Week 3: Pharmacology of Airway Control Flashcards
Briefly describe the main features of the pharmacology of the autonomic innervation of the human bronchial airway.
How will this determine therapeutic choice?
β-adrenoreceptors are abundantly expressed on airway smooth muscle (especially β2), epithelium glands and mast cells - targeted Pharmacologically with β-agonists such as salbutamol. This results in: bronchodilation; reduced histamine release; increased mucociliary clearance.
Muscarinic receptors are present on airway and vascular smooth muscle and glands. The M3 muscarinic receptor is pharmacologically the most important. Broad muscarinic receptor antagonists such as Ipatropium and Tiotropium bind to the M3 receptor and block the constricting effect of ACh and also inhibits mucus secretion.
What is unusual about the sympathetic receptors in bronchial smooth muscle and from this, what constitutes the main sympathetic control signal for bronchodilation?
Bronchial smooth muscle has an abundance of B2 receptors. These are activated not by direct sympathetic nervous activity, but instead indirectly by adrenaline.
List some of the short and long acting β2-agonists used as relievers in asthma. What is their typical duration of action and when would these be most likely to be used?
Short acting: E.g. salbutamol Duration of action: 3-6 hours. Indications: rescue medications in exacerbations of asthma and COPD
Long acting: e.g. salmeterol, formoterol Duration of action at least 12 hours. Indications: maintenance therapy in COPD and asthma
Describe the features of how β2-agonists exert their main pharmacological effect as bronchodilators
B2 agonist bind to Gs protein, resulting in an increase in cyclic AMP, which stimulates PKA and results in bronchodilator.
Why are Methylxanthines generally not used in ‘first line’ treatment of asthma?
Due to their side effects: psychomotor agitation and tachycardia
Due to a narrow therapeutic window (plasma levels ≈ 30-100 uM)
As with LTRAs, often poorly efficacious
Frequent side-effects – nausea, headache, reflux
Potentially life-threatening toxic complications – arrhythmias,
fits
Important drug interactions – levels increased by cytochrome
P450)inhibitors eg erythromycin, ciprofloxacin
Anticholinergic muscarinic receptor antagonists are also not in ‘first line’ use for asthma. Why is this and what does their mode of action make them better suited for?
Anticholinergic muscarinic receptor antagonists like ipratropium bromide are bronchodilators. They are different from beta agonists however in that beta agonists are able to dilated constricted airways, whereas anticholinergic muscarinic receptor antagonists can only prevent constriction, they are not able to reverse already constricted airways. Therefore they must always be used in combination with a beta agonist. Consequently they do not work well to relieve asthma symptoms, but work well to prevent asthma symptoms
Corticosteroids - List the main glucocorticoids used in treating asthma.
Steroids used in inhalers for prevention of asthma symptoms:
Beclometasone
Fluticasone
Budesonide
At which receptors do corticosteroids bind and how do they exert their primary effect. Name some of the main groups of asthma mediators that are affected
Corticosteroids diffuse across cell membranes and bind to glucocorticoid receptors in the cytoplasm. They Inhibit phosphliase a2 which blocks release of arachidonic acid. This is the precursor of prostaglandins and leukotrienes, by blocking release of these this results in antinflammatory actions.
outline the five steps as recommended by the British Thoracic Society in managing asthma
- regular preventer: low dose ICS
- initial add-on therapy: add LABA to low dose ICS
- additional add on - if no response to LABA, stop and consider increased does os ICS
- high dose therapies - increasing ICS dose, fourth drug e.g. LTRA, SR theophylline, beta agonist tablet, LAMA
- continuous or frequent use of oral steroids
A 21-year-old male student had a history of asthma dating back over 15 years. He had been well, but suffered from exercise-induced wheeze, usually responding to a couple of puffs of a salbutamol inhaler.
On a winter’s night, he was admitted to AandE ‘breathing his last’ after a particularly long run. On examination, HR 120 bpm, Respiratory rate 40, BP 100/60 mmHg, oxygen saturations 91%, little to hear on respiratory auscultation, unable to perform a peak expiratory flow rate (PEFR).
How would you classify the severity of his asthmatic attack?
life threatening
A 21-year-old male student had a history of asthma dating back over 15 years. He had been well, but suffered from exercise-induced wheeze, usually responding to a couple of puffs of a salbutamol inhaler.
On a winter’s night, he was admitted to A&E ‘breathing his last’ after a particularly long run. On examination, HR 120 bpm, Respiratory rate 40, BP 100/60 mmHg, oxygen saturations 91%, little to hear on respiratory auscultation, unable to perform a peak expiratory flow rate (PEFR).
What is your first treatment?
oxygen
A 21-year-old male student had a history of asthma dating back over 15 years. He had been well, but suffered from exercise-induced wheeze, usually responding to a couple of puffs of a salbutamol inhaler.
On a winter’s night, he was admitted to A/E ‘breathing his last’ after a particularly long run. On examination, HR 120 bpm, Respiratory rate 40, BP 100/60 mmHg, oxygen saturations 91%, little to hear on respiratory auscultation, unable to perform a peak expiratory flow rate (PEFR).
Other than oxygen, what other priority treatments would you administer initially? Include mechanism of drug delivery.
1) Salbutamol- nebuliser
2) Steroids- oral prednisolone is can swallow, IV hydrocortisone if can’t
swallow
3) Ipratropium- nebuliser
4) Magnesium sulphate IV
Note: Magnesium sulphate wasn’t mentioned in the lecture but it is in the BTS
guidelines for treatment of acute severe asthma. Its actual mechanism in
relaxing bronchial smooth muscle is unclear but the following proposed mechanisms are suggested most often: inhibition of calcium influx and stimulating mast cells to release histamine. It has also been linked to decreased acetylcholine release and increasing agonist affinity to the β2-adrenoceptor
A 21-year-old male student had a history of asthma dating back over 15 years. On a winter’s night, he was admitted to A/E ‘breathing his last’ after a particularly long run. On examination, HR 120 bpm, Respiratory rate 40, BP 100/60 mmHg, oxygen saturations 91%, little to hear on respiratory auscultation, unable to perform a peak expiratory flow rate (PEFR).
Your initial treatments appear to have little success. The patient is beginning to tire. Arterial blood gases reveal a pO2 of 8 kPa and pCO2 of 6.5 kPa. You think admission to ITU is warranted.
What other investigation might be useful and why?
Chest x-ray- look for infection or pneumothorax
Bloods- look for infection, electrolyte imbalances,
Repeat ABGs
Define asthma.
It is primarily an inflammatory disease that leads to airway obstruction characterised by bronchoconstriction and mucus plugging, which can be severely debilitating, leading to life threatening hypoxaemia without therapeutic intervention.
Bronchoconstriction leads to increased lower airway resistance. Where does the majority of airway resistance occur?
Normally about 40-50% of flow resistance is in the upper respiratory tract where no gaseous exchange takes place. The remainder of resistance is provided by the trachea and down to 7th generation bronchi.
Does sympathetic or parasympathetic activation lead to bronchodilation?
Sympathetic activity results in bronchodilation with nerves innervating bronchial blood vessels and glands, but not bronchial smooth muscle.
β-adrenoreceptors are abundantly expressed on airway smooth muscle (especially β2), epithelium glands and mast cells. Binding at B2 receptors results in bronchodilator.
Beta-adrenoreceptors are abundantly expressed on airway smooth muscle (especially Beta2), epithelium glands and mast cells. Binding at these sites of Beta-agonists results in which three effects?
bronchodilation;
reduced histamine release;
increased mucociliary clearance.
All these will improve gaseous exchange.
Is parasympathetic or sympathetic activity dominant in maintaining smooth muscle tone in the airways?
Parasympathetic activity is normally dominant in maintaining smooth muscle tone in the airway and muscarinic receptors are present on airway and vascular smooth muscle and glands. The M3 muscarinic receptor is pharmacologically the most important.
The presentation differentiates between the immediate and late phase of an asthmatic attack following allergen exposure. Describe the pathophysiology of the immediate phase.
In allergic asthma, the initial response to allergen provocation is due to interaction with Mast Cell fixed IgE. This results in the release of histamine and a host of potent spasmogens leading to immediate bronchospasm.
The presentation differentiates between the immediate and late phase of an asthmatic attack following allergen exposure. Describe the pathophysiology of the late phase.
Co-release of a range of mediators and chemotaxins activate a complex immune system response that bring leucocytes to the area. This sets off a further chain of events leading to exacerbated bronchospasm and congestion due to epithelial damage, thickening of the basement membrane, oedema and mucus production.
Additionally, the epithelial damage leads to increased exposure of the sensory irritant receptors, which further exacerbates bronchial hyperactivity and sensitivity. While this dual response to allergen challenge is relevant to symptoms in some atopic individuals, the pathophysiology of ongoing day-to-day symptoms and asthma exacerbations is undoubtedly much more complex and the mechanisms are poorly defined.
Define Bronchial hyper-responsiveness
Bronchial hyper-responsiveness is defined as an exaggerated bronchoconstrictor response to direct pharmacological stimuli such as histamine, or indirect stimuli such as exercise. These indirect stimuli cause
bronchoconstriction at least in part through the direct or indirect activation of airway mast cells. Mast cell mediators then induce the bronchoconstriction
How do indirect stimuli such as exercise induce bronchoconstriction in asthma?
These indirect stimuli cause bronchoconstriction at least in part through the direct or indirect activation of airway mast cells.
Mediators from which cell type induce bronchoconstriction in asthma?
Mast Cells
What are the two broad categories of Asthma therapeutics?
Bronchodilators or relievers – acute symptomatic relief.
Anti-inflammatories - used to control the inflammatory mechanisms underlying asthma.
Depending on the severity of the asthma, these two types are commonly used in combination.
