asthma Flashcards
what is asthma?
An inflammatory disease of the airways characterized by:
Recurrent reversible airways obstruction in response to irritant stimuli
Hypersecretion of mucus by bronchial epithelial cells
Eosinophil infiltration
Bronchial smooth muscle cells hyperplasia causing airway hyper-responsiveness and bronchospasm
whats the difference in structure between a healthy airway, with asthma and asthma attack?
Asthma: smooth muscle cells increased in airway
asthma attack: constricted airway, contracted smooth muscle cells
Hyperplasia of goblet cells
glandularsimple columnarepithelialcellswhose function is to secretemucin,
what is hyperplasia?
increase in the number of cells in an organ or tissue.
what is hypertrophy?
Hypertrophy =increase in size of of smooth muscle suspected to contribute to the irreversible airflow obstruction and permanently impaired pulmonary function observed in patients with chronic asthma
what is airway hyper responsiveness?
Airway hyperresponsiveness is a characteristic feature of asthma and consists of an increased sensitivity (abnormal sensitivity) of the airways to chemicals, cold air, stimulant drug e.g., an inhaled constrictor agonist, a steeper slope of the dose-response curve, and a greater maximal response to the agonist. Certain inhaled stimuli, such as environmental allergens, increase airway inflammation and enhance airway hyperresponsiveness.
what is bronchospasm?
Bronchospasmis an abnormal contraction of the smooth muscle of the bronchi, resulting in an acute narrowing and obstruction of the respiratoryairway.
what are the causes of asthma? (pathogenies)
Factors increasing chances to develop the condition: identified!
A family history of asthma /allergic conditions Bronchiolitis as a child Exposure to tobacco smoke Being born prematurely Type of job- occupational exposures
what are the triggers of asthma?
Triggers: Indoor environment House dust mites Moulds & fungi Pollen Food drugs Stress or even a fit of laughter cold and viral infection
what is intrinsic asthma?
Intrinsic asthma/Or Not obvious allergic bases: : historical definition: asthma caused by substances from “within the body.” These patients usually have a negative allergy skin test, and therefore do not have allergies and do not benefit from allergy shots or allergy medications
intrinsic asthma
what is extrinsic asthma?
Extrinsic asthma/Allergic bases: historical definition asthma caused by inhaling or ingesting foreign substances (later known as allergens) from “without the body.” Some causes were in the air, such as horse hair, plant pollens, and feather dust, and some were in the foods ingested, such as eggs, berries, fish and cereals
what are the symptoms of asthma?
Wheeze Breathlessness Cough (occasionally) Daily or seasonal variation Chest tightness Any triggers that make symptoms worse?
what are objective tests for asthma ?
Airway inflammation measurement
Lung function tests
Airway hyperreactivity measurement
how does Airway inflammationmeasurement work?
Measure Fractional exhaled Nitric Oxide in the breath (FeNO).
normal epithelial cell release minimal NO
during imflammation , activated epithelial cell increase production of NO
Where is the NO coming from?
In inflammatory diseases, such as asthma, the increase in exhaled NO may reflect, at least in part, induction of NOS2.
In adult asthmatic patients there is evidence of increased expression of NOS2 in airway epithelial cells
Pro-inflammatory cytokines, which may at times be involved in asthmatic inflammation, induce the expression of NOS
Patients with asthma caused by allergic airway inflammation have high levels of FeNO that decrease with corticosteroid treatment
Knowing whether airway inflammation is present can help avoid an empiric trial of steroids
Positive test:
FeNO level of 40parts per billion (ppb) or more(adult)
what is the lung function test?
Obstructive spirometry
Measure lung volumes and capacity to determine the presence of an obstructive or a restrictive diseases. FEV1 and FVC changes will differe depending on the type of diseases.
Obstructive spirometry
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
what is lung function test? Bronchodilator reversibility (BDR) test
Bronchodilator reversibility (BDR) test
Spirometry after inhaling 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
Rationale for this test:
Determine the presence of a reversible airways obstruction
what is lung function test?
peak flow variability?
Rationale for this test:
Determine the presence of daily variability of air peak flow.
Peak flow variability
Monitor peak flow variability for 2to 4weeks
If the difference between the highest and lowest values divided by their mean exceeds 20% (and is at least 60 l/min) the diagnosis of asthma is strongly supported.
explain the airway hyperreactivity measures?
Direct bronchial challenge test- with histamine or methacholine
Rationale:
Airway hyperresponsiveness is a characteristic feature of asthma and consists of an increased sensitivity (abnormal sensitivity) of the airways to chemicals, cold air, stimulant drug
In this test, bronchospasm is deliberately induced by controlled and measurable exposure to a specific stimulant. The direct tests aim to detect and quantify airway hypersensitivity: inhaled aerosols of histamine and methacholine act directly on receptors on the bronchial smooth muscle to cause contraction. Results are most often presented as dose-response curves that may be used as an index of the patient’s sensitivity to the stimulant in question
Asthmatics usually demonstrate an excessive response to an inhaled dose of methacholine or histamine which causes little or no change in lung function in normal healthy individuals.
Chronic Asthma: Non Pharmacological Management
primary preventions
Multifaceted approach to avoid indoor asthma
Aeroallergen 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 preventions
House dust mite avoidance: should not be routinely recommended
Breathing exercise programmes (as adjuvant to pharmacological treatment) can be offered to adult to improve quality of life and reduce symptoms.
Family therapy with pharmacotherapy
Asthma Management: Pharmacological Treatment
Relievers
Relievers
What: Bronchodilators
Inhaled short-acting fast onset β2 adrenoceptor agonists
Inhaled long-acting fast onset β2 adrenoceptor agonists as MART ONLY
Why: Fast control of symptoms given the fast onset of action ≤ 7 min
When: to relieve asthma symptoms and for asthmatic patient with infrequent, short-lived wheeze and normal lung function
Asthma Management: Pharmacological Treatment
controller/preventer
Controllers/Preventers
What: Long-acting bronchodilators and anti-inflammatory drugs
Inhaled long-acting β2 adrenoceptor agonists (in combination with ICS)
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 attack.
Chronic Asthma : Pharmacological Management
according to nice guidelines
SABA
SABA + ICS
SABA + ICS + LABA
* check this
what is b2 Adrenoceptor Agonists mechanism?
Mechanism of action
Activate b2AR in airway smooth muscle
Cause airway smooth muscle relaxation by cAMP-dependent (and independent!) mechanism(s)
what is the mechanism of action of salbutamol ?
use
Salbutamol
Hydrophilic, it enters the binding site of b2AR, fast onset BUT short action (~3-6 hours)
(Terbutaline)
Use:
Occasional reliever
For acute asthma attacks
Monitor and repeat treatment if needed
Inhaled but also oral, s.c., slow i.v.
what is the mechanism of action for salmeterol?
Long-acting b2 adrenoceptor agonists
Salmeterol
Long, lipophilic side chain binds to exosite: active portion of the molecule remains at the receptor site
Slow on-set but longer duration of action (~12 hours
what are the lung function tests?
obstructive spirometry
bronchodilator reversibility
peak flow variability
what is the mechanism of action of fometerol?
Formoterol
Long-acting b2 adrenoceptor agonists
Moderately lipophilic, taken into depot at cell membrane
Fast onset
name some b2-adrenergic agonists and their mechanism?
- salbutamol - Hydrophilic, short action, fast onset
-formeterol - intermediate, long action, fast onset
salmeterol - lipophilic, short action, fast onset
what is the use of long acting b2 adrenoreceptor agonist?
Use:
Inhaled
Chronic asthma
Maintenance And Reliever Therapy- Formoterol
Only in combination with ICSwhat is the advantage and disadvantage of long acting b2 adrenoreceptor agonist?
Advantages:
Allow reduction of corticosteroid dose
Reduction of symptoms and improvement of lung function
Disadvantages:
Risk increase of asthma exacerbation, hospitalization, death
b2 adrenoceptor agonists- what are the adverse effects
Adverse effects: Arrythmias, angina precipitation, palpitation, tachycardia Peripheral vasodilation Headache Tremor (route/dose-related)
Increased mortality/morbidity (LABA)
what are the contradictions of b2 adrenoreceptor agonist?
Contraindications and use with caution:
Cardiovascular diseases
Pregnancy
what interactions can b2 adrenoreceptor agonist have on other drugs?
Interactions with other drugs
Hypokalaemia
what is corticosteriod?
Most effective anti-inflammatory therapy for asthma
what is the mechanism of action of corticosteriod - trans-repression and trans-activation
TRANS-REPRESSION Switch off multiple activated inflammatory genes and decrease transcription of: Cytokines (IL1, TNFa) Chemokines (IL8) Inflammatory enzymes (COX2, iNOS) Inflammatory receptors Others
TRANS-ACTIVATION Activate anti-inflammatory gene expression and increase transcription of: b2-Adrenergic receptor IL-1 receptor antagonist Others
what can corticosteroids do?
- eosinophil numbers decrease
- cytokines decrease
- mast cells decrease
- macrophages decrease
- dendritic cells decrease
endotheial cell leak
airway smooth muscle - b2 receptor increase
mucus secretion decrease
what are examples of inhaled, oral and parental cortiscosteriod?
and its use?
Inhaled: Beclometasone dipropionate Budesonide Fluticasone propionate 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
what are the side effects of corticosteriod?
esp. long term use
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 larynx!
Pathobiology of asthma: bronchial hyper-reactivity, bronchial spasm and inflammation of the airways
immediate phase of asthma attack: trigger: pollen, airpollutant release of mast cell spasomogen - histamine , ltc4 , ltd4 release of chemotoxins (cytokines) causes bronchospasm
delayed phase of asthma attack
- chemotoxins
- causes influx / activation of imflammatory cells (eosinophil, monocytes, T cells) which release leukotrine, eosinophil protein
- which causes bronchospasm- wheezing and coughing
- increase in hyper reactivity and imflammation
- which causes mucus
Leukotriene Receptor Antagonists(LTRA)
mechanism of action and use
Mechanism of action:
Block cysteinyl-leukotrienes receptors on bronchial tissue (and other cells) to reduce bronchoconstriction, mucus secretion, edema, eosinophil migration.
Montelukast
Zafirlukast
Use: Oral asthma preventer NOT as reliever/rescue remedy!
- increased mucus secretion
- bronchoconstriction
- easoniphil and chemotaxin activation
Anticholinergic agents
mechanism of action and use
example
Mechanism of action:
Antagonist of muscarinic acetylcholine receptors.
-Blockage of M3receptors reduces bronchoconstriction (promoting relaxation of pulmonary smooth muscle and bronchodilation) and reduces mucus secretion
Tiotropium Bromide: long-acting muscarinic antagonist(LAMA)
Use: Recently approved for maintenancetreatment of asthma
In combinations with ICS and LABA
Bigger role in the management of COPD
Theophylline
mechanism of action
Mechanism of action:
Non-selective phosphodiesterase inhibtor (=↑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 reponsiveness
inhibits release of inflammatory mediators
use of theophylline
Use:
oral or parenteral, for chronic and acute asthma
NOTE:
Very small therapeutic window…
Extensively metabolized by liver…
Serum levels must be monitored to avoid toxicity!
Severe Persistent Allergic Asthma: Anti-IgE
mechanism of action and use
Mechanism of action
Antibody binds to circulating IgE decreasing binding of 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!
IgE for antigen connect to the mast cell causes histamine, tryptase, leukotrienes and prostaglandins which causes the asthma symptoms (allergic inflammation)
omalizumb can attach to the IgE antigen and prevent this.
Acute Asthma Management:
Pharmacological Treatment in Adults
generic - SIGN guidelines
Supplementary oxygen High-dose inhaled β2 agonists - Nebuliser / Intravenous Steroids- Oral/ Parenteral Nebulised ipratropium bromide I.V. aminophylline
