There are a number of definitions of asthma in the literature, one of which states that the disease is "An acute respiratory disorder characterised by unusually reactive, constricting airways" (1). Asthma is a chronic condition that affects the airways. Although usually asthma is thought to be a chronic condition in reality it can take both acute and chronic forms. Whatever the time scale it does affect the airways and the resulting problems cause symptoms such as wheeze and chest tightness. Overall the condition may be characterised by variable and widespread airflow obstruction.
The typical symptoms of asthma are coughing, wheezing, chest tightness and shortness of breath (2). The condition causes local inflammation due to the local release of inflammatory mediators of these can cause local oedema bronchoconstriction and so tissue stretching which limits air flow in the bronchial airways (3). Common triggers of the condition are tobacco smoke, dust mites, pollen and cold air and this range of stimuli clearly show that one factor is not responsible for all cases of asthma.
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Classification of asthma can simply be made into two categories, either extrinsic or intrinsic. Extrinsic asthma is caused by the type of immune system response to inhaled allergens such as pollen, animal dander or dust mite particles, which is the classical hypersensitivity type 1 reaction (2). People suffering Atopic asthma or as its known more commonly as extrinsic asthma, usually have other allergy related problems such as hay fever, eczema and rhinitis. Atopic asthma suffers usually respond well to inhaled steroids as they suppress the immune system (3). Intrinsic asthma on the other hand is non-allergy related, it is triggered by tobacco smoke and stress. However the treatment is more complicated so simply avoiding triggers is not as easy.
The onset of asthma can occur at two different stages, childhood and adulthood. If the onset of asthma begins in childhood it is often associated with atopy, which is the genetic susceptibility to produce IgE to common environmental allergens (4). A cell which is central to the problem of extrinsic asthma is the mast cell. This cell is rather unusual since it possesses membrane receptors which bind immunoglobulin E. Once attached these immunoglobulins remain and when they come in contact with the allergen (airborne antigen) an antigen, antibody response occurs which releases the intracellular grammar some of which cause bronchi constriction. Wheezing occurs during a viral infection in childhood, a family history of allergies is strongly associated with recurrent asthma throughout childhood (4). Commonly identified in children, it can also occur later in life. Adult-onset asthma also associated with atopy. Some adults develop asthma without IgE antibodies to allergens. These adults often suffer from coexisting sinusitis, nasal polyps and aspirin or NSAID allergies. Occupational exposures to materials such as, animal products, wood dusts and biological enzymes can also cause asthma (5).
When air enters the lung under normal conditions, the thorax expands due to a pressure decrease in the thoracic cavity. The pressure decreases due to the descent of the diaphragm and the upward movement of the rib cage. The pleura are a layer of membrane surrounding each lung separately. When the chest expands, there is a pull force on the pleura, as the pleura cannot be separated from the lung. Due to this reason, the lung expands filling with air. In expiration, the passive of the structures in the lung, cause a decrease in the size of the chest, allowing the diaphragm to relax. This recoil makes expiration a passive process in contrast to the active process of inspiration (6).
Figure 1: Diagram representing the onset of asthma showing the different pathways of how shortness of breath is induced.
In asthma which is usually a reversible airway disease in addition to the bronchoconstriction effect is usually characterized by over developed mucus gland. These glands produce an excess of mucus which has also an increased viscosity which makes its clearance by the cilia involved in the mucociliary escalator more difficult than normal (7). Consequently the mucus is retained and effectively reduces airway diameters so compromising air flow and so respiratory gas exchange, the mucus which causes a thick layer to form hence reducing the size. Inflammation often occurs due to release of anti inflammatory mediators, and form cells involved in the immune response such as lymphocytes and especially in the lung, cosmophils due to immune response. Bronchconstriction causes narrowing of airway muscle, due to stimulation of smooth muscle (8). During an asthma attack the lungs expand because there is a large amount of air trapped within them. As a result of this the proprioceptors in the pleurae stretch effectively and this may cause pain (2).
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There are many drugs on the market to help relive asthma suffers of their symptoms. The principle aims of the pharmacological treatment of the disease are threefold. Firstly to control the symptoms, including nocturnal symptoms, secondly prevent of exacerbations and thirdly to achieve of the best possible pulmonary function with minimal side effects.
There are many drug strategies in the treatment of asthma. This dissertation will focus on 3 of them namely, leukotriene antagonists, immunoglobulin E antagonists (omalizumab) and sodium cromoglycate. First of all the leukotrienes are synthesised from arachidonic acid, a normal constituent of the phospholipid bilayer which is liberated by the action of phopholipases in response to various stimuli.
Leukotrienes are naturally produced eicosanoid lipid mediators. They are considered to have roles in both autocrine signalling and paracrine signalling as in to regulate the body`s response (9). Leukotrienes are produced from arachidonic acid by the enzyme 5-lipoxygenase in the body. These agents are not stored inside a cell but are always made "de novo", on demand and then they exert their physiological effects.
Leukotriene antagonist (sometimes referred to as a leukast) is a drug that blocks the receptors since it can classed as a "receptor antagonist" leukotrienes, are "fatty compounds" which are produced by the cells in immune system that cause inflammation in asthma and bronchitis, and constrict airways. Montelukast, zafirlukast and zileuton, are all leukotriene antagonists which are used to treat those diseases because of their perceived safety. Leukotriene receptor antagonists have largely replaced sodium cromoglycate as the non-corticosteroid treatment of choice (10).
Asthma is controlled using a step-wise approach which relies on symptom severity as a guide to treatment options. Patients with severe asthma are likely to be treated with regular high-dose corticosteroids (inhaled or oral), inhaled B2 agonists and standard adjunctive treatment (e.g. leukotriene receptor antagonists, sustained release theophylline or B2 agonist tablet).
Current asthma treatments act directly on smooth muscle to cause bronchodilation (B2 agonists, theophylline) or by interfering with the inflammatory process (inhaled corticosteroids - ICS). As doses of ICS rise, consideration of the risk and implications of associated side-effects becomes important, especially with long-term use.
Novel treatment options have focussed on a group of patients who cannot obtain symptom control using currently available treatments. A subgroup of these patients will have allergic type asthma and produce excess IgE in response to allergens. Exposure to the allergen leads to initiation of an inflammatory response and subsequent bronchoconstriction. The prevalence of asthmatic patients who have an allergic component to their disease is usually less than 50%. Antibodies to IgE can reduce the allergen response by binding with free IgE preventing its involvement in this part of the inflammatory cascade. http://www.nyrdtc.nhs.uk/docs/eva/Omalizumab.pdf
Omalizumab is a humanised antibody drug approved for patients with moderate-to-severe or severe allergic asthma (11), which is caused by hypersensitivity reactions to certain environmental substances. The cost of the drug is high (annual cost for England and Wales could be between £2.6 million and £7.1 million), compared to other drugs used for asthma. Omalizumab is mainly prescribed for patients with severe persistent asthma, which cannot be controlled even with high doses of corticosteroids. Omalizumab may potentially cause anaphylaxis (a life-threatening systemic allergic reaction) in 1 to 2 patients per 1,000.
Disodium cromoglycate is described as a mast cell stabilizer, and is commonly marketed as the sodium salt sodium cromoglicate. This drug prevents the release of inflammatory chemicals such as histamine from mast cells. (requires administration four times daily, and does not provide additive benefit in combination with inhaled corticosteroids).
There are many concerns with regards to the diagnosis of asthma, nowadays doctors are quick to diagnose children without going through the necessary procedures and looking at the symptoms before diagnosing a child. Parents would bring their children to the surgery with a cold or an infection of both breathing difficulties is a symptom, doctors would be too quick to diagnose it as asthma. However the over diagnosis does not just refer to children it also applies to obese and smokers. Chirag et al carried out a study in relation to the over diagnosis of asthma and its relationship to BMI, they found that doctors over diagnosed asthma upon those who were clinically obese.
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