Airway Control Flashcards
Describe the innervation of the airway and how constriction/dilation occurs.
Sympathetic innervation of the bronchi results in bronchodilation. There are nerve ending in the vessels and glands, but not in the bronchial smooth muscle, but β2 receptors are found in abundance in the smooth muscle, epithelial glands and mast cells, and circulating β agonists can cause bronchodilation, reduced histamine release by preventing degranulation of mast cells, and increased mucociliary clearance, all of which improve gaseous exchange.
Parasympathetic innervation usually dominates smooth muscle tone in the airways – muscarinic receptors are found on airway and vascular smooth muscle and glands (the most important muscarinic receptor is M3)
There is also inhibitory and excitatory non-adrenergic non-cholinergic (NANC) innervation – this uses a variety of neurotransmitters – they have not been fully characterised in humans
How do beta agonists cause patent airway?
circulating β agonists can cause bronchodilation, reduced histamine release by preventing degranulation of mast cells, and increased mucociliary clearance, all of which improve gaseous exchange.
Describe the pathophysiology of asthma
Asthma is an inflammatory disease that causes airway obstruction due to bronchoconstriction – which increases the resistance of the lower airways - and mucus plugging. This can lead to life threatening hypoxaemia without treatment.
There is a two phase response. The early or immediate phase following allergen exposure is due to the cross linking of IgE on the cell surface of mast cells, which leads to the mast cells degranulating and releasing histamine, as well as other mediators which cause immediate bronchospasm. The late phase occurs when the release of mediators has triggered an immune response which leads to leucocytes arriving at the area. The leucocytes act to worsen bronchospasm and congestion by damaging the epithelia, thickening the basement membrane, oedema and mucus production. The epithelial damage also increases the exposure to the allergen which further exacerbates bronchial hypersensitivity.
Bronchial hyperresponsiveness refers to the “twitchiness” of airways in asthma – an exaggerated bronchoconstrictor response to stimuli – including histamine or exercise.
What are short acting B2 agonists? examples? MOA?
salbutamol, terbutaline
Agonise β2 receptors, which are coupled to Gs proteins. This leads to increases intracellular cAMP levels, decrease in intracellular calcium, reduced binding of calcium by light chain myosin – ends up with bronchodilation and hyperpolarisation of the muscle cells
What are ADRs and DDIs of SABAs
Tachycardia
Tremor
Arrhythmia
DDI:
Beta-blockers (atenolol, propranolol etc) – binds to receptors and can make asthma refractive to treatment with β2 agonists
What are examples, MOA, ADRs, DDIs of long acting B2 agonists?
Formoterol, Salmeterol
MOA: Agonise β2 receptors, which are coupled to Gs proteins. This leads to increases intracellular cAMP levels, decrease in intracellular calcium, reduced binding of calcium by light chain myosin – ends up with bronchodilation and hyperpolarisation of the muscle cells
ADR:
Tachycardia
Tremor
Arrhythmia
DDI:
Beta blockers
Examples and MOA of methylxanthines
Theophylline & aminophylline
MOA
Either act downstream of β2 agonists – phosphodiesterase inhibitors, resulting in less breakdown of cyclic AMP, however it is more likely to act by antagonising adenosine receptors
What are ADRs and DDIs of methylxanthines?
Nausea Headache Reflux Psychomotor agitation Arrthymias seizures Tachycardia (because of this 3rd or 4th line, used more in COPD and status asthmaticus)
DDI:
Levels increased by CYP450 inhibitors (erythromycin, ciprofloxacin)
What are examples of muscarinic receptor antagonists? MOA?
SAMA - ipratropium bromide, LAMA - tiotropium bromide
Blocks the effects of acetycholine in the airway – prevents bronchoconstriction and mucus secretion
What are ADRs of muscarinic receptor antagonists? Why are anticholinergic side effects limited?
Dry mouth
Urinary retention
Glaucoma
Not well absorbed across the lungs
When are SAMA/LAMA sued?
Used in patients insensitive to beta-2 agonists, or when its contraindicated such as cardiac ischaemia and arrthymia, also used in COPD as bronchoconstriction is mediated by the PNS
Examples, MOA and ADR of leukotriene receptors antagonists
montelukast
Prevents leukotriene mediated bronchoconstriction, mucus secretion, inflammatory cell recruitment and mucosal oedema, useful in 15% of patients
Angioedema Dry mouth Anaphylaxis Arthralgia Fever GI disturbance nightmares
Describe how corticosteroids work in airway disease.
Corticosteroids are the second stage in the stepwise management of asthma, and they can be given inhaled, or in severe cases orally.
They bind intracellular receptors and supress transcription of genes involved in inflammation, which reduces the infiltration of the lungs by eosinophils and other cells involved in the immune response.
They also increase the expression of β2 receptors and interleukin proteins (which are anti-inflammatory), induce apoptosis in inflammatory cells, and reduce the number of mast cells in the respiratory mucosa.
They take weeks or even months to reach their optimal effect. If they are delivered by inhaler a high proportion of the drug is deposited in the mouth or upper airway and doesn’t reach its target site.
What are the steps in acute severe asthma management?
- Oxygen (at high flow) to achieve 94-98% saturations
- Nebulised salbutamol (continuous if necessary, with oxygen)
- Oral prednisolone (for 10-14 days)
- If not responding add in nebulised ipratropium bromide
- If no improvement (or life threatening) give IV aminophylline
