Respiratory therapeutics - Asthma week 1 Flashcards
what is asthma?
inflammatory disease of the airway caused by:
- recurrent reversible obstruction in response to irritant stimuli
- hypersecretion (increased) of mucus by bronchial epithelial cells
- eosinophil infiltration (WBC)
- bronchial smooth muscle cells hyperplasia causing hyper-responsiveness and bronchospasm (increased sensitivity to stuff in airway and bronchospasm means increased contraction)
what happens in asthma (airways) and in asthma attack?
with asthma, increased airway smooth muscle
in asthma attack:
airway is constricted due to contracted airway smooth muscle
what causes asthma?
exact causes not sure:
- genetic
- environmental
- combination of factors
increased chances to develop the conditions:
- family history
- bronchiolitis as a kid
- exposure to tobacco smoke
- being born prematurely
- type of job
asthma triggers
dust pest fungi smoke some drugs like salicylic acid
what are symptoms of asthma?
wheeze
breathlessness
cough
chest tight
what are the objective tests for asthma?
lung function tests
airway inflammation measurement
airway hyper-reactivity measurement
what is the airway inflammation measurement?
measure Fractional exhaled nitric oxide (FeNO) in the breath
positive tests:
FeNO level of 40 parts per billion (ppb) or more in adult
during inflammation, the epithelial cells increase production of NO.
tell me about lung function tests?
spirometry can be used to measure lung function
forced expiratory volume 1 sec = volume of air exhaled during the first second of the FVC
forced vital capacity = maximal amount of air that can be exhaled after a maximal breath
positive test for obstructive airway disease: FEV1/FVC <70% or below the lower limit of normal
BDR (bronchodilator reversibility test)
you do a spirometry after inhaling a short-acting B2AR agonist
positive test for reversibility: an improvement in FEV1 of 12% or more, and with an increase in volume of 200ml or more
peak flow - lung function
positive test of more than 20% variability
airway hyperreactivity measures?
direct bronchial challenge test with histamine or methacholine
positive test: provocatine concentration of methacholine causing a 20% fall in FEV1 (pc20) of 8mg/ml or less
pathobiology of asthma
- immediate phase of asthma attack - (bronchial hyper-reactivity of and spasm)
triggers (allergens, air pollutants) can cause an asthma
this causes release of spasmogens (e.g. histamine, LTC4, LTD5 etc) and causes bronchospasm
also release chemotaxins (cytokines) which causes the delayed phase of asthma:
- delayed phase:
influx of inflammatory cells which relaase: cytokines, eosinophil etc which cause:
bronchospasm, wheezing and coughing
and also increase hyperreactivity & inflammation, increased mucus
chronic asthma: non pharmacological management
primary prevention ?
mainly supported by observational studies:
multifaceted approach to avoid indoor asthma
aeroaallergen and food avoidance
weight-loss interventions for overweight and obese adults and children with asthma
microbial exposure and hygiene hypothesis
avoid smoking and air pollution
chronic asthma: non pharmacological management
secondary prevention ?
house dust mite avoidance: should not be routinely recommended
breathing exercise programmes
family therapy with pharmacotherapy
asthma management:
pharmacological treatment:
relievers
relievers
what: bronchodilators:
inhaled short-acting fast onset b2 adrenoreceptor agonists
inhaled long-acting fast onset b2 adrenoreceptor agonists as MART ONLY
why: fast control of symptoms given the fast onset of action less than 7 mins
when: to relieve asthma symptoms and for asthmatic patient with infrequent, short lived wheeze and normal lung function
asthma management:
pharmacological treatment:
preventers
what: long acting bronchodilators and anti-inflammatory drugs
inhaled long acting b2 adrenoreceptor agonists
inhaled and systemic corticosteroids
leukotriene receptor antagonists
long-acting muscarinic receptor antagonists
theophylline
why: control symptoms and reduce inflammation
when: regular maintenance therapy to improve symptoms, lung function and prevent asthma
B2 adrenoreceptor agonist - mechanism of action
activate b2AR in airway smooth muscle
cause airway smooth muscle relaxation by cAMP-dependent (and independent mechanisms)
short acting b2 adrenoceptor angonists
salbutamol: hydrophilic, it enters the binding site of B2AR, fast onset but short action (3-6 hours)
use:
occasional reliever for acute asthma
monitor and repeat treatment if needed
inhaled but also oral, s.c., slow IV
salmeterol:
long, lipophilic side chain binds to exosite: active portion of the molecule remains at the receptor site
- slow onset but longer duration of action (12 hours)
formeterol:
moderately liphophilic, taken into depot at cell membrane
fast onset
b2-adrenergic agonists
salbutamol - hydrophilic short duration, fast onset
formoterol - intermediate, long duration, fast onset
salmeterol - lipophilic, long duration, slow onset
long acting b2 adrenoceptor agonists
use: inhaled chronic asthma Maintenance And Reliever Therapy - formoterol only in combination with ICS
Advantages:
allow reduction of corticosteroid dose
reduction of symptoms and improvement of lung function
disadvantages:
risk increase of asthma exacerbation, hospitalisation, death
adverse effects of B2 adrenoceptor agonuists
arrthymias, angina precipitation, palpitation, tachycardia
peripheral vasodilation
headache
tumour mortality/morbidity (LABA)
contraindications:
cardiovascular diseases
pregnancy
interactions with other drugs:
hypokalaemia
corticosteroids - most effective anti inflammatory therapy for asthma
mechanism of action - TRANS REPRESSION
switch off multiple activated inflammatory genes and decrease transcription of:
cytokines (IL1, TNFs) chemokine (IL8) inflammatory enyzmes (COX2, iNOS) inflammatory receptors others
TRANS-ACTIVATION - activate anti inflammatory gene expression and increase transcription of:
B2-adrenergic receptor
IL-1 receptor antagonist
others
corticosteroids - further information
inhaled:
beclometasone dipropionate
budesonide
use: recommended preventer drug for adults and children for achieving overall treatment goals
oral:
prednisolone
use: acute and severe asthma
parenteral:
hydrocortisone (i.v.)
use: life-threatening acute asthma
corticosteroids: unwanted/side effects ?
with long term use: many
reduction of bone mineral density, osteoporosis
hypertension
cataracts and glaucoma
hyperglycaemia, diabetes
weight gain
increased vulnerability to infection - lower respiratory tract infections
thinning of the skin and easy bruising
hoarseness, dysphonia, throat irritation and candidiasis - local deposition of inhaled glucocorticoid in the oropharynx and larnyx
what does cyst Ts do?
LTC4, LTD4, LTE4
AHR
myofibroblast accumulation
increased collagen deposition
eosinophil chemotaxis activation - decreased apoptosis
increased mucus secretion
plasma leak
bronchoconstriction smooth, smooth muscle hyperplasia
LTB4
AHR
neutrophil chemotaxis
increased mucus secretion
plasma leak
leukotriene receptor antagonists (LTRA) mechanism of action:
block cysteinyl-leukotrienes receptors on bronchial tissue (and other cells) to reduce bronchoconstriction, mucus, secretion, edema,
treatment:
montelukast & zafirlukast
use: oral asthma preventer NOT as reliever/rescue remedy
anticholinergic agents
mechanism of action:
Antagonist of muscarinic acetylcholine receptors - blockage of M3 receptors reduce bronchoconstriction (promoting relaxation of pulmonary smooth muscle and bronchodilaton) and reduces secretion
tiotropium bromide: long acting muscarinic antagonist (LAMA)
USE: recently approved for maintenance treatment for asthma:
in combination with ICS and LABA
BIGGER ROLE IN MANAGEMENT OF COPD
Theophylline - mechanism of action
non-selective phosphodiesterase inhibitor (increase cAMP)
Non-selective antagonist at adenosine receptors
activates histone deacetylases (HDACs)
others unknown
induces relaxation of the smooth muscle of bronchial airways reducing airways obstruction and airway responsiveness
inhibits release of inflammatory mediators
use:
oral and parenteral, for chronic and acute asthma
very small therapeutic windows - extensively metabolised by the liver. serum levels must be monitored to avoid toxicity
severe persistent allergic asthma: Anti-IgE
mechanisms of action:
antibody binds to circulating IgE decreasing binding if iGE to the high-affinity IgE receptor (FceRI) in mast cells
OMALIZUMAB
use: subcutaneous injections every 4 weeks, severe persistent IgE-mediated asthma
NOTE effect is not immediately apparent: 12 weeks treatment required
