that current treatment of asthma (only symptom-based) is not sufficient and the chronic remodelling/inflammation should be targeted early for true disease-modifying effects.
• Asthma that is not well controlled can progress to COPD through the remodelling effects

Question 22

List the long-term physiological consequences of asthma:

Answer 22

• Increased airway resistance leads to decreased VQ
  
  • Hypoxia
  • Hypercapnia
  • Respiratory acidosis
• Decreased expiratory volume leads to lung hyperinflation
  
  • Resulting in:
    
    • Compression of the pulmonary vasculature
    • Pulmonary hypertension
      
      • Cor pulmonale
        
        • Abnormal enlargement of right side of heart
• Status ashtmaticus
  *

Question 23

Explain how asthma can result in hypoxia and respiratory acidosis

Answer 23

• Increased airway resistance leads to an increase in force required to move air out of the lungs
  
  • Manifests as wheezing and is a sign of the increased work of breathing
  • This decreases the ventilation of some alveoli, decreasing VQ
    
    • leading to VQ mismatch
  • Ventilation-perfusion mismatch (V/Q) leads to reduced gas exchange, resulting in progressive:
    
    • hypoxia,
    • hypercapnia,
    • respiratory acidosis.
• Lactic acidaemia can occur in some patients, this leads to decreased CNS activity and fatigue and fatal ventilatory depression

Question 24

Explain how asthma can result in pulmonary hypertension

Answer 24

• Decreased expiratory flow leads to lung hyperinflation resulting:
  
  • Compression of the pulmonary vasculature
  • Pulmonary hypertension
    
    • Cor pulmonale
      
      • Abnormal enlargement of right side of heart
  • Increased risk of right heart failure
  • Increased risk of pneumothorax
    
    • due to a higher alveolar pressure

Question 25

Explain status ashmaticus. Why does it result in alkalosis and then acidemia?

Answer 25

* **Status asthmaticus (SA)** is an acute, severe asthmatic exacerbation (attack) that is often resistant to normal treatment. * It has a number of physiological consequences, that occur in a stepwise manner, described by the mechanisms below: * This also displays how asthma is not always purely just bronchoconstriction mediated 1. The initial trigger of SA leads to an **acute inflammatory response** * In 80% it is due to viral infection * Shown by lung sample PCR 1. **Oedema** in the **lung parenchyma** and in the **airways** * **Decreasing lung compliance** 1. The oedema and increased work are detected by and **stimulate juxtacapillary receptors** resulting in feelings of **dyspnoea** but there is **no actual gas exchange impairment** * Juxtacapillary receptors are located within the alveolar walls and are innervated by the vagus nerve * Stimulation of J-receptors causes a reflex **increase in breathing rate** which is responsible for **dyspnoea** (shortness of breath) * Because there is no actual gas exchange impairment, arterial blood gases are normal or even with a raised PO₂ 1. The **increased work & dyspnoea** lead to an increased ventilation rate leading to **alkalosis** * This leads to an increase in blood pH and a decrease in free calcium, as plasma proteins donate their protons and become **negatively charged, binding calcium** * This results in the loss of the **Faraday cage effect** on voltage-gated calcium channels leading to **CNS hyperexcitability** and contributing to the anxiety of the patient 1. As the attack persists, there is a further increase in the **oedema** and **bronchoconstriction** leading to **acidaemia** * This impairs the exhalation of air leading to **hyperinflation** * Hyperinflation is initially beneficial as it pulls the airways open, however there is no static equilibrium leading to CO₂ retention, due to the **increased resistance to flow** * The pH falls as PCO₂ increases, giving a false normal ABG which then is a sign of consequent **acidaemia** 1. The work of breathing is increased, with impaired gas exchange leading to **anaerobic respiration** of the respiratory muscles contributing to the acidaemia 2. The **acidaemia** can lead to fatigue and result in the patient losing the motivation to breathe which can be fatal by hypoxia

Question 26

Treatment for status asthmaticus

Answer 26

* **Oxygen therapy** * Increases the FIO₂, which increases the alveolar O₂ through the alveolar gas equation * P alveolar = inspired O₂ – (PaCO₂ / RQ) * Raises PAO2 for diffusion * **Magnesium sulphate** * Bronchodilator * Used after beta-agonist and anticholinergic agents have been tried * Thought that Mg acts by inhibiting calcium channels in the smooth muscle of the airways, preventing calcium induced contraction * It can also reform the faraday cage on VGNaC, decreases CNS excitability and reduce the anxiety associated with asthma * **Hydration** * There is loss of water by hyperventilation, decreasing mucus viscosity leading to patients being unable to drink * Systemic SABA – (more side effects – tachycardia, low BP - but cannot inhale to deep parts of the lung

Question 27

List short and long-acting drugs used to treat asthma

Answer 27

* Short-acting drugs are used for quick relief of **symptoms**, while long-acting agents are used for **disease control** if attacks become more frequent or severe and prophylactically. * Short acting * Short acting beta 2 agonists * Muscarinic antagonists * Long acting * Glucocorticoids * Leukotriene receptor antagonists * Long acting beta2 agonists * Anti-IgE antibodies

Question 28

What are the two mechanistic categories for the treatment of asthma?

Answer 28

* **Bronchodilators** * act by relaxing bronchial smooth muscle, which counteracts bronchoconstriction and increases airway lumen diameter. * Beta-2 receptor agonists * Xanthines * **Anti-inflammatory drugs** * Glucocorticoids * Omalizumab * Cromones

Question 29

List examples of bronchodilators

Answer 29

* ​Beta-2 adrenoreceptor agonists * Xanthines * Muscarinic antagonists

Question 30

Discuss short and long-acting beta-2 adrenorecpetor agonists. What are their mechanism of action, side effects etc?

Answer 30

* The most important bronchodilators are the **b₂-adrenoceptor agonists**. * **Mechanism of action** * They act on **bronchial smooth myocytes**, provoking relaxation and bronchodilation by activation of the **G_s** cascade, which involves an **increase in [cAMP]_i** and consequent **inhibition of myosin light chain kinase.** **Short acting** * **Short acting** **b₂** adrenoceptor agonists such as **salbutamol** and **levalbuterol** rapidly reverse airway obstruction and are used to relieve acute symptoms. * **Administration** * They are normally administered by aerosol using a metered-dose inhaler. **Time course** * Their onset of action is 5 minutes, with peak effect achieved in 30-60 minutes and a duration of action of 4-6 hours. **Side effects** * **Increase anxiety** * Increasing SNS activity leads to increased feeling of anxiety which can exacerbate asthma * **Tachycardia** * **Non-selectivity** * Via non-selective action on cardiac b₁ * To increase CO when there is a lowered oxygen supply (in extreme cases) leading to acidaemia * Cardiac dysrhythmia * Hypokalaemia (via PKA-mediated stimulation of the Na⁺/K⁺ ATPase leading to K⁺ movement into cells) * Tremor **Resistance** * A major problem with b₂ agonists is that overuse causes resistance by **receptor** **desensitisation**, leading to a loss of efficacy and worsening of the asthma. * They should therefore only be used when needed. **_Long acting_** * **Long acting** b₂-agonists include salmeterol and formoterol. * They are given regularly (twice daily) independently of symptom episodes as an **adjunct** if steroid therapy is inadequate. * They are effective when used in combination with inhaled **glucocorticoids**. * They are associated with **fewer** side effects due to higher b₂ selectivity.

Question 31

Discuss the usage of xanthines. Why are they less popular nowadays?

Answer 31

* The **xanthines** promote bronchodilation by **inhibition of phosphodiesterase** isozymes in bronchial smooth muscle, with resultant increases in [cAMP]_i or [cGMP]_i that promote relaxation. * Examples include: * **Aminophylline** (short acting) * **Theophylline** (long acting). * A number of limitations have made the xanthines less popular 1. **Narrow therapeutic concentration range** 2. **Side effects** * Dysrhythmia * Seizures * Insomnia 3. **Metabolism** by liver P450 enzymes, therefore the half-life is increased in liver disease and viral infections and decreased in heavy smokers (enzyme induction). 4. **Interactions with other drugs** * Antibiotics interfere with P450 expression * Asthma precipitated by a chest infection is often treated with **clarithromycin**, therefore the xanthine dose must be altered to **avoid toxicity**.

Question 32

Discuss muscarinic antagonistic drugs. What is their mechanism of action and what are their limitations?

Answer 32

* Examples * **Ipratropium** (short acting) * **Tiotropium** (long acting) * **Mechanism** * **M₃ blockade** * **Smooth muscle** * Blockade of smooth muscle M₃ mAChRs promotes bronchodilation by downregulation of the **G_q** cascade that promotes contraction via an **IP₃-mediated** increase in [Ca²⁺]_i. * During asthma exacerbations, there is an increased sympathetic drive, however residual PS activity is also present * ACh is released with VIP that under normal conditions, dampens the effect of ACh at the mAChR * In the inflammatory conditions, proteases from **eosinophils** lead to VIP breakdown and thus ACh is more potent * Mucus * M₃ on mucus-secreting cells is also blocked, decreasing mucus production * **M1 blockade** * Inhibition of the **M₁** mAChR in the **parasympathetic ganglia** inhibits cholinergic transmission, contributing to both **smooth muscle relaxation** and **decreased mucus secretion** * **Limitations** **1)** **Slow acting** * The mAChR antagonists are **slower acting**, and therefore less useful in managing acute asthma attacks. **2)** **Low efficacy** * They are also **less effective** than b₂ agonists and thus may be given to patients who are unable to use salbutamol or as an adjunct for moderate to severe exacerbations **​ 3) Low selectivity** * They are given as inhalers whenver possible to reduce side effects mAChR antagonists are **not very selective**, thus are given in inhalers where possible to reduce side effects.

Question 33

List examples of anti-inflammatory drugs used to treat asthma

Answer 33

* Glucocorticoids * Antileukotrienes * Omailizumab * Cromones

Question 34

List examples of glucocorticoids

Answer 34

* **Beclomethasone** * **Fluticasone**

Question 35

Explain the mechanism of action of glucocorticoids

Answer 35

* GCs act by binding to intracellular **glucocorticoid receptors** that modulate the **transcription** of genes encoding proteins involved in inflammation and thus have broad immunosuppressive action. * Targets that are **downregulated** include: * **Cyclo-oxygenase 2** (COX-2) * Enzyme that synthesises **PGE₂** and **PGI₂** * **Phospholipase A₂** * Enzyme **that** synthesises **prostaglandins** and **leukotrienes** * Production of the pro-eosinophil cytokines **IL-5** and **IL-3.** * **Induced** targets include: * **Annexin-1** * **Inhibitor** of **phospholipase A₂** results in more inhibition of synthesis of prostaglandins and leukotrienes * **b₂ adrenoceptors** * Potentiate the action of b₂ agonists

Question 36

Give experimental evidence illustrating that glucocorticoids inhibit mediator release

Answer 36

* Evidence that glucocorticoids inhibit the release of **inflammatory mediators** comes from an experiment by **Gryglewski et al (1975).** * Method * The lungs of **guinea pigs** sensitised to antigen were perfused and the effluent fluid delivered to a bath containing a **rat stomach strip**. * The **tone** of the strip was recorded and used as a measure of prostaglandin and histamine release from the lung upon challenge with **antigen**. * The administration of **hydrocortisone** during challenge significantly decreased prostaglandin and histamine release compared to control challenge

Question 37

Explain the effect of glucocorticoids

Answer 37

* Because they affect transcription, GCs act on a **long timescale** and their effects are gradual (6—12 hours). * Beneficial tissue effects of GCs include: * (1) Reduced numbers of **eosinophils** **and T cells** in the airway wall due to induction of apoptosis. * (2) Reduced **epithelial cell** injury * (3) Reduced airway **vascularity** * (4) Decreased bronchial **hyper-responsiveness** to irritants

Question 38

Descrieb the advantages of glucocorticoids

Answer 38

* The great benefit of GC therapy is **decreased progression** of chronic asthma (disease modification), rather than pure symptom relief. * GC therapy strongly decreases the **incidence** and **severity** of asthma

Question 39

Dicuss the limitations of glucocorticoids

Answer 39

* **Side effects** * **Side effects** Above 400 mg per day, severe side effects may be apparent such as * Increased risk of **infection** due to immunosuppression * particularly oral candidiasis and chest infection * Stunted growth * Muscle wasting * Gastric ulceration * Bone weakness * Fluid retention * **Inhaled glucocorticoids** are associated with fewer **systemic side effects** * Their action is **mainly restricted to the lungs** * **Symptom-treating** * Another limitation is that GCs do not **cure** asthma (symptoms recur weeks to months after withdrawal), therefore most patients require **long term** or **lifelong** treatment (and side effects) * **Resistance** * In addition, GC **resistance** can develop in chronic asthmatics for reasons that are not completely understood. * It may be linked to a decrease in GC receptor number or reduced activity of **histone deacetylase**, which has been implicated in smokers. * **Variable response** * Furthermore, GC efficacy depends on the **asthma phenotype**. * GCs are more effective in patients with high **eosinophil counts** than those with low counts. * *Patients on high doses of steroids are considered for mcAB therapy*

Question 40

Give examples of antileukotrienes

Answer 40

* Montelukast * Zafirlukast

Question 41

Discuss antileukotrienes

Answer 41

* The **leukotriene receptor antagonists (LRAs)** such as montelukast and zafirlukast block the action of the cysteinyl leukotrienes C₄, D₄, and E₄ at the **cysteinyl leukotriene receptor type 1 (CysLT₁).** * **Effects** include: * Bronchodilation * Decreased blood eosinophil count * **Evaluation** * Because of their selectivity they are not as **effective** as GCs, but they also have **fewer side effects** and are thus a useful alternative.

Question 42

Discuss the mechanism of omalizumab

Answer 42

* **Omalizumab** is an anti-IgE monoclonal antibody (Ab) that decreases the frequency of exacerbations in asthma of varying severities. * **Mechanism** * It binds to **the Fc portion** of IgE that recognises **the Fc receptor** (FceR1) on the surface of mast cells and basophils. * It therefore prevents the **coating** of these cells with allergen-specific IgE (from plasma cells), preventing mast cell activation and the release of inflammatory mediators. * It also promotes **downregulation** of the FceR1.

Question 43

What are the advantages to omalizumab?

Answer 43

* Potential benefits of omalizumab include improved asthma control, with the possibility of a reduction in the use of oral corticosteroids, fewer presentations to emergency care, reduced exacerbations and improved quality of life. * Based on prospective studies. * **PERSIST study** * PERSIST study was a prospective, open label, observational, open-centre study in 158 patients with severe persistent allergic asthma. * The effectiveness of omalizumab as add-on therapy was evaluated after 16 and 52 weeks of treatment and compared to the year prior to starting therapy. * Patients had better physician-rated effectiveness, greater improvements in quality of life, greater reductions in exacerbation rates and greater reductions in healthcare utilisation than previously reported in efficacy studies.

Question 44

What is the disadvantage of omalizumab?

Answer 44

* The **high cost** of omalizumab limits its use to moderate and severe persistent asthma when other treatments have proved inadequate or cannot be tolerated. * clinical efficacy takes longer to emerge as the IgE bound to mast cells and basophils takes several weeks to be downregulated.

Question 45

Discuss cromones

Answer 45

* Cromones are a type of anti-inflammatory drug used as a prophylactic treatment * Not used anymore * Mechanism * Traditional view * **Blocks Cl^- channels** resulting in **mast cell depolarisation** and reducing the electrical gradient for calcium entry through the **CRAC** and thus decrease granule release * CRAC = calcium release activated channel – opens when ER is depleted of Ca²⁺ to replace the lost calcium * Debated as in human mast cells other drugs have been shown to stabilise mast cells better but do not improve asthma outcomes * Alternative view * **Increase** production of **bradykinin** and **metabisulphite** that act on sensory nerves and reduce their firing, decreasing neurogenic stimulation for constriction. * **Block** the release of **substance P** from neurones in the bronchial plexus * Advantage * *Only* asthmatic that works both in early and late stage * Relatively few side effects * Very safe * Disadvantage * Skin rash, dizziness, headaches, heart burn * Not used anymore as they worked in only around 5% of people

Question 46

What are the non-pharmacological treatments of asthma attacks?

Answer 46

* **Humidifiers** * Increase the air humidity and decrease the viscosity of the mucus to ease the removal of the mucus plug * **Mechanical ventilation** * Although it would seem to be of obvious use in asthma attack where there is fatigue of the respiratory muscles, it blows the mucus plug further into the airway – preventing the reversal of symptoms * Increases risk of hyperinflation and pneumothorax, atrophy of the diaphragm over a long period of time, damage to the cilia * **Blows to the back** * Removes the mucus plug

Question 47

What are the reasons to develop new drugs?

Answer 47

* Reasons for new drugs: * **Drug ineffectiveness** * Conventional treatments are ineffective in 5-10% of asthmatics * **Asthma** **subtypes** * it has been recognised that asthma is a **heterogenous** disease with different subtypes based on the underlying inflammatory mechanisms. * This may explain: 1. The lack of a perfect therapy, as current treatments are not tailored to patient-specific disease processes. 2. The variable effectiveness of targeted treatments such as the **antileukotrienes** and **omalizumab** * Further understanding of asthma subtypes may lead to targeted treatment strategies that match therapy to the underlying pathology, in place of a standard anti-asthma regime * **Drug action** * Current drugs are only symptom-modifying * Current drugs are not disease modifying, they do not act to prevent / reverse the airway remodelling * **Side effects** * Difficult to modify asthma mechanisms without incurring side effects * Poor understanding of underlying mechanisms, especially in intrinsic asthma