Week 11 Flashcards
Asthma: definition?
Severe attacks can cause…
3 essential features
Defined as: recurrent, reversible airway obstruction
Attacks of wheezing, shortness of breath
Often nocturnal dry cough
Severe attacks can cause hypoxaemia
3 features:
- Airway inflammation
- Bronchial hyper-responsiveness
- Recurrent, reversible airway obstruction
Pathogenesis of asthma?
3 important mediators
Activation of the Th2 profile of cytokine production in genetically susceptible people
– Attracts inflammatory granulocytes (eosinophils) to mucosal surface
– IL-5 and GMCSF cause eosinophils to produce cysteinyl leukotrienes
and release granule proteins
– IgE synthesis is promoted, as is expression of IgE receptors on mast
cells and eosinophils
Important mediations:
– leukotriene B4 and cysteinyl-leukotrienes (C4 and D4)
– interleukins IL-4, IL-5, IL-13
– tissue damaging eosinophil proteins
What is the part played by t-lymphocytes in allergic asthma?
- The allergen activates CD4 t cells
- This then forms a Th2 helper cell
- These produce plasma cells which produce IgE antibodies
- IgE antibodies stimulate expression of IgE receptor on mast cells and eosinophils
Describe the immediate phase of asthma?
Inhibited by?
- Eliciting agent (allergen/ non-specific stimulus)
- Activates mast cells
- Produces chemotaxins/chemo kines and Spasmogens/cysLTs/H1PGD2
- Spasmogens /cysLTs/H1PGD2
- BRONCHOSPASM
Inhibited by: B2-adrenoceptor agonist, CysLT-receptor antagonist and theophylline
Describe the late phase of asthma?
Inhibited by?
- Infiltration of cytokine-releasing Th2 cells, and monocytes, and activation of inflammatory cells, particularly eosinophils
- Produces mediators (e.g. cysLTs) and EMBP/ECP
- Airway inflammation, airway hypersensitivity
- BRONCHOSPASM, WHEEZING, COUGHING
Inhibited by: Glucocorticoids
What is consequence of eosinophils infiltration in to airways in asthma?
Thickened BM
Oedema
Mucus plug formation with sequamated epithelial cells
Treatment and management of asthma
Anti-asthmatic drugs include bronchodilator and anti-inflammatory agents
Treatment is monitored by measuring peak expiratory flow rate
Name 5 main groups of drugs used to treat asthma? Examples
- B2-adrenoceptor agonists
– short-acting (SABA), e.g. salbutamol
– long-acting (LABA), e.g. salmeterol - Anti-inflammatory agents
– Glucocorticoids, e.g. beclometasone, budesonide - Cysteinyl leukotriene antagonists (LTRA)
– Montelukast - Methylxanthines
– theophylline and derivatives - Anti-IgE treatment
– Omalizumab
B-adrenoreceptors agonists
Mechanism?
SABA vs LABA?
Mechanism:
- Dilate bronchi via smooth muscle b2 receptors
- Physiological antagonists of the airway spasmogenic mediators
- Have little effect on bronchial hyper-reactivity
Short acting (SABA) e.g. Salbutamol
– given by inhalation
– effects start immediately and last 3-5 hours
– “ Rescue remedy”: treats wheeze in patients
Long acting (LABA) e.g. Salmeterol
– lasts longer (8-12 hours)
– given to prevent bronchospasm (at night or during exercise) in patients
requiring long-term therapy
Glucocorticoids (ICS) Action? Decrease... Given by \_\_\_\_ e.g. In deterioration asthma, use? Administration?
Main drugs used for anti-inflammatory action in asthma
– not bronchodilators but prevent the progression of chronic asthma
– don’t prevent the immediate response to allergen or other challenges
They decrease:
– formation of cytokines (particularly those released by Th2 lymphocytes)
– generation of vasodilators such as prostaglandins by inhibiting induction of COX
– activation of eosinophils and other cells
Given by inhalers (not nebulised)
– Main one is beclometasone
In deteriorating asthma oral (e.g. prednisolone) or IV (e.g.
hydrocortisone) can be given.
Cysteinyl-leukotriene receptors antagonists:
Mechanism?
Two receptors?
Target of lukast drugs
Two receptors for cysteinyl-leukotrienes (LTC4, LTD4 and
LTE4) have been cloned (CysLT1 and CysLT2)
– expressed in respiratory mucosa and infiltrating
inflammatory cells
The lukast drugs (e.g. montelukast) antagonise only CysLT1
– ↓ exercise-induced asthma and decrease both early and
late phase responses to allergens
– relax airways in mild asthma
– used mainly as add-on therapy to ICS and LABAs
– ↓ acute reactions to aspirin
Methylxanthines:
- Main drug in use? Mechanism?
- Administration?
- When used as an IV?
Main drug = Theophylline:
- Cyclic nucleotide phosphodiesterase inhibitor
- Increase cyclic nucleotides in the cell to relax smooth muscle
Administration: Oral sustained release formulations used in addition to steroids (e.g. Uniphyllin) in COPD
Rarely used as an IV drug in acute severe asthma
What is the immediate treatment of acute severe asthma?
- Oxygen
- Salbutamol or terbutaline PLUS ipratropium via nebuliser
- IV hydrocortisone or prednisolone tablets
If patient still not recovered:
- IV magnesium sulphate
- Switch from nebulised to IV salbutamol / aminophylline
What is ipratropium?
Uses? (4)
Non-uses? (3)
SAMA Uses: -Patients with COPD -For cough due to irritant stimuli -Decrease mucous secretion and increase clearance of bronchial secretions -Bronchospasm precipitated by b-blockers
Not:
- Uses as an asthma adjunct
- effective against allergen challenge
- selective for one muscarinic receptor
How to construct a well structured clinical question?
E.g. A parent asks whether a single steroid injection would work as
well as five days of oral steroids for their child, John who is about
to be discharged from hospital after an asthma attack. What is
the question you would ask?
Use PICE
- Patient/Population/Problem
- Intervention = Option you are considering
- Comparison = Possible other option
- Outcome = Define the desired outcome
E.g. A parent asks whether a single steroid injection would work as
well as five days of oral steroids for their child, John who is about
to be discharged from hospital after an asthma attack. What is
the question you would ask?
P = Young children I = Single dose of intra-muscular desamethasone C= 5 day treatment with prednisolone O = Resolve the symptoms of asthma
Difference between a null and alternative hypothesis?
Null hypothesis= Two sets of data that are from the same population and not different
Alternative hypothesis = Two sets of data that are from different populations and are different
Two forms of quantitative data?
Discrete: Can only have certain numerical values e.g. Number of children
Continuous: Do not have discrete steps e.g. height and weight
What are the two types of categorical variables?
Nominal (unordered categories)
- Male/female
- Alive/dead
Ordinal (ordered categories)
- Objective: Heavy, moderate or light drinkers (based on no. units of alcohol)
- Subjective: Health status questionnaires
What is the p-value?
Cut off?
The probability that the null hypothesis is correct (meaning the chance there is no difference between the data sets)
An arbitrary cut-off of P> 0.05 has been chosen to indicate that the null hypothesis can be reasonably rejected.
(I.e. low P value means there is a statistically significant difference)
What is a Type I error?
Rejecting the null hypothesis when it’s true (false positive)
Concluding there is an effect when there isn’t (P is small)
Type II error?
Not rejecting the null hypothesis when it is false (false positive)
Concluding there is no effect when there is (P is large)
What is the power of a test?
Its ability to reject the null hypothesis when it is false.
The capacity to detect an effect if there is one present
Sample size is key*
What are the stages of atherosclerotic plaque destabilisation?
Rupture or erosion
Platelet adherence and aggregation
Intracoronary coagulation
