Week 1/2 - C - Asthma - Pharmocology (airway control), symptoms, diagnoses, management (SIGN), drug mechanisms, ACUTE Flashcards
Where are the cell bodies of the preganglionic autonomic fibres for the airways located? Where are the cell bodies of the postganglionic autonomic fibres for the airways located? Answer for both sympathetic and parasympathetic Airways refers to the bronchial smoo
* The cell bodies of the preganglionic parasympaethtic airway fibres are located in the brainstem * The cell bodies of the postganglionic parasympathetic airway fibres are embedded in the bronchii and bronchioles There are no sympathetic cell bodies in the bronchial smooth muscle in humans
What is the main neurotransmitter in both the sympathetic and parasympathetic nervous systems at the preganglionic fiber? In relation to the airways, what are the neurotransmitters in both the sympathetic and parasympathetic nervous systems at the postganglionic fiber?
The main preganglionic neurotransmitter for sympathetic or parasympathetic fibres is acetylcholine (ACh) Postganglionic airway neurotransmitters - parasympathetic: Acetylcholine (cholinergic fibres) Nitric oxide (NO) and vasocactive intestinal peptide (VIP) (non-cholinergic) Postganglionic airway neurotransmitters - sympathetic: * Adrenaline
Noradrenaline is the most common sympathetic neurotransmitter released by the postganglionic neurones (fibres) Where is adrenaline released from for the airways?
Once acetylocholine reaches it receptors on the postganglionic neurones, the postganglionic sympathetic neurones normally release noradenaline The chromaffin cells in the adrenal medulla are the cells which release adrenaline (and noradrenaline to a lesser extent) - a distinguishing feature of chromaffin cells compared to postganglionic sympathetic neurons. * The adrenal medulla acts as a modified sympathetic ganglioon
As there are no sympathetic cell bodies in the bronchial smooth muscle, how does the sympathetic system manage to exert its effect on bronchial smooth muscle?
Pre-ganglionic cell bodies are located in the spinal column (sympathetic chain) (thoracolumbar distribution) - actylcholine is released from the preganglionic neurones and travels to the adrenal medulla that releases a adrenaline that will travel in the bloodstream to the adrenoreceptors in the airways
Adrenergic receptors include A1, A2, B1, B2, B3 What is the main location fo these receptors?
A1 - blood vessels A2 - pancreas, CNA, GI B1 - heart B2 - lungs B3 - adipose tissue
What effect will adrenaline released by the post-ganglionic neurotransmitters have on the airways? (4 effects, bronchial smooth muscle, mucus x2, vascular smooth muscle)
Bronchial smooth muscle relaxation via B2-ADR on airway smooth muscle Decreased mucus secretion via B2-ADR on goblet cells Increased mucociliary clearance via B2 -ADR on epithelial cells Vascular smooth muscle contraction via A1-ADR on vascular smooth muscle (blood vessels)
PARAYMPETHETIC effect on airways * Once acetylocholine is released from the preganglionic cell bodies in the brainstem, it reaches it receptors on the postganglionic neurones. These the release transmitters via the cholinergic (ACh) or non cholinergic pathway (VIP and NO) What does stimulation of postganglionic cholinergic fibres cause to the airway?
Stimulation of postganglionic cholingeric parasympathetic fibres causes: * Bronchial smooth muscle contraction via M3 muscarinc ACh receptors on airway smooth muscle * Increases mucus secretion via M3 muscarinc ACh receptors on goblet cells
PARAYMPETHETIC effect on airways * Once acetylocholine is released from the preganglionic cell bodies in the brainstem, it reaches it receptors on the postganglionic neurones. These the release transmitters via the cholinergic (ACh) or non cholinergic pathway (VIP and NO) What does stimulation of postganglionic non-cholinergic fibres cause to the airway?
Stimulation of parasympathetic postganglionic non-cholinergic fibres (NO and VIP) * bronchial smooth muscle relaxation mediated by VIP and NO
Asthma affects 5-10% of the population What main symptoms characterize asthma? Is it an obstructive or restrictive type of lung disease? Is it reversible or irrevversible?
Asthma is characterised by recurrent episodes of a non-productive cough, wheeze (expiratory polyphonic wheeze), dyspnoea / SOB and a tight chest - also has diurnal variation It is caused by reversible airway obstruction
What are common precipitants to asthma? Which drugs?
* Allergens - common in atopic individuals eg dust mite faeces and pollen * Exercise - cold/dry air * Smoking/passive smoking * Respiratory infections Drugs include NSAIDs and non selective B-Blockers (B2-ADR cause bronchial smooth muscle relaxation, blocking this worsens asthma)
Chronic asthma involves pathological changes to the bronchioles that result from long standing inflammation What factors contribute to the airway narrowing? (three)
There is bronchial muscle contraction narrowing the airways There is mucosal swelling/inflammation caused by inflammatory released by mast cells and basophil degrnaulation There is also an increase in mucus prouction
Airway inflammation caused by mediators released from mast cells in asthma patients leads to a bronchial hyperesponsiveness - which causes airway obstruction which cause the symptoms seen What happens in bronchial hyperresponiveness?
Bronchial hyperresponsiveness Epithelial damaged leads to exposed sensory nerve endings - C-fibres which contain irritant receptors These exposed sensory nerve endings increase sensitivity of the airways and bronchoconstrictor influences
How is bronchial hyeprresonsiveness tested for? (provocation tests) (name the two chemical used)
Bronchial hyerpresonsiveness is tested for by what is known as challenge testing Histamineor methacholine are gradullay inhaled in increasing doses of a medication that can irritates the airways and cause them to get narrower. People with sensitive lungs will be affected by a much lower dose of this medication than people with healthy lungs
Bronchial challenge testing - stated that hsitamine or methacholine inhalations are increased gradually used to induce bronchial hyperresponsiveness How do these agenets cause bronchial constriction?
Histamine causes bronchial constriction via airway smooth muscle H1 receptors Methacholine is a non selective muscarinic agonist and causes bronchial constriction via airway smooth muscle M3 receptors
When is testing for bronchial hyperresponsiveness normally carried out? What are the tests that test for airflow obstruction?
Referral for challenge tests should be considered in adults with no evidence of airflow obstruction on initial assessment in whom other objective tests are inconclusive but asthma remains a possibility * ie after airflow obstruction tests (spirometry and bronchodilator reversibility) show no evidence and if peak expiratory flow variability remains inconclusive
What concentration of airway provacation agent counts as a diagnosis of asthma?
PC20 (provacation concentration causing a 20% drop in FEV1) - PC20 of 8mg/ml or less of histamine or methacholine used counts as a positive result indicating asthma
Adults and children with a typical clinical assessment including recurrent episodes of symptoms (attacks), wheeze heard by a healthcare professional, historical record of variable airflow obstruction and a positive history of atopy and without any features to suggest an alternative diagnosis have a high probability of asthma What is carried out if there is a high probability of asthma? What tests provide objective evidence of variable airflow obstruction?
In patients who have a high probability of asthma, they should be coded as suspected asthma and initiated on treatment Obstructive spirometry and a positive bronchodilator test provide objective evidence of variable airflow obstruction, and further increase the probability of asthm Monitoring peak flow vaiability can further support the diagnosis of asthma if positive
In patients who have a high probability of asthma, they should be coded as suspected asthma and initiated on treatment What is the treatment and when is the response assessed?
Typically six weeks of low dose inhaled corticosteroid as a preventer (SABA is given as a reliever) is given and then the spirometry/bronchodilator reversibility is reassessed (pea flow variability monitoring can also be looked at) Good response = asthma = continue treatment
What spirometry results give a positive result for asthma? What bronchodilatory response gives a positive result? (in response to either SABA or corticosteroid trial)
Spirometry - Forced expiratory ratio Bronchodilatory response - In adults with obstructive spirometry, an improvement in FEV1 of 12% or more in response to either β2 agonists or corticosteroid treatment trials, together with an increase in volume of 200 ml or more, is regarded as a positive test
How is peak flow variability measured in a patient?
Positive peak flow variability is where there is a 20% variability in peak flow over at least 2 weeks of measurement
If there is doubt, the diagnosis should be considered as being of intermediate probability and further investigations will be needed What are the first line investigations carried out in patients with an intermediate probability - either on clinical suspicion or poor response to initiated treatment?
Test for airway obstruction - spirometry + bronchodilator reversibility And test patients peak expiratory
Spirometry, with bronchodilator reversibility as appropriate, is the preferred initial test for investigating intermediate probability of asthma in adults In adults and children with an intermediate probability of asthma and normal spirometry / bronchodilator results - what tests can be carried out?
Bronchial challenge tests and/or measurement of FeNO to identify eosinophilic inflammation can be carried out
What again is a positive result for provocative testing (bronchial challenge testing?
Provocative agenet concentration causing a 20% decrease in FEV1 when less than 8mg/ml used is a positive result Agents used typically are histamine or methacholine
Why is fractional exhaled nitrogen oxygen levels raised in asthma?
Nitric oxide is produced throughout the body, including in the lungs, to fight inflammation and relax tight muscles. High levels of exhaled nitric oxide in your breath can mean that your airways are inflamed Several inflammatory cells including eosinophils will produce nitric oxide to help combat inflammation
SUMMARY What are the steps into diagnosing asthma? * If intermediate probability
Intermediate probability Measure spirometry and bronchodilator reversibility (if improvement of FEV1 of 12% and 200ml increase in response to SABA or ICS trial - positive result) If airway obstruction tests negative, carry out bronchial challenge tests (PC20 of 8 mg/ml or less) and/or FeNO test (40ppb))
What type of hypersensitivity is asthma? What is this immunoglobulin raised in response to?
Asthma is Type 1 hypersensitivity - IgE mediated Antigen presenting cell of the allergen presents to CD4+ T helper cells which signal the production of Th1 and Th2 cells Th2 cells promote B cell maturation which produces IgE
Which lymphocyte is raised in the blood if it were to measured?
There is a raised peripheral eosinophil blood count
We shall first discuss the mechanism of action of the drugs and then the stages of treatment How do SABAs and LABAs act? Give examples of both How long do each take to act?
SABAs and LABAs act as short or long acting beta-2 adrenoreceptor agonists * Meaning they promote bronchial smooth muscle relaxation, decreased mucus production and increased mucociliary clearance SABA - salbutamol, terbutaline LABA - salmeterol, formeterol
Let’s now discuss cysteinyl leukotriene 1 receptor antagonists (CystLT1) receptor antagonist What are CystLT1s derived from and what do they cause? How do CystLT1s receptor antagonists work?
CystLT1s are derived from mast cells and infiltrating inflammatory cells - they cause smooth muscle contraction, mucus secretion and oedema via cysteinyl leukotriene receptor 1 CystLT1 receptor antagonists block this effect therefore relaxing bronchial smooth muscle
Methylxanthines Give two examples? Why are they not regularly prescribed? (name the side effects)
Theophyline and aminopphylline They are not regularly prescribed as they have a very narrow therapeutic window At supra-therapeutic concentrations they exert adverse effects such as arrythmias, GI upset, seizures
Why do methylxanthines have many drug to drug interactions making it problematic? Where are they metabolised? How does the drug help reduce bronchostriction/ exert anti inflammatory effects in asthma?
Metabolised in the liver via cytochrome P450 - many drugs inhibit this and therefore would increase levels of this medication Methylxanthines are thought to inhibit involve phosphodiesterases that inactivate cAMP and cGMP (these are second messengers that relax smooth muscle and perhaps exert an anti-inflammatory effect)
We have now discussed the relievers used in asthma, now we discuss the maintenance therapy (preventers) Glucocorticoids What are the three layers of the adrenal cortex and what do they produce?
Adrenal cortex Zona glomerulosa - produces mineralocorticoids (aldosterone) - helps regulate blood pressure Zona fasciculata - produces glucocorticoids (cortisol) - regulates numerous essential processes Zona reticularis - produces androgens
Glucocorticoids have no direct bronchodilator action and are ineffective in relieving bronchospasm when given acutely. However, they are the mainstay of treatment in the prophylaxis of asthma and are preferably delivered by the inhalational route to minimise adverse systemic effects What is the mechanism of action of glucocorticoids (corticosteroids) used in allergy?
Corticosteroids bind to receptors within the cell which cause the nucleus to down-regulate production of inflammatory mediators
More recent but very expensive approaches to asthma treatment to reduce anti-inflammatory actions include monoclonal antibodies What is the name of one and what is this monoclonal antibody directed against?
Monoclonal antibodies directed against IgE such as omalizumab Prevents IgE binding to mast cells and other lymphocytes that releases inflammatory mediators
Run through the different stages in the treatment of asthma in adults
Refer to specialist Either increase ICS to high dose OR add theophylline OR add tiortropium ORAL steroids and immunotherapy are SPECIALIST LAST LINE
- Moderate -
- * Increasing symptoms
- * PEF 50%-75% of best predicted
- * No features of acute severe attack
- Severe - Any one of the following
- * PEF 33%-50%
- # * Respiratory rate ≥ 25/min;
- * Heart rate ≥ 110/min;
- * Inability to complete sentences in one breath.
Criteria for life threatening attack? (33,92, CHEST - mnemonic)
33-92-CHEST
- PEF <33%
- SpO2 <92%
- Cyanosis/Confusion,
- Hypotension,
- Exhaustion,
- Silent chest,
- Tachycardia
Why are magnesium suplhate and IV aminophylline given if no response to other bronchodilators (SABA and SAMA)?
There is some evidence that magnesium sulfate has bronchodilator effects. A single intravenous dose of magnesium sulfate may be considered in patients with severe acute asthma In an acute asthma attack, IV theo/aminophylline is not likely to produce any additional bronchodilation compared to standard therapy with inhaled bronchodilators and corticosteroids. However, in some patients with near-fatal or life-threatening acute asthma with a poor response to initial therapy, intravenous aminophylline may provide some benefit
