Asthma 1 Flashcards
What is chronic obstructive pulmonary disease (COPD)?
- Chronic condition
- Narrowing of airways
- Predominantly inflammatory
- Combination of chronic bronchitis and emphysema
- Poorly reversible
What is chronic bronchitis?
Persistent cough with mucus production
What is emphysema?
Destruction of tissues around alveoli
What is bronchial asthma?
- Chronic condition
- Narrowing of airways
- Occurs in attacks
- Predominantly inflammatory
- Can involve structural changes to airways
Narrower lumen
Airway plugged with mucus - Obstruction largely reversible, remodelling less so
What do we use to measure levels of obstruction?
FEV1 – forced expiratory volume (1 sec)
PEFR – peak expiratory flow rate
What are background tendencies for asthma?
- Genetic factors – allergy and atopy genes
- Environmental influences in early life (e.g. maternal smoking, intrauterine nutrition, avoidance of dietary and environmental allergens in first few years of life
What are specific triggers for asthma?
- Excreta of house dust mites
- Pollen
- Exercise or emotion
- Cold air
- Respiratory tract infections
- Animal fur, dander, saliva
- Fungal spores
- Occupational factors
- Drugs (e.g. aspirin)
- Environmental pollutants
What are the two broad categories asthma can be divided into?
- Intrinsic/ non-atopic/ non-allergic (from within – exercise and emotion)
- Extrinsic/ atopic/ allergic (from outside – pollen/ animal fur)
What are the trachea and bronchi supported by?
- Trachea and primary bronchi are supported by rings of cartilage
- Plates of cartilage in secondary and tertiary bronchi
Bronchioles don’t have cartilage. What do they have instead and what is important in determining the diameter of airways?
- They have rings of smooth muscle that surround them
- Muscle tone important in determining diameter of airways
What are features of a healthy airway?
- Lined with ciliated epithelium
- A few goblet cells
- Relatively thin basement membrane
- Sparse smooth muscle
- A few submucosal glands
What are features of an asthmatic airway?
- Epithelial desquamation – lost a lot of ciliated cells
- More goblet cells – produce more mucous (hyperplasia)
- Thicker basement membrane
- Smooth muscle hypertrophy and hyperplasia
- Submucosal glands increase in number and size (hypertrophy and hyperplasia)
- Infiltration be eosinophil and neutrophils (immune system cells)
- May have oedema taking place
What has been hypothesised to cause an asthma attack during exercise?
It has been hypothesised that during exercise we bring large volumes of air into the lungs via the mouth, and this is not warmed and humidified by passage through the nasal cavity, as occurs in normal breathing. This leads to dehydration of the airway surfaces, which initiates the asthma attack
What happens with allergic airway sensitisation?
- Inhalation of allergens trigger airway allergic immune responses
- Dendritic cells sample allergen (take in in and digest in by endocytosis) and display pieces of the allergen on their surface on MHCII
- DCs migrate to the LN (lymph node), activate allergen-specific T cells and induce clonal expansion and TH2 polarisation
- TH2 cells produce inflammatory cytokines which induce allergic inflammation and asthmatic responses
- B cell recognises allergen because it has antibodies on it’s cell surface. It the antibody is compatible with the allergen the B cell will start the process of activation.
- The B cell will internalise the antigen and present fragments of the antigen on it’s cell surface using the MHCII proteins
- The B cell can now interact with one of the expanded T cells
- This triggers B cell clonal expansion and start the production of antibodies (most important class in allergic asthma in IGE)
Are asthma attacks biphasic or monophasic?
Biphasic
What happens in the early phase of an asthma attack?
- Early phase: bronchoconstriction
Mast cell degranulation
Increased acetylcholine from parasympathetic neurones
These produce bronchoconstriction
Occurs immediately after someone inhales allergen
What happens in the later phase of an asthma attack?
- Later phase: inflammation (and bronchoconstriction)
Recruitment of leukocytes
Production of inflammatory mediators
Delayed by up to 6 hours
Give features of a mast cell and what happens when it activates
- Cytoplasm full of granules
- Granules containing pre-formed (early) mediators e.g. histamine, proteases, proteoglycans chemotactic factors
- Degranulates when activated (releases contents into extracellular environment)
- Other mediators are often derived from membrane lipids when mast cell is activated:
Leukotrienes, prostaglandins, thromboxanes, prostacyclins
What induces mast cell activation and degranulation and how does this work?
• IgE cross-linking induces Mast cell Activation and degranulation
- Mast cell recognises antigen through IgE antibodies to become activated (IgE binds to receptors on mast cells)
- IgE is the antibody class produced when someone becomes sensitised to an allergen
- When mast cell becomes activated it will degranulate and will start producing lipid-derived signalling molecules leading to events in early phase
- Immune system cells important in later phase
- Eosinophils will be attracted into the areas by the molecules released by mast cells
- Eosinophils will release signalling molecules (leukotrienes, interleukins) and will also release major basic protein which leads to:
- Tissue damage, mucus secretion, remodelling, sensitisation
What are the early mediators of bronchial asthma and what do they do?
- Acetylcholine, leukotrienes C4, D4, E4 (prostaglandin D2, histamine)
Contraction of airways smooth muscle, increased vascular permeability, increased bronchial secretions - Chemotactic factors
Infiltration of lung tissue by neutrophils and eosinophils
What are the later mediators of bronchial asthma and what do they do?
- Leukotrienes C4, D4, E4, interleukins, growth factors
Contraction of airways smooth muscle, increased vascular permeability, increased bronchial secretions, remodelling - Major basic protein from eosinophils
Epithelial desquamation, cell death
What are the NICE guidelines for asthma?
- If the patient has fewer than three asthma attacks per week then they will be given a short acting beta agonist (SABA) inhaler
- If their asthma is uncontrolled with a SABA alone, then they will also be given a low dose inhaled corticosteroid (ICS)
- If this still does not bring their asthma under control, then a leukotriene receptor antagonist (LTRA) will be prescribed
- The next step is to add in a long acting beta agonist (LABA) e.g. salmeterol, with or without the LTRA
4a. If control is still not achieved, then the patient may be offered maintenance and reliever therapy (MART). MART combines a preventer (corticosteroid) and reliever (long acting, fast onset beta agonist e.g. formoterol) in a single inhaler
5A) If the patient’s asthma is still not controlled by the MART, or if it has no been prescribed and they are continuing with a SABA, ICS, LABA +/- LTRA, then the next step is to increase their steroid dose (moderate dose ICS)
6A) a further increase to high dose ICS may be considered
7A) An additional drug e.g. muscarinic receptor antagonist or theophylline may be added - If control is still not achieved, then specialist advice: ae should be sought
What are some bronchodilator drugs used in asthma?
B2 adrenoceptor agonists Long acting B2 agonists Theophylline mAChR antagonists Leukotriene antagonists
What are anti-inflammatory drugs used in asthma?
Glucocorticosteroids
Monoclonal antibodies
What do relievers and preventers do with asthma and give examples of them
- Reliever (relieves symptoms) Short acting B2 adrenoceptor agonists Sometimes Long acting B2 agonists - Preventer (tries to prevent it) Glucocorticosteroids - The rest of the drugs are add-on’s if the initial drugs aren’t working
What are the non-selective agonists at the B-adrenoceptor and their relative potencies?
Isoprenaline > adrenaline > noradrenaline
What are agonists selective for subtypes of the B-adrenoceptor?
B1: dobutamine
B2: salbutamol
What is a selective antagonist at the B-adrenoceptor?
B1: atenolol
What is a non-selective antagonist at the B-adrenoceptor?
propranolol
What are the effects mediated by B1 receptors?
- SA node: increased rate
- Ventricular myocardium: increased force
- Propulsive smooth muscle of gut: relaxed
- Renal juxtaglomerular cells: release of renin
- Adipocytes: lipolysis
- Hepatocytes: glycogenolysis
What are the effects mediated by B2 receptors?
- Airway smooth muscle: relaxed
- Uterus: relaxed
- All blood vessels: dilated
- Skeletal muscle: tremor and glycolysis
What is the development of B2-selective agonists as bronchodilators?
- Adrenaline is non-selective between alpha and beta receptors
- If you modify it’s structure it becomes effective as a bronchodilator
- Increasing the size of the substituent of the nitrogen increases selectivity for B-receptors and then for B2 receptors, it also reduced inactivation by neuronal uptake and by monoamine oxidase
- Replacing one of the catechol -OH groups by -CH2OH or changing its ring position reduces inactivation and can increase selectivity for beta 2 receptors
What can B-agonist bronchodilators be divided into?
Short acting and long acting
What are some short acting (SABAs), what is their relative lipophilicity and how are they delivered?
Salbutamol
Terbutaline
Similar structures but in the terbutaline the position of the OH group is moved along the ring
Relative lipophilicity is low (1)
Mainly delivered by metered dose inhalers
What are the uses of SABAs?
All asthmatics should have a reliever inhaler
If asthma occurs twice a week or less, may be sole drug
In many people, used in addition to preventers
Preventers most commonly inhaled, but available as tablets, oral solutions, injectable solution and infusions
What are some long acting agents, how are they taken, what is their lipophilicity and structure?
Salmeterol
Formoterol
Only taken twice a day as they are long acting
Normally given in combination with glucocorticoid steroid (add on treatments to improve preventer actions)
Can occasionally be used as relievers
Relative lipophilicity very high (3200)
Have long lipophilic chain
What are the mechanisms (two theories) underlying the long duration of action of salmeterol?
Two sites on the B2 adrenoceptor which drugs can bind
First site is the site salbutamol and adrenaline normally bind to
Second site is called the Exosite. The drug can bind to the exosite and then repeatedly act on the active site to activate the receptor
The terminal portion of the alkylamine chain anchors the molecule to the receptor
- Second theory underlying the long duration of action of salmeterol
These drugs are very lipophilic
Dissolve in lipid bilayer – provides reservoir of drug which slowly leaks out of lipid bilayer and acts on the receptor
How does B2 adrenoceptor signalling work?
- Coupled by Gs to adenylate cyclase
- When activated increases the amount of cAMP in the cell
- This increases activation of pKA
- pKA phosphorylates protein targets in the cell
- End result is smooth muscle relaxation and reduced mast cell degranulation
What are B2 receptor agonists acting as?
functional antagonists of the pro-asthma mediators
What are the unwanted effects of B-agonist bronchodilators, why and how may they be minimised?
- Tremor
Peripheral effect involving interference with muscle spindle function - Tachycardia, palpitations
Activation of cardiac B-adrenoceptors - Nervous tension
Effect on CNS - Hypokalaemia
Stimulation of Na+/K+ ATPase in skeletal muscle (uptake of potassium out of plasma and into skeletal muscle) - Headaches
- Muscle cramps
- These may be minimised by inhalation rather than oral administration
How can SABAs be administered and how do you use this device?
- Short acting beta adrenoceptor agonists are administered using ‘metered dose inhalers’ (MDIs)
- MDIs have pressurised cannisters of drug housed inside a device with a mouthpiece
- To use the device the used removes the cover and places the mouthpiece in their mouth. They then press down on the canister and the device dispenses a fixed dose of the drug that the user then inhales
What is the effectiveness of an MDI?
- the aim of using an MDI rather than a tablet is to get the drug into the lungs and reduce the amount that enters the systemic circulation. This enables side effects to be minimised.
- Many asthmatics do not use their inhalers correctly
- MDIs are quite ineffective at delivering drug to the lungs, even when used with optimal technique
What is a spacer device?
plastic chamber that the medication is dispensed into before the user breather it in
What is a nebulizer?
- This uses compressed air or ultrasound to atomize the medication into the patient’s air stream
- The medication is loaded into the device in liquid form
- Studies suggest that nebulizers are no more effective than MDIs with spacers. They are considerably more expensive and are bulkier but are still often used with hospital inpatients
