Case 7- asthma Flashcards
Intrinsic asthma
Causative agent is unknown but may be associated with irritants or sensitisation to chemicals or biological products at work. Aspirin and beta blockers may induce asthma. Triggers include: exposure to chemical agents/drugs, exercise, respiratory infection or stress.
Extrinsic asthma
In atopic individuals with reactions to common allergens like dust mites, animal dander and pollens. More common in childhood where it is associated with eczema. Triggers include: allergens i.e. pollen, dust mites, animals, peanuts and eggs
Symptoms of asthma
Wheezing, shortness of breath and cough. Tends to be more severe at night or in the early morning
What causes an asthma attack
Normally a trigger such as exposure to dust, cold air or exercise
What causes the symptoms of asthma
Reversible airway obstruction, inflammation of airways, bronchial hyper-reactivity. Acute episodes of asthma can cause Hypoxaemia (abnormally low amounts of oxygen in the blood)
Pathophysiology of asthma
Asthma occurs due to a sustained inflammatory response. There is an infiltration of the airway wall with pro-inflammatory lymphocytes and mast cells which release cytokines and also eosinophils. This leads to swelling of the airway wall due to smooth muscle thickening or hypertrophy, a thickened basement membrane and the leaking of fluid from dilated blood vessels (oedema). This is associated with damaged epithelial cells, increased mucus production and bronchospasm which together may significantly reduce the airway lumen causing obstruction of movement of air.
The immediate phase of asthma
Begins within minutes of contact with the trigger and may last several hours, it mainly consists of shortness of breath and wheezing. It is when the mast cell degranulates leading to a bronchospasm
The late phase of asthma
Follows the immediate phase with sustained breathlessness and wheezing associated with an inflammatory response. It is when inflammatory cells like eosinophils release mediators. The late phase is a sustained inflammatory response
Asthma- irreversible remodelling
After years of repeated allergen exposure and exacerbation, there is remodelling of the airways
Irreversible remodelling- ciliated epithelial damage
Increases risk of secondary infections as it is easier for micro-organisms to get into the Lamina propria
Irreversible remodelling- mucus production
There is an increase in mucus production due to Goblet cell metaplasia, the epithelia cells undergo a differential change and turn into Goblet cells. There is also an increase in the number of mucus glands and the volume of mucus secreted by both the goblet cells and mucus glands.
Irreversible remodelling- basement membrane
In the inflammation and repair process, the ciliated epithelium undergoes fibrosis. This increases the thickness of the basement membrane
Irreversible remodelling- smooth muscle
Increase in airway smooth muscle, this can be due to Hyperplasia (increased number) or Hypertrophy (increased size). The smooth muscle is able to constrict the bronchiole even more.
Irreversible remodelling- immune cells
Immune cell infiltration causes an increase in Macrophages, Mast cells and Eosinophils. They get into the Lamina propria.
Irreversible remodelling- vascular changes
There is vasodilation and an increase in vascular permeability. This helps the Leukocytes get into the Lamina propria
Irreversible remodelling- chronic inflammation
Chronic inflammation- all the changes lead to a narrow airway and a decrease in bronchiole lumen diameter
Pathology of asthma
1) An allergen enters the bronchioles and damages the epithelial barrier
2) The allergen is phagocytosed, there is antigen presentation and activation of B cells
3) Mast cells are sensitised, secondary exposure to the allergen causes Mast cell degranulation
4) Histamine, Leukotrienes and Prostaglandins are releases
Risk factors for asthma
- Family history of Atopy and genetics (6x)
- Maternal smoking, can lead to epigenic changes in the foetus,
- Bronchiolitis, especially if hospitalised.
- Premature/low Birth rate
- Urban environment
- Early antibiotic exposure, remove commensal and pathogenic bacteria. Cant test out their immune system.
Protective factors for asthma
Vaginal birth, breast feeding, large number of siblings, daycare attendance and animal exposure. Increases the number of pathogens you will be exposed to so trains your immune system to respond appropriately.
Airway hyper-responsiveness
Often induced with asthma. Involves exaggerated bronchoconstriction and breathlessness. It is a combination of both hypersensitivity to a stimulus and a larger response then expected. You are more susceptible in asthma due to the damaged epithelia exposed nerves
Hypersensitivity
A normal response but at lower levels of stimulus
Hyperreactivity
An exaggerated response at normal doses of the stimulus.
Types of asthma
Atopic or non-atopic
Non-atopic asthma triggers
Exercise, smoking, emotions, the cold, a viral infection
Atopic asthma exposure
Environmental exposures to allergens (i.e. pollen, pets, mold). Irritant dusts, vapour and fumes (i.e. perfume, smoke). Medication (NSAIDs, B-blockers). Atmospheric pollution and occupational sensitisers.
Why do NSAID’s cause asthma
They block the effects of Prostglandins. Leukotrienes are released instead causing an immune response
Why do beta blockers cause asthma?
They block beta adrenergic receptors which are responsible for bronchodilation, this causes bronchoconstriction
How does physical exercise and cold air induce asthma
1) There is an increase in ventilation and air flow through your mouth.
2) This causes respiratory induced water loss from the respiratory cells. This is due to the difference in temp between the external air and your mouth.
3) This causes an increase in intracellular osmolarity.
4) This will cause an influx of intracellular Ca+, activating a signalling cascade leading to the activation of Phospholipase.
5) This causes the Mast cell to degranulate releasing Histamine leading to bronchoconstriction and increased Mucus production.
6) Prostoglandin and Leukotrienes are also released which are inflammatory mediators leading to immune cell recruitment.
What inhaler should you take before exercise
The blue preventative inhaler which is a beta-2 Adrenergic agonist- Salbutamol
Lung sensitizer
Something which increases a persons pre-disposition to develop a lung disease
Occupational lung sensitizers
People who work in these jobs are more likely to develop a lung disease. Normally due to long term exposure but can be from a single hazardous agent.
How to prevent occupational lung diseases
With Hypoallergic materials and chemicals, PPE and ventilation
Cause of asthma in a farmer
Allergens from animals and insects. Will also affect lab workers
Cause of asthma in health care workers
Latex, antibioitics
Cause of asthma metal refining
Complex salts of platinum
How can the immediate phase of an asthma attack be treated?
This can be treated with beta2- adrenoceptor agonists, CysLT-receptor antagonists and theophylline. Cysteinyl LT1 receptor antagonists are a type of leukotriene receptor antagonists.
How can you treat the late phase of an asthma attack?
Glucocorticoids- the lowest effective dose should be used to avoid adverse effects
The aims of pharmacological interventions in asthma
Abolish symptoms, restore normal or best possible lung function, reduce the risk of severe attacks, enable normal growth to occur in children and minimise absence from school or treatment.
Prevention and asthma
Education about managing treatment is important, especially to the family and school. Avoiding coming into contact with triggers is advised.
Newly diagnosed asthma treatment
Newly diagnosed patients may use a short acting beta-2-agonist (SABA) when they need to relieve symptoms, they may also consider a low dose inhaled Corticosteroid (ICS) to control the frequency of asthma episodes.
The initial add on therapy for asthma
Adding a long acting beta2-agonists (LABA)
Second add on therapy for asthma
1) Consider increasing ICS to the medium dose
or
2) Adding a Leukotriene receptor antagonist (LTRA)
If there is no response to LABA consider stopping it
Highest step for asthma treatment
Refer the patient to specialist care, maybe use an oral corticosteroid
Uncontrolled asthma
Asthma that has an impact on a persons life and restricts their normal activities
Thresholds to define uncontrolled asthma
3 or more days a week with symptoms or 3 or more days a week with required use of a SABA or symptomatic relief or 1 or more nights a week with awakening due to asthma.
Mechanism of action of bronchodilators
They stop membrane bound phospholipids from entering the arachidonic acid metabolism pathway, which produces lots of signalling molecules
Mechanism of action of Corticosteroids (bronchodilator)
Blocks the enzyme Phospholipase A2 which makes Arachidonic acid. It also blocks the enzyme Cyclooxygenase from producing Prostaglandins. This inhibits the production of pro-inflammatory mediators and the bronchoconstrictor prostaglandin
Mechanism of action of Leukotriene antagonists and 5-lipoxygenase inhibitor
It blocks the production of Leukotrienes from Arachidonic acid, using the enzyme 5-lipoxygenase, blocking its inflammatory and bronchoconstrictor effect.
Classification of asthma treatment
Drugs used to treat asthma may be classified as Relievers or Preventers/controllers (Mathylxanthines are both)
Asthma treatment- relievers
Beta 2 adrenoreceptor agonists, Methylxanthines and Anticholingerics.
Asthma treatment- Preventers/controllers
Anti-inflammatory agents, corticosteroids and leukotriene receptor antagonists.
Metered dose inhalers
They use a compressed gas (freon) which propels a fixed dose of a drug. There needs to be coordination between inhalation and activation of the device to ensure the drug passes down the respiratory tract to the target
Drug powder inhaler
The act of inhalation creates turbulent flow which scatters the drug powder moving down the respiratory tract
Nebulisers
Can be used at hospitals and at home. They use compressed gas to create a mist of drug particles permitting deep penetration down the respiratory tract
Asthma treatment- beta 2 agonists
Cause relaxation of airway smooth muscle by increasing cAMP through activation of Gs protein coupled receptors, they act as a physiological antagonist to bronchoconstrictor mediators. BRONCHODILATOR. Can be given via IV in life threatening situations.
Short-acting beta2 agonists SABA
Salbutamol, terbutaline- commonly used as needed for infrequent episodes and also for acute exacerbation. Maximum effect is 30 min but lasts 3-5 hours.
Longer acting beta 2 agonists LABA
Salmeterol, formoterol- these drugs are used for regular twice daily administration, they have a slow onset so are not used for an acute episode. Last for 12 hours and are used in addition to corticosteroids. Side effects are minimised with delivery via inhalation, you may get muscle tremors at high doses as well as tachycardia and a risk of cardiac dysrhythmia.
Leukotriene receptor antagonists
Examples include montelukast, zarfirlukast. These drugs block the Cysteinyl LT1 receptor located on the respiratory mucosa reducing the infiltration of inflammatory cells. This reduces exercise-induced asthma, the response to inhaled allergens and reduces the acute response to aspirin in sensitive patients. It can be administered orally 1-2 times daily and undergo extensive metabolism and biliary excretion. LTRA’s are often used in combination with steroids if a patient does not respond to beta2 agonists.
Side effects of Leukotriene receptor antagonists
Abdominal pain, thirst and headache
Methylxanthines
They are phosphodiesterase inhibitors preventing the breakdown of cAMP in cells causing smooth muscle relaxation. Can be administered via IV for treatment of severe acute asthma. The drug may be administered as a 2nd line drug treatment in addition to steroids in patients who respond poorly to beta2 agonists. Narrow therapeutic window. Adverse effects can be significant and include cardiac dysrhythmias, seizures, tremor, positive inotropic/chronotropic actions on the heart and insomnia.
Methylxanthines example
Theophylline which causes bronchodilation and a reduction in the late phase effects of asthma
Examples of antimuscarinic drugs
Ipratropium (derived from atropine) and tiotropium
Antimuscarinic drugs
Are muscarinic (M3) receptor antagonists which cause bronchodilation and reduce mucus secretion. They can be used in addition to beta 2 agonists and steroids but they are mostly used to treat COPD. They increase mucociliary clearance. Administered by inhalation (3-4 times daily) and are highly absorbed via the respiratory epithelium with ~8% bioavailability. If these drugs are taken orally bioavailability drops to 2%. Onset is 30-60 minutes and lasts 4-6 hours. Side effects include dry mouth, gastrointestinal motility disorder(constipation), tachycardia and nausea
Examples of inhaled corticosteroids ICS
Beclomethasone, budesonide
When to use inhaled corticosteroid ICS
Not bronchodilators but a preventative form of medication , can take weeks till they achieve their full effect. They are administered via metered dose or dry powder inhalers.
Mechanism of action of inhaled corticosteroid ICS
- Reduced transcription and decreased formation of pro-inflammatory cytokines, Th2 cytokines.
- Reduced activation of eosinophils.
- Reduced production of IgE.
- Reduced production of leukotrienes and PAF
- Inhibition of the cyclooxygenase pathway,
- Possible upregulation of beta 2 receptor expression.
Side effects of oral corticosteroid ICS
Prolonged use can lead to suppression of the immune response to infection, Crushing’s syndrome, Osteoporosis, Hyperglycaemia, Muscle wasting and inhibition of growth in children. So, its use is limited to a short time.
How oral corticosteroids produce their effect
The steroid is bound to albumin and corticosteroid binding-globulin (CBG) in the plasma and is in its inactive form. The steroid then enters the target cell by diffusion across the cell membrane where it binds to its intracellular steroid receptor in the cytosol before migrating to the nucleus where it interacts with DNA, modifying gene transcription and protein synthesis. Last 2-8 hours. Have anti-inflammatory, immunosuppressive and metabolic action.
How to treat a severe asthma attack
Oxygen (> 60%), Nebulised salbutamol and IV hydrocortisone followed by oral prednisolone. Other drugs may also be considered if the patient does not improve including: Nebulised ipratropium and IV salbutamol or theophylline (or aminophylline).
Sensitivity
Of all the people who have the disease it the percentage who are picked up on the test (true positives). Quantifies the avoidance of false negatives
Specificity
Of all those who do not have the disease, % who are correctly undetected by the test (false positives). The true negative rate
Positive predictive value (PPV)
Of all the people who test positive, its the percentage who actually have the disease
The cardinal symptoms of respiratory disease
- Chest pain
- Wheeze/cough
- Sputum (colour/amount)
- Odema
- Fever/general malaise
- Haemoptysis
- Breathlessness
- Pain
