Asthma 1 Flashcards by Miayla Marcus

What is chronic obstructive pulmonary disease (COPD)?

Chronic condition
Narrowing of airways
Predominantly inflammatory
Combination of chronic bronchitis and emphysema
Poorly reversible

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What is chronic bronchitis?

Persistent cough with mucus production

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What is emphysema?

Destruction of tissues around alveoli

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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

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What do we use to measure levels of obstruction?

 FEV1 – forced expiratory volume (1 sec)

 PEFR – peak expiratory flow rate

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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

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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

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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)

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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

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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

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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

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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

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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

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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)

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Are asthma attacks biphasic or monophasic?

Biphasic

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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

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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

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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