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The following report will contain information on Asthma, and how chemical and environmental factors affect this condition. The report will consist of primary research, gathered mainly from journals, peer review articles, and textbooks. The overall objective of this assignment is to establish the relationships between asthma and chemical and environmental factors.
Asthma affects approximately 300 million individuals worldwide. Currently there is no cure for asthma and people can be diagnosed with this problem at any stage during their lives. Therefore I believe it is of great importance to have knowledge of it so that relevant steps can be taken to avoid and manage the symptoms. It is equally important to know what medication is available for patients who have asthma, and the underlying chemistry of the drugs which help relieve the symptoms. Due to the fact that there is currently no cure for the condition, asthma management is an area that will need to be explored on, in order to prevent the symptoms from worsening.
Many of us will have heard the term asthma mentioned during our lives, and may even know someone who suffers from this condition. But what is asthma? According to the international consensus report of 1992, asthma is described as " a chronic disorder of the airways which occurs in susceptible individuals; inflammatory symptoms are usually associated with widespread but variable airflow obstruction and an increase to a variety of stimuli. Obstruction is often reversible, either spontaneously or with treatment"  . A term frequently used in connection with asthma is Bronchitis. The "itis" means inflammation, and "Bronchi" refers to the passage of airway in the respiratory tract that conducts air into the lungs. One of the ways in which narrowing of the airways occurs in asthma is by an excess production of mucus.
The picture above illustrates, the difference between a person who has normal airway and that of an asthma sufferer. The muscle surrounding the bronchi in the asthma sufferer is more tense compared to that of a normal airway. This contraction of the bronchial muscle is also known as bronchospasm, and is one of the reasons behind the narrowing of the airway. Also, the lining of the bronchi has a significant amount of swelling . The presence of this bronchial narrowing, slows down the movement of air into and out of the lungs and is referred to as Bronchoconstriction. As a result more effort is required to achieve an adequate flow of air. The greater effort produces a sense of difficulty in breathing. Consequently, this results in a high-pitched whistling sound that is usually heard on expiration commonly known as wheezing. The information above relates to the effects that asthma has on the airways, but what are the factors that cause these changes to take place?. Hyperresponsivness is the expression used to describe the increased tendency of the asthmatic airway to react to a variety of stimuli (triggers) that would not cause a response in a normal airway. These triggers can cause an asthmatic attack in an inflamed airway. For example irritants such as smoke, dust, cold-air and perfume can stimulate the airways and trigger an asthma attack. Research has shown that the extent of bronchial hyperesponsivness (BHR) shows a relationship with the number of inflammatory cells recovered in the bronchial alveolar fluid from the airways of asthmatic patients. The degree of BHR decreases when asthma is well controlled with medication .
The symptoms associated with asthma are:
- Wheezing ; This is the audible evidence of air being forced through narrow airways.
- Coughing ; could be the result from stimulation of sensory nerves in the airways by inflammatory mediators that are released by various inflammatory cells involved in asthma.
- Shortness of breath; Asthmatics can experience a shortness of breath more quickly than others. The difficulty in breathing can be described in a number of different ways. For example, you may be short of breath, unable to take a deep breath, gasping for air, or feel like you're not getting enough air.
- Chest tightness; is a feeling of resistance when breathing in and out.
Statistics show that an estimated 5.2 million people in the UK are currently receiving treatment for asthma, at a cost of over £2.3 billion a year . £659 million of this is spent on drugs alone. In 2006 there were 1,200 deaths from asthma in the UK. Although the mortality rate of asthma has decreased since the 1980's, many patients however still die as a consequence of asthma. It is therefore a condition which needs to be understood and taken seriously.
Cigarette smoke contains over 4000 chemical constituents and additives including known carcinogens, toxic heavy metals, and many chemicals untested for developmental toxicity . The smoke given off from the burning end of the cigarette is known as "side-stream" smoke - "mainstream" smoke is that inhaled by the smoker. Environmental tobacco smoke (ETS) consists mainly of side-stream smoke, with a small amount of exhaled mainstream smoke. Exposure to ETS has been shown to be associated with increased prevalence of upper respiratory tract infections, wheeze, asthma and lower respiratory tract infections . When a person inhales tobacco smoke, irritating substances settle in the moist lining of the airways. These substances act as stimuli, triggering an attack in a person who has asthma. Hydrogen cyanide, a colourless, poisonous gas, is one of the toxic by products present in cigarette smoke. Tobacco smoke damages tiny hair-like structures in the airways called cilia, which have the function of sweeping dust and mucus, out of the airways. Consequently, cilia are unable to work, allowing dust and mucus to build up in the airways. Smoke also causes an increase of mucus production in the lungs than normal. As a result, more mucus than normal can build up in the airways, initiating an attack.
Inhaling second-hand smoke, also known as "passive smoking" may well be more harmful than actually smoking. This is because the smoke that burns off the end of a cigarette contains more harmful substances (such as tar, carbon monoxide and nicotine) than the smoke inhaled by the smoker. People who have asthma are more susceptible to the harmful effects of second-hand smoke. When a person with asthma is exposed to second-hand smoke, he or she is more likely to experience; shortness of breath, wheezing, and coughing associated with asthma, than a non-asthmatic.
The negative effects of smoking on asthma have been attributed to the observations that smoking can promote inflammation and remodelling of the airways. Asthmatics who smoke could be blocking the effects of treatment that can prevent their asthma from deteriorating.
House dust contains a mixture of different allergens, but the major allergen is derived from mites, especially the species Dermatophagoides pteronyssinus . A common site for house dust mites is the bed, where pillows, quilts and mattresses often serve as reservoirs for the allergen. Carpets and upholstered furniture may also contain high mite levels.
The excretion of the dust mites contains many different protein substances. When these substances are inhaled or touch the skin, the body reacts by producing antibodies. These antibodies cause the release of a chemical called histamine that leads to swelling and irritation of the upper respiratory passages. The protein attacks the respiratory passages causing hay fever as well as asthma. It will aggravate atopic (immediate allergy) dermatitis in people who have a tendency to this problem. Dust mites are inhaled involuntarily through the eyes, nose and mouth, and are to some extent unavoidable, since all homes collect dust, skin and hair which mites feed upon. The effects of dust mite allergies include; allergic rhinitis, symptoms of nasal congestion, coughing, watery eyes, runny nose and headaches. These effects are due to histamine responses that cause the mucous membranes to become inflamed.
Measures that can help reduce the effects of asthma from dust mites are
- Wash bedding at a temperature of at least 60°C to kill the house dust mites
- Keep the humidity level in your bedroom at or below 40% as too much humidity encourages dust mites
- Use vinyl covers on mattresses and pillows
In a person who is not allergic to pollen, the mucus in the nasal passages would simply move these foreign particles to the throat, where they are swallowed or coughed out. However, as soon as the allergy-causing pollen lands on the mucous membranes of the nose, a chain reaction occurs that leads the mast cells in these tissues to release histamine. This potent chemical dilates the small blood vessels present in the nose. Fluids can escape through these expanded vessel walls, which in turn cause the nasal passages to swell and results in nasal congestion.
Histamine can also cause itching, irritation, and an excess production of mucus. Other chemicals, such as prostaglandins and leukotrienes, also contribute to allergic symptoms.
Some people with pollen allergy can experience respiratory problems, and show symptoms of asthma . While asthma may reappear each year during pollen season, it can gradually become a chronic condition. The symptoms of asthma include wheezing, coughing, shortness of breath due to the narrowing of bronchial passages, and excess mucus production. Asthma can be disabling and can sometimes life threatening. If both wheezing and shortness of breath occur along with hay fever symptoms, it is a signal that the bronchial tubes have also become involved, signifying the need for medical attention.
A common trigger which can quickly cause severe symptoms of asthma, is exposure to cold air. This mainly affects those individuals with exercise-induced asthma who take part in winter sports. When cold air is inhaled into the lungs, it triggers a release of histamine, which causes wheezing in people with asthma. Dry and windy weather can cause pollen and mold to be suspended in the air, leading to problems for some people. Hot, humid air can too trigger asthma symptoms, and wet weather promotes the growth of mold spores, another asthma trigger. In certain areas, heat and sunlight combine with pollutants to produce ground-level ozone, which is also an asthma trigger.
Studies have shown that thunderstorms can trigger asthma attacks . One study has shown that during thunderstorms, the daily number of emergency department visits for asthma increased by 15%. The study concluded that the trouble was caused by several fungal spores in the air, which almost doubled. The was not the rain, but the wind, that caused this increase. Changes in barometric pressure can also be an asthma trigger.
Isocyanates are the most common cause of occupational asthma in the world . They are a group of aromatic and aliphatic compounds of low molecular weight containing the isocyanate group (-NCO). Compounds that contain alcohol groups, react with isocyanates to make polyurethane polymers. Some of the materials that are made from polyurethane include; thermoplastic elastomers, spandex fibers, and adhesives.
The isocyanates most widely used in industry are the Toluene di-isocyanate (TDI) and diphenyl-methane di-isocyanate (MDI). TDI is a combination of 2,4-toluene di-isocyanate and 2,6-toluene di-isocyanate, and is usually found in an 80:20 mixture of these two forms. Toluene di-isocyanate (TDI) is a highly volatile liquid and an effective trigger for respiratory symptoms. Its vapour is a direct irritant to the nose, throat and chest. When exposed to high concentrations, it causes immediate breathlessness, coughing, sweating and prostration which leads to death. Lower concentrations such as those released in manufacturing industry give an irritating cough and asthmatic wheezing. In the USA, polyurethane foams can be purchased in pressurized cans as DIY kits. When the chemical atmosphere around these cans were analysed, the concentrations of TDI were found to exceed those that would be acceptable to industry standards.
Experimental evidence suggests that complex organic molecules from diesel exhaust may act as allergic adjuvants through the production of oxidative stress in airway cells.Sulphur dioxide is a powerful irritant to the bronchi. Within ten seconds of inhaling it the airways tighten . When sulphur dioxide is inhaled, it causes tightening of the airways (trachea and bronchi) and can therefore cause discomfort by choking and aggressive coughing. People who suffer from asthma are considerably more sensitive to sulphur dioxide and relatively small amounts of exposure can bring on an asthmatic attack . Prolonged exposure to sulphur dioxide can damage the air sacs in lungs and cause emphysema, chronic bronchitis and acute chest illnesses.
As the bronchial muscles are central to the condition of asthma, it is important to know how they function. Unlike the muscles of the arms or legs, the bronchial muscle is an involuntary muscle. This means we cannot contract the bronchial muscle at our own will. Instead, the fibrils of the central nervous system controls the activity of the bronchial muscle. This network of nerves is collectively known as the autonomic nervous system.
The autonomic nervous system regulates key functions of the body and can be divided into two parts, the sympathetic and the parasympathetic . The sympathetic nerves are where emergency situations are handled and is described as fight or flight. During this process, the blood pressure rises, and blood is diverted from the skin and digestive organs to the muscles and brain. Consequently the bronchi dilate. The parasympathetic nervous system on the other hand is concerned with the relaxing functions of the body such as lowering the pressure of blood, causing the muscles to relax and enabling the bronchi to contract. Information is conveyed along a nerve and converted into activity using a form of electrical energy.
Between the muscle and nerve there is a small gap. This gap is linked by a chemical messenger known as a neurotransmitter. For the sympathetic nervous system the transmitter is noradrenaline, and for the parasympathetic it is acetylcholine. The parasympathetic nerves lie within the vagus nerve and are activated by what is known as a reflex 
The main difference between the two parts of the autonomic nervous system is that the sympathetic system prepares us for activity whilst the parasympathetic system is involved with more restful functions. When the lung is concerned, the parasympathetic nervous system is responsible for various reflexes including the bronchial narrowing which occurs in response to the inhalation of irritants. Sympathetic nerves on the other hand are not involved in the nerve supply of the bronchial muscle. Rather, it is responsive to the chemical messengers or neurotransmitters of the autonominic nervous system, which the body depends on for a rapid call-up of sympathetic activity in emergency situations.
Bronchodilators are medications that relax the bronchial muscles. By relaxing these muscles, the airways become larger, allowing air to pass through the lungs easier. Bronchodilators, as the name suggests, relieve the symptoms of asthma by relaxing the muscle bands that tighten around the airways, thus dilating the bronchi. This action rapidly opens the airways, allowing more air to flow in and out of the lungs. As a result, breathing becomes easier. Bronchodilators can also help clear mucus from the lungs. When the airways open, the mucus moves more freely and can be coughed out more easily. In short-acting forms, bronchodilators relieve or stop asthma symptoms and are very effective during an asthma attack. In long-acting forms, bronchodilators help to control asthma symptoms and prevent asthma attacks.
The three main groups of bronchodilators are beta-agonists, anticholinergics and theophyllines.
Anticholinergic drugs are a group of bronchodilators that affect the muscles around the bronchi . When the lungs are irritated, these bands of muscle can tighten, making the bronchi narrower, making breathing difficult . Anticholinergics work by preventing the muscles from tightening.
Atropine is a compound which occurs naturally from the plant Atropa belladonna, and was the first antichlorogenic to be used in the treatment of asthma . There are two major classes of anticholinergic agents. These are 1. naturally occurring agents such as atropine and 2. Synthetic agents such ipratropium bromide.
Atropine is well absorbed from mucosal surfaces and reaches peak blood levels within one hour. The bronchodilatory effects last between 3-4 hours. However, Atropine produces numerous side effects which can be unsafe for patients with glaucoma or prostatism. At low doses it can cause an abnormally slow heart beat (bradicardia) and at high doses, a rapid heartbeat (tachycardia). It also reduces salivary secretions and the mucus clearence in the airways by cilia.
Ipratropium bromide on the other hand has poor absorption across the respiratory and other mucous membranes. It reaches peak blood levels between 1-2 hours and its bronchodilators effect is longer, lasting between 5-6 hours. The poor absorption results in a lack of side effects and allows ipratropium to remain longer in the airways than atropine. The mild side effects associated with ipratopium bromide are; dryness of the mouth, and some patients complain of a bad taste or worsening of bronchospasm (22).
Theophylline, caffeine and theobromine are chemically classified as xanthine derivatives. They occur naturally in tea, coffee, and chocolate, but are prepared synthetically for medical purposes. Out of the three, theophylline has been used most commonly for therapeutic use of chronic asthma.
There have been many mechanisms used to explain the action of theophyllines. One explanation used is that, by increasing the intracellular concentration of 3`,5`-cyclic adenosine monophosphate (cAMP) the bronchial smooth muscle cells are, as a result, dilated (bronchodilation). Theophylline works by inhibiting the enzyme phosphodiesterase, therefore preventing the hydrolysis of cAMP.
The major pharmological action of theophylline is its ability to relieve bronchospasm and decrease airways reactivity i.e. it decreases the airways hyperresponsivness. Theophylline may therefore be used to relieve acute symptoms of asthma and even some symptoms of chronic asthma.
- Beta 2 agonists
Beta 2 agonists are medications that stimulate the beta receptors. These receptors are found in many organs of the body including; lungs, heart and blood vessels. In the lungs, the receptors cause dilation of the bronchi. Consequently, beta agonists stimulate the beta receptors in order to dilate the bronchi, mimicking the effects of the sympathetic nervous system, allowing adequate air flow in to the lungs. As the heart and blood vessels also have receptors, a common side effect with the use of beta agonists, is that it stimulates them thus resulting in an increase in heartbeats and blood pressure.
When the beta receptors have been activated by the beta 2 agonists, it results in the activation of the enzyme adenyl cyclase, which leads to an increase in intracellular cyclic 3,5-adenosine monophosphate (cAMP). Consequently, protein kinase A is activated and phosphorylates several target proteins within the cell. As a result, the phosphorylation process leads to muscle relaxation of the bronchi by several steps:
- By lowering the calcium ion concentration associated with muscle contraction, by active uptake of calcium ions from the cell into intracellular stores
- By inhibiting the hydrolysis of phosphoinositide, resulting in the reduction of cytosolic free calcium concentration
- By opening of the large-conductance calcium-activated potassium channels that repolarise the smooth muscle cell.
- There is some evidence to suggest that beta-2-agonists increase mucociliary clearence in patients with asthma 
Beta-2-agonists can be divided into two main groups; i) short-acting and ii) long acting agonists. Short acting beta-2 agonists such as salbutamol and terbuline relax bronchial smooth muscle which in turn enables an increase in airflow. Its bronchodilatory effect occurs within 3-5 minutes and lasts for between 4-6 hours.
On the other hand, long acting beta-2 agonists such as salmeterol and formoterol cause bronchodilation for at least 12 hours.
The devices used to relieve the symptoms of asthma, by delivering the drug to the lungs, can be divided into 3 main groups. These are;
- Metered-dose inhalers (MDI's)
- Dry-powdered inhalers (DPI's)
In 1998 about 80% of inhalers dispensed on prescription in England were MDI's and are still the most commonly used inhaler device. In MDI's the drug is dissolved or suspended in a propellant under pressure. When activated, a measured volume of drug and propellant is released. The propellant provides the force to push and break up particles so they can be inhaled more easily. There has gradually been a change in the type of propellant used in MDI's. Initially they were chlorofluorocarbons (CFC's) but have now been replaced by ozone-friendly propellants such as hydrofluoroalkanes (HFA's).
MDI's are also available as breath-activated devices, which can operate at low inspiratory flow rates. This makes them more effective for the elderly and those suffering from an attack, since it does not require coordination of releasing and inhaling the drug.
The drug in DPI's is formulated as a dry powder without a propellant, unlike MDI's. They are designed to be inhaled through inspiratory airflow, which releases the powder and disperses the drug into small particles so it can be delivered to the lungs effectively. Examples of dry powder inhalers include; Diskhaler, Accuhaler and Turbohaler. The diskhaler and accuhaler can be categorised into one group as they both contain lactose which acts as a carrier. Turbohaler on the other hand, is an inhaler device which delivers the pure drug without a carrier.
A nebuliser is a delivery system that converts drug solution into a spray of droplets that are between 1-5 micrometers in diameter. It is driven by a compressor (electric or battery operated). These droplets are inhaled directly into the lungs via a mouthpiece or facemask. Indications for use of nebuliser treatment in asthma have declined.
As mentioned earlier, there is currently no cure for asthma suffers. The best way to minimise the effects and symptoms of asthma would be to manage the condition by the use of both medication and therapy. Medication such as inhalers act as bronchodilators, allowing suffers to breath more easily. When an asthmatic, inhales an allergen such as pollen, the body responds by producing IgE antibodies, and releases inflammatory mediators such as histamine and leukotrienes from mast cells and basophils. As a result of these inflammatory mediators, breathing becomes difficult and symptoms of asthma are experienced. There have been various strategies investigated to reduce this problem.
Omalizumab is a highly specific monoclonal antibody that binds to circulating IgE and prevents the receptor from binding onto the effector cells (mast cells and basophils). As a result the number of receptors decrease. Studies have shown that omalizumab reduces the rate of asthma exacerbations and visits to hospital emergency departments. Omalizumab therefore, represents a new approach for the treatment of asthma. It is however more expensive than the current devices used to treat the symptoms.
Located in the airways are adhesion receptors, that have an important role in the immune response.
Agents that block the action of these receptors have the potential to be potent anti-inflammatory drugs. However, there are dangers that this method could inhibit natural immune responses, leading to an increased risk of infections. It is therefore essential that further studies are carried out.
This dissertation has investigated the chemical and environmental factors that affect asthma. Factors such as dust mites, environmental tobacco smoke and isocyanates were analysed to establish how they affected the respiratory system. From conducting this research I have found out that the bronchi are central to the condition of asthma and symptoms such as coughing, wheezing and breathlessness are all related to the bronchi. One of the important features of asthma was found to be hyperresponsivness. This term is used to describe the increased tendency of the asthmatic airway to react to a variety of stimuli (triggers) that would not cause a response in a normal airway. One of the interesting points that was looked at was how the autonomic nervous system plays an important role in the lungs. From this I learnt, that the parasympathetic nervous system is responsible for various reflexes including the bronchial narrowing which occurs in response to the inhalation of irritants.
The report also contained information on the different medications that are used to relieve the symptoms of asthma, that are known as bronchodilators. The three main groups of bronchodilators were found to be; beta-agonists, anticholinergics and theophyllines. Beta agonists work by stimulating the receptors found in the bronchi, anticholinergic drugs work by preventing the muscle surrounding the bronchi from contracting and theophylline has the ability to relieve bronchospasm and decrease airways reactivity i.e. it decreases the airways hyperresponsivness.