Jane Slater LO's Flashcards
1
Q
Define asthma
A
- chronic inflammatory disease of the respiratory system characterized by bronchial hyper-responsiveness, episodic exacerbation (asthma attacks) and reversible airflow obstruction
- manifests with reversible cough, wheezing and dyspnea
2
Q
Clinical features of asthma
A
persistent dry cough that worsens at noight, with exercise or on exposure to triggers/irritants
End expiratory wheezes
Dyspnea
Chest tightness
Prolonged expiratory phase on expiration
Hyperresonance to lung percussion
Co-morbid atopic conditions (allergic rhinitis, eczema)
3
Q
Causes of asthma
A
Exact aetiology unknown
Risk factors include : family hx, past hx allergies, atopic dermatitis, low socioeconomic status, childhood exposure to secondhand smoke
4
Q
Airway hyper-responsiveness
A
- excessive bronchoconstrictor response to multiple inhaled triggers that would have no effect on normal airways
5
Q
Atopy/atopic
A
- genetic tendency to develop allergic diseases such as allergic rhinitis, asthma and atopic dermatitis (eczema)
- exaggerated IgE mediated immune response
6
Q
Types of asthma
A
- Atopic
- Non-atopic eg rhinovirus, parainfluenza virus
- Drug induced asthma
- Occupational asthma eg fumes, formaldehyde, organic and chemical dust and gases
7
Q
Airway resistance increases in asthma and how they relate to pathological changes of the airways
A
- diameter of airway
- whether airflow laminar or turbulent
8
Q
Factors that trigger asthma attacks
A
- atmospheric pollution
- dust
- pollen
- fumes
- cigarette smoke
- strong perfumes
- house dust
- mite and animal fur and hair
- cold air
- exercise
- infections
- anxiety
- NSAIDs (aspirin)
- Beta blockers
9
Q
NSAID’s and asthma
A
-NSAIDs reduce PGE2 in lungs, lowers partial inhibitory effect which PGE2 has on leukotriene synthesis and mast cell degranulation
10
Q
Beta blockers and asthma
A
block beta receptors through which bronchodilation is mediated via sympatheitc nervous system , can be used in patients with well controlled asthma
11
Q
Pathological changes seen in the airways in asthma
A
-
12
Q
Pathological changes seen in the airways in asthma (morphological)
A
- lungs overdistened due to overinflation, may be small areas of ateletasis (airway collapse)
- occlusion of bronchi and brochioles with mucous plug that contain:
13
Q
Immunological and inflammatory response in asthma and allergic rhinitis
A
- bronchial hyperresponsiveness –> bronchial inflammation –> ovrexpression of Th2 cells –> inhalation of antigen reesults in production of cytokines (IL3/4/5/13) –> activation of eosinophils and induction of cellular response (B cell IgE production). –> bronchial submucosal edema and smooth muscle coontraction –> bronchioles collapse
Increase in histmaine, leukotrienes and PG’s–> bronchoconstriction
Il4: class switching M to E
IL5: eosinophils produced
Il-9: mast cell activity
14
Q
Abnormalities in ABG’s in asthma attack
A
- initially respiratory alkalosis due to decreased CO2 (V/Q mismatch) –> reduced ventilation
- may progress to respiratory acidosis if bronchospasm not relieved –> indicative of severe exacerbation –> normal or increased O2 is a dangerous sign as patient can no longer hyperventilate –> indication for intubation/mechanical ventilation
15
Q
V/Q mismatch in asthma
A
reduced ventilation due to smooth muscle contraction, increasing resistance of airflow to alveoli
16
Q
O2 dissociation curve to right and factors
A
- less O2 on Hb, O2 in tissue
- CADET
- increased CO2
- increased acid (increased H+, decreased PH, acidosis)
- increased 2,3 DPG
- increased exercise
- increased temperature
- increased altitude
17
Q
Management of asthma
A
- reduce exposure to triggers
- Manage co-morbidities (obesity, rhinosinusitis, nasal polyps)
- Reduce risk of infection eg vaccines
- lifestyle (physical activity, stop smoking, self-monitoring)
- relievers/ preventers medication
18
Q
O2 dissociation curve to left and factors
A
- more O2 in Hb, Hb away from tissue
- CADET
- decreased CO2
- decreased acid (decreased H+, increased PH, alkalosis)
- decreased 2,3 DPG
- decreased/no exercise
- decreased temperature
- decreased altitude
- increased methemoglobin
- increased HbF
- increased CO
19
Q
FEV1
A
- forced expiratory volume: volume of air that is forcefully exhaled in one second
20
Q
FVC
A
- Forced vital capacity: volume of air that can be maximally forcefully exhaled after max inspiration
21
Q
FEV1/FVC
A
Ratio, expressed as a %, reflects amount of air you can forcefully exhale from your lungs, above 70% is normal
22
Q
Types of pulmonary function tests
A
- peak flow meter
- spirometry
- bronchial provocation tests
- bronchial reversibility tests
23
Q
Peak flow meter test (PFM)
A
Breath as deep as possible and blow as hard and as quickly as possible x3, record highest
Decreased peak expiratory flow during asthma attacks
24
Q
Spirometry
A
used to measure rate of airflow during maximal expiratory effort after maximal inhalation
distinguishes between obstructive and restrictive disease
Asthma: decreased FEV1 and FEV1/FVC ratio
25
Spirometry (obstructive)
patients cannot inhale air in lungs quickly
Decreased FEV1, FVC relatively preserved, FEV1/FVC ration below 70%
26
Spirometry (restrictive)
FEV1/FVC ration \>70% can be normal or restrictive
Absolute values FEV1 amd FVC normal, test is normal, FEV1 and FVC proportionally rduced, may be restrictive
27
Bronchial reversibility tests
obstruction is reversible with a bronchoodilator eg increase in FEV1\>12%
28
Bronchial provocation tests
29
Define allergic rhinits and clinical features
inflammation of mucosa of nasal cavity
When allergens contact the respiratory mucosa specific IgE antibody is produced in susceptible hosts
Nasal obstruction, clear rhinorrhea, itchy nose throat, eyes, swollen, pale, boggy mucosa, frontal head ache and pressure
30
Define nasal polyps and clinical features
benign lesions of nasal mucosa or paranasal sinusses due to chronic nasal inflammation
postnasal drip, bilateral nasal obstruction, frequently impaired olfactroy function, mouth breathing
31
Describe the cough reflex
Triggers (histamine, foreign bodies etc) cause irritation of mechanoreceptors (cough receptors)--\> RARS, SARS, C-fibers --\> sensory afferent via vagus nerve to nucleus tractus solatarus in the medulla --\> efferent nerves (phrenic, spinomotor, recurrent laryngeal, vagus)--\> effector muscles (expiratory muscle)--\> cough --\> inspiratory phase (big breath in, stretch of expiratory muscles, increase in lung pressure)--\> compression phase (glottis closes, respiratory muscles contract, pressure increases more in lung)--\> expiratory phase (glottis opens, air pushed oput due to high pressure in lungs)
32
Asthma exacerbation
typically reversible episode of lower airway obstruction characterized by a worsening of asthma symptoms within a short period of time (acute or subacute) and accompanied by a change in baseline lung function
33
Signs of a severe asthma exacerbation
- dyspnea at rest
- ability to talk in words
- Agitation
- Severe tachypnea (\>30/min)
- inspiratory and expiratory wheeze
- use of accesssory muscles
- Tachycardia \>120/min
- pulsus paradoxis
- PEFR \<40% predicted
- SpO2\< 90%
- Hypercapnia PaCO2: \>42mmHg
- severe (silent chest) --\> severe bronchial spasm
34
Management of a severe asthma exacerbation
Lung function tests (may not be possible)
ABGs: respiratory alkalosis--\> later respiratory acidosis
O2 therapy
Salbutamol vis nebulizer
Ipratopium via nebulizer (severe)
IV hydrocortisone/ presnisolone
IV Mg
Monitor electrolytes/ECG for arrythmias
Rehydrate
35
Drugs that relieve asthma
- Short acting B-2 adrenoreceptor agonists (SABA) eg Salbutamol/terbutaline
- increasing cAMP levels causes bronchodilation (drugs binds to beta receptor)
- G protein activated--\> adenylyl cyclase --\> cAMP synthesis--\> PKA phosphorrylats myosin light chain kinase and decreased intracllular calcium leading to muscle relaxation ( check video????)
- short acting: salbutamol, terbutaline, hydrophilic, onset within 5 mins, max effect 30 mins, lasts 3-6 hours
- long acting: salmetrol, formotrol (LABA), lipophilic, 12 hours
- route: inhalation, minimal effect at b1 and b2 receptor outside of trachobronchial tree, less unwanted side effects, salbutamol (IV and PO)
36
Side effects beta agonists
- muscle tremor
- tachycardia
- arrhythmia
- hypokalemia due to promotion of K+ into skeletal muscle
37
Drugs that prevent asthma
- corticosteroids
- leukotriene receptor antagonists
- antimuscarinics
- Antibody to IgE
- Antibody to IL-5
- Antibody to IL4/13 receptor
38
Mode of action of corticostroids
IV: hydrocortisone, oral: prednisolone, inhalation asthma: beclomtasone dipropionate, fluticasone propionate, budesonide, nasal spray (allergic rhinitis): beclometasone, dipropionate, fluticasone
Cortisol travels in the blood bound to transcortin.
Lipophilic steroid molecules that diffuse passively from blood across cell membranes into cytosol and bind to glucocorticoid receptors in cytoplasm (GR is expressed in virtually all cells)
The GR is bound to molecular chaperones including heat shock protein (HSP) which unbind when cortisol bind to receptor
Hormone receptor complex enters the nucleus and then binds to and interacts with specific regulatory DNA sequences called glucocorticoid response elements (GRE’s) → induce/repress gene transcription
Transactivation: Induction of→ annexin-1 and MAPK phosphatase-I
Annexin-1 (lipocortin): inhibits cytosolic phospholipase A2→ blocks the release of arachidonic acid which then inhibits its conversion to eicosanoids (prostaglandins don’t get produced)
MAPK phosphatase-I: It dephosphorylates and inactivates the MAPK (mitogen activated protein kinase) family of proteins involved in intracellular signalling which results in inhibition of cytosolic phospholipase A1
Transrepression: inhibition of pro-inflammatory transcription factors . Inhibition of:
NF-kB in the nucleus: NF-kB binds DNA sequences and stimulates transcription of inflammatory mediators. NF-kB also induces the transcription of cyclooxygenase 2 essential to the production of prostaglandins
Activator protein 1: An inflammatory transcription factor which regulates gene expression in response to inflammatory agents eg cytokines
Molecular mechanism: non genomic mechanisms (changes not mediated by changes in gene expression
Activation of PI3K-Akt-eNOS pathway: the best described nongenomic mechanism involves the activation of endothelial nitric oxide synthase. In mice, induction of this pathway protects against ischemia or reperfusion-induced injury in the heart
39
Leukotriene receptor antagonists
- Leukotriene receptor antagonists are selective competitive inhibitors of the cysteinyl leukotriene receptor preventing bronchoconstriction mediated by cysteinyl leukotrienes
- montelukast, zafirlukast
- oral therapy
- GI upset, headache, neuropsychiatric events with montelukast, suicidality in adults and adolscents, nightmares and behavioural problems in children
40
Muscarinic receptor antagonists
- Ipratropium bromide (short acting) and tiotropium (long acting)
- long acting (LAMAs)
- competitive antagonists at M1, M2 and M3 receptors blocking postsynaptic M3 receptors results in bronchodilation ( usually M3 G coupled receptors activate phospholipase C leading to formation of IP3 and DAG leading to an increase in intracellular calcium
41
Antibody to IgE
- omalizumab binds to IgE forming an immune complex that reduces circulating free IgE and prevnts their interactions with IgE rceptos on dendritic, mast and basophils and eosinophils
- injection site reaction, anaphalyxis
42
Antibody to IL-5
- IL5 recruits eosinophils from bone marrow, eosinophils then modulate immune response, including hyper-responsivenemss and remodeling in asthma
- Mepolizumab and reslizumab bind to IL5 preventing IL5 from binding to its receptor on the eosinophil cell surface, inhibiting IL5 signalling and reducing the production and survival of eosinophils
- Benralizumab binds to IL5 receptos resulting in apoptosis of eosinophils and basophils
43
Antibody to IL4 and IL13 signalling
- Dupilumab is a recombinant human monnoclonal antibody that inhibits IL4 signalling through the type I receptor and both IL 4 and IL13 through the type II receptor
- IL13 and 4 are the major drivers of inflammation in asthma and blocking this pathway decreases many of the mediators of inflammation including IgE
44
Side effects of glucocorticoids
- Central obesity
- buffalo hump
- moon face
- abdominal striae
- skin atrophy
- osteoporosis
- hyperglycemia
- increased susceptibility to infection
- increased appetite
- psychosis
- growth retardation in children
- acute adrenal crisis
- local (inhalation): dysphonia and oral candidiasis
- nasal spray: dryness and irritation of nose
45
How can oral candidiasis be avoided with inhaled glucocorticoids?
- using a spacer
- rinsing out mouth after a dose
46
Leukotriene and proinflammatory actions in asthma
inflammatory molecule produced by body after coming into contact with an allergen (released from mast cells)
tighten airway muscles
produce excess fluid and mucous
47
Biosynthesis of leukotrienes
formed from the breakdown of arachidonic acid which os bound to phospholipids of cell membranes
