Asthma Flashcards
What is asthma?
A common chronic inflammatory condition of the airways in which there is reversible airway obstruction
Classically asthma has which 3 pathophysiological characteristics?
- Airflow limitation (reversible spontaneously or w/ treatment)
- Airway hyperresponsiveness to a wide range of stimuli
- Bronchial inflammation with T cells, mast cells, eosinophils with associated plasma exudation, oedema, smooth muscle hypertrophy, matrix deposition, mucus plugging and epithelial damage
What are the symptoms and signs of poorly controlled asthma?
- Intermittent dyspnoea
- Wheeze
- Cough
- Sputum
- Chest tightness
Often worse at night and reversible
Give a differential diagnosis for wheeze
- asthma
- COPD
- acute viral or bacterial bronchitis
- acute ventricular failure
- anaphylaxis
- PE
- pneumothorax
- inhalation of foreign body
- sleep apnoea
- obstructive heart failure
- lung cancer
Which clinical features increase the probability of asthma in adults?
- Wheeze, SoB, chest tightness
- Diurnal variation
- Response to exercise, allergen, cold air
- Symptoms after aspirin or B-blocker
- History of atopy
- Family history of atopy/asthma
- Widespread wheeze heard on auscultation
- Unexplained low FEV1 or PEF
- Unexplained peripheral blood eosinophilia
What investigations are used to confirm the diagnosis of asthma?
- FEV1/FVC ratio - <80% of predicted
- FEV1 - <80% of predicted
- Bronchodilator should show 15% improvement in spirometry^
If both above are normal but there are signs/symptoms of asthma then do pulmonary function tests before and after a methacoline challenge(*)
- Peak expiratory flow rate - on walking, prior to taking bronchodilator and before bed after bronchodilator, compare patient’s to personal best/normal values for height + gender (reference) -> show diurnal variation
- Chest X-ray - normal or hyper-inflated (exclude pneumothorax)
- FBC - normal or raised eosinophils and/or neutrophilia
- Bronchial challenge test - positive - methacholine or histamine, tests airway hyperresponsiveness, good for those mainly presenting with cough, don’t do in those w poor lung function/history of brittle asthma or in kids
- Immunoassay for allergen-specific IgE - positive
- Skin prick allergy testing - positive
- Sputum eosinophillia - increased
- Exercise test (children) - FEV1 decreases
- Trial of corticosteroids - prednisolone, measure lung function before + after (>15% improvement)
What are the aims of asthma treatment?
to..
- abolish symptoms
- restore normal or best possible lung function
- reduce risk of severe attacks
- enable normal growth in children
- minimise absence from school/employment
How are aims of asthma treatments met?
- patient and family education about asthma
- patient and family participation in treatment
- avoidance of identified causes where possible
- use of the lowest effective doses of convenient medications to minimise short term and long term side effects
What extrinsic factors can be controlled to manage asthma?
- Avoid causative allergens (dustmites, pets, moulds, foods)
- Avoid active/passive smoking
- Investigate all possible occupational causative agents
- No beta-blockers in eye drop or tablet form
- Aspirin intolerent individuals should avoid dietary salicylates and NSAIDs
How are asthma medications delivered to patients and why is this important/useful?
- As aerosols or powders directly into lungs
- Delivered direct to the airways and first-pass metabolism in the liver is avoided
- Lower doses necessary and systemic unwanted effects minimised
What is the stepwise management of asthma?
- Step 1: occasional short-acting inhaled B2 agonist as required for symptom relief (eg. salbutamol), if used more than once daily or night-time symptoms, move to step 2
- Step 2: add standard dose inhaled steroid (eg. beclometasone)
- Step 3: add long-acting B2 agonist (eg salmeterol), continue inhaled corticosteroid, if no effect stop LABA and increase ICS. Leukotriene receptor antagonist (eg montelukast) or oral theophylline may be tried or LAMA
- Step 4: increase high-dose inhaled corticosteroids up to 2000μg, plus regular LABA plus either LTRA or modified release oral theophylline or B2 agonist or LAMA
- Step 5: add regular oral CS (prednisolone) at lowest possible dose (on top of prev therapy/ICS)
- Step 6: hospital admission / referral
Both national and international guidelines have been published on the stepwise treatment of asthma, based on which 3 principles?
- Asthma self management with regular asthma monitoring using PEF meters + individual treatment plans that are discussed with each patient + written down
- The appreciation that asthma is an inflammatory disease + that anti-inflammatory therapy should be started even in mild cases
- Use of short-acting inhaled bronchodilators (eg salbutamol) only to relieve breakthrough symptoms. Increased use of bronchodilator treatment to relieve increasing symptoms is an indication of deteriorating disease
Why do we use B2-Adrenoreceptor agonists for asthma?
- Selective for respiratory tract
- Do not stimulate B1 adrenoreceptors on myocardium
- Potent bronchodilators as they relax bronchial smooth muscle
- Relieve symptoms but do little for underlying inflammation
- SABAs (salbutamol + terbutaline) - 2 puffs when required, for mild asthma only
- LABAs (salmeterol + formoterol) - must always be given with inhaled CS
What is the mechanism of action of B2-agonists?
- B2 receptors found in smooth muscle of bronchi, GI, uterus + blood vessels
- Stimulates Gs pathway -> increased cAMP -> PKA -> Phosphorylates MLK -> smooth muscle relaxation
- Improved airflow in constricted airways
- B2-agonists also stimulate Na/K-ATPase pumps
- Causing shift of K+ from extracellular to intracellular compartment
- Useful adjunct in treatment of hyperkalaemia
What are side-effects of B2 agonists?
Acitvation of B2-receptors in other tissues accounts for the common ‘fight or flight’ adverse effects
- Tachycardia
- Palpitations
- Anxiety
- Tremor
- Increased serum glucose conc
- Muscle cramps (LABAs)
How do antimuscarinic bronchodilators help in asthma? Examples?
- M3 receptors found in large airways
- Peripheral lung tissue contains M3 and M1 receptors
- Stimulated by ACh -> parasympathetic effect (eg. bronchoconstriction)
- Blocking receptors -> bronchodilation
- Non-selective short acting muscarinic antagonists:
- Ipratropium bromide
- Long acting antimuscaranic:
- Tiotropium
List precipitating factors, including drugs, for an asthma attack
- Dust mite (+ its faeces), pollen, fur
- Viral infections
- Cold air
- Exercise
- Vapours + fumes: cig smoke, perfume, exhaust fumes
- Emotion
- Drugs: NSAIDs, beta-blockers
What would you say to a patient on how to reduce exposure to allergens including house dust and house dust mite?
- Keep windows and doors closed
- Keep pets out of bedroom / house
- Minimise household humidity
- Use “mite-proof” cases on mattresses and pillows; wash bed linens frequently in hot water
- Install a high-efficiency media filter in your furnace and air conditioning unit
- Discourage smoking
- Avoid household pets
- Identify + remove occupational exposure asap
Inhaled corticosteroids:
- examples
- common indications
- beclometasone, budesonide, fluticasone
- asthma: treat airways inflammation and control symptoms at ‘step 2’ of therapy where asthma is not adequately controlled by a short-acting B2-agonist alone
- COPD: control symptoms + prevent exacerbations in pts who have severe airflow obstruction on spirometry and/or recurrent exacerbations. ICS are usually prescribed in combo w/ LABA and/or LAMA (antimuscarinic bronchodilator)
What is the mechanism of action of inhaled corticosteroids?
- corticosteroids pass through plasma membrane
- interact w/ receptors in cytoplasm
- activated receptor then passes into nucleus
- to modify transcription of large # of genes
- pro-inflammatory interleukins, cytokines, chemokines downregulated
- while anti-inflammatory proteins upregulated
- in airways:
- reduced mucosal inflammation
- widens airways
- reduces mucus secretion
- this improves symptoms and reduces exacerbations in asthma + COPD
What are the important adverse effects of inhaled corticosteroids?
- immunosuppressive -> oral candidiasis
- hoarse voice
- COPD -> cause pneumonia
- few systemic adverse effects
What are the indications for systemic corticosteroids (eg. prednisolone)?
- to treat allergic or inflammatory disorders eg. anaphylaxis, asthma
- suppression of autoimmune disease, eg. IBD, inflammatory arthritis
- in treatment of some cancers as part of chemo or to reduce tumour-associated swelling
- hormone replacement in adrenal insufficiency or hypopituitarism
What is the mechanism of action of systemic corticosteroids?
- exert mainly glucocorticoid effects
- bind to cytosolic glucocorticoid receptors
- receptors translocate to nucleus
- bind to glucocorticoid-response elements -> regulate gene expression
- systemic CS commonly prescribed to modify immune response
- they upregulate anti-inflammatory genes
- downregulate pro-inflammatory genes (cytokines, TNF-a)
- direct actions on inflammatory cells incl suppression of circulating monocytes + eosinophils
- metabolic effects -> inc gluconeogenesis
- also have mineralocorticoid effects -> stimulate Na+ and water retention and K+ excretion in renal tubule
What are the important adverse effects of systemic corticosteroids?
- immunosuppression -> inc risk of infection
- metabolic: DM, osteoporosis
- Inc catabolism -> prox muscle weakness, skin thinning w/ easy bruising + gastritis
- mood + behavioural: insomnia, confusion, psychosis + suicidal
- hypertension, hypokalaemia, oedema (from mineralocorticoid actions)
- suppresses pituitary ACTH secretion, switching off stimulus for normal adrenal cortisol production, in prolonged tx -> adrenal atrophy
- if corticosteroids withdrawn suddenly -> acute Addisonian crisis w/ CV collapse
- slow withdrawal required to allow recovery of adrenal fxn
- symptoms of chronic glucocorticoid deficiency occur during tx withdrawal -> fatigue, weight loss, arthalgia