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Asthma is a disease that affects a large proportion of the general population and inhaled glucocorticoids have become the predominant form of anti-inflammatory treatment for mild to severe asthma. This paper looks at the different mechanisms through which glucocorticoids exert their effects in addition to the side effects of these drugs, both local and systemic. It also compares the use of the many available inhaled corticosteroids in the treatment of asthma and the use of different inhaler devices. This paper investigates the use of inhaled glucocorticoids as a whole and in all aspects so as to ascertain why these drugs are first line therapy for anti-inflammatory treatment in asthma.
WHAT IS ASTHMA
Asthma is an immune mediated response characterized by the reversible narrowing of the bronchi which changes in severity over short periods of time(Oxford Concise Medical Dictionary. 2010, Oxford Concise Medical Dictionary. 2010, Merck Sharp & Dohme Corp 2001) (Oxford Concise Medical Dictionary. 2010). It is "a chronic inflammatory disorder characterized by increased responsiveness of the bronchi to various innocuous stimuli, manifested by widespread and variable airway narrowing" due to a mixture of mucus hypersecretion, bronchial smooth muscle contraction and inflammatory cell release from the bronchial epithelium.
The prevalence of asthma in the world is currently on the rise in both adults and children. At present, it is estimated to be at about 7.2 percent worldwide, 6 percent in adults and 10 percent in children. Asthma has been observed to be more common in male children than in females with a male to female ratio of 3:2. However, in adults aged 45-74 asthma is more prevalent in females than males.(Merck Sharp & Dohme Corp 2001)
There is no known cause of asthma, but it seems to be a multi-factorial disease caused by a mixture of genetic and environmental factors. Specific environmental factors include both indoor and outdoor pollution, exposure to specific allergens such as animal dander, tobacco smoke, cold air and also fungi in the form of mould spores. Studies have proved that children living in rural areas are at a lesser risk of developing asthma because they are less exposed to these factors. (Priftis, Mantzouranis et al. 2009)
A diagnosis for asthma is usually made by spirometry- measuring the ratio of the patient's functional expiratory volume in one second to forced vital capacity (FEV1/FVC) and by using peak flow metres to measure the patient's peak expiratory flow. The peak flow of an asthmatic patient should be at its highest when the patient least experiences the symptoms of asthma. In the United Kingdom, asthma is diagnosed by taking a very careful patient history followed subsequently by spirometry tests (, NHS choices, your health, your choices2007) . Once the diagnosis of asthma has been made, regular peak flow measurements should be taken to assess the severity of the patient's asthma and their response to treatment and management of the disease (Taylor 1997).
Asthmatic patients usually exist in two states, a steady chronic state and an acute state (asthma attack) in which their 'steady-state' symptoms are exacerbated. The principal clinical features of an asthma attack include wheezing, shortness of breath, cough and chest tightness. Other symptoms include tachycardia and abnormal chest sounds. Patients experiencing an asthma attack are seen to use their accessory muscles of respiration to increase the amount of air they can get into their lungs.
The above symptoms are representative of the underlying pathophysiology of the disease. The immediate asthmatic response is a type of hypersensitivity called Type 1 hypersensitivity and it occurs over a time frame of approximately 1-2 hours. This is an immunoglobulin E (IgE) mediated response. IgE antibodies for certain allergens are present in the system of those patients with atopic asthma. Therefore when these allergens are inhaled, adjacent IgE molecules on mast cells recognise this antigen and cross-link; this is what triggers mast cell degranulation. The degranulation of the mast cells leads to the release of inflammatory mediators such as histamine, prostaglandins and leukotrienes and the recruit eosinophils and lymphocytes which are the cause of the chronic inflammation observed in asthma (Professor Jeremy Ward 2009).
As a result of the activation of this inflammatory response, epithelial cells lining the bronchi are shed and can be observed in the sputum of asthmatic patients. This suggests a disruption in the attachment of the epithelial cells to the basement membrane. Inflammatory mediators such as prostaglandins and cytokines increase the permeability and diameter of blood vessels in the bronchi leading to microvascular leakage. Endothelins released by bronchial epithelial cells are powerful bronchoconstrictors and therefore worsen the airway narrowing. The presence of inflammatory cells and mediators cause airway hyperresponsiveness which leads to bronchial smooth muscle contraction. Over time, hyperplasia and hypertrophy of the bronchial smooth muscle is observed. The inflammatory response also leads to proliferation of mucus-producing cells which brings about an increase the production of mucus resulting in a "mucus plug" in the airways and further limiting the amount of air reaching the lungs.
As we have seen above, the inflammatory response in asthma is root of most of the underlying pathology causing airway narrowing in asthma. Bronchoconstriction, airway hyperresponsiveness and an increase in mucus production all occur as a result of activation of the inflammatory response and lead to airway narrowing. Therefore treatment of asthma with first line anti-inflammatory drugs such as glucocorticoids is essential in relieving many of the chronic symptoms of the disease.
HOW DO THEY WORK?
The endogenous glucocorticoid is cortisol which is produced in the zona fasciculata of the adrenal glands. Its release is controlled by the corticotrophin releasing hormone produced in the hypothalamus. This stimulates the anterior pituitary to release corticotrophin resulting in the secretion of cortisol from the adrenal cortex. Cortisol is released in an irregular manner, with its highest systemic levels observed early in the morning and its lowest levels at about three to five hours after the onset of sleep. Cortisol is commonly referred to as the "stress hormone" as it is released in stressful circumstances. Its major function is to help restore homeostasis after a period of stress. It has widespread effects on most of the body's systems. It increases blood pressure, counteracts insulin to increase blood sugar, increases gastric secretion and also acts as an anti-diuretic hormone (S. T. Holgate, Martin Church, Lawrence M. Lichtenstein 2006). Most importantly in relation to therapy in asthma, it suppresses the immune system, and hence inflammation by preventing proliferation of T-cells.
Pharmacologically synthesised steroids exert their effects in a similar manner to the endogenous steroid cortisol. Due to the fact that cortisol acts on many of the body's systems, side effects from glucocorticoids are observed over almost all systems.
Glucocorticoids (GC) used in the treatment of asthma are of the inhaled form. When a drug is properly inhaled only approximately 20 percent of the drug reaches the lung, the remaining 80 percent is swallowed (Johnson 1996). GCs are highly lipid soluble compounds and diffuse with ease through the phospholipid bilayer of cell membranes. The more lipophilic steroids are likely to be deposited on bronchial mucosa as 'micro depots' therefore extending the duration of their local anti-inflammatory effects (Johnson 1996). GCs act by binding to the glucocorticoid receptor GR which is expressed in most cells of the body. It is a cytoplasmic receptor which migrates to the nucleus upon binding of the glucocorticoid. The binding site for GC on the receptor is located at the C-terminal whilst the binding site on the receptor for the chromatin is located in the middle of the molecule between two zinc fingers (van der Velden 1998). In the inactivated state, the GR is bound to several proteins including two molecules of heat-shock protein 90 (hsp90) which bind at the C-terminal. The hsp90 protein act as a chaperone protein stopping the inactive GR from translocating to the nucleus (Barnes 1998). When GC binds, these proteins dissociate and the receptor-drug complex translocates to the nucleus where it forms homodimers which regulate gene transcription in one of three major ways:
1)by binding to glucocorticoid responsive elements (GRE) on the chromatin. Here, they act to suppress or activate the genetic transcription of certain inflammatory and anti-inflammatory mediators respectively.
2)by interacting with certain transcription factors
3)by modifying the stability of certain mRNA
action of glucocrticoids in the nucleus.jpg
Fig 1.Direct interaction of NF-kB, AP-1 and GC-GR causes mutual suppression: Diagram adapted from (Barnes 1998)
The GC-GR complex may bind to GREs on certain steroid-responsive genes. The GREs are usually located in close proximity to the 5' upstream promoter region of that gene; and the interaction of the homodimers with the GRE alters the rate of transcription of the genes (Barnes 1998). The rate at which transcription of the genes is altered depends on the affinity of the GC-GR complex for the GRE, the location of the GRE relative to the site at which transcription of the gene occurs and the number of GREs. They can be either positive or negative responsive elements which act to activate or suppress gene transcription. Genes that contain positive GREs are up-regulated by GCs. These are anti-inflammatory proteins such as lipocortin-1. Lipocortin-1 is a protein which inhibits the intracellular protein PLA2 thereby inhibiting the production of lipid inflammatory mediators. The beta-2 adrenergic receptor present in the bronchi (which when stimulated causes bronchial relaxation) is also up regulated by GCs. Inducible nitric oxide synthase (iNOS) is an enzyme found in airway epithelial cells. It is responsible for the production of nitric oxide which is thought to contribute to the transformation of T-helper cells to Th2 cells promoting the production of IgE and recruitment of eosinophils. Glucocorticoids block the production of iNOS and hence nitric oxide by inactivating the transcription factor- NF-kB involved for the production of this enzyme (van der Velden 1998). An enzyme whose transcription is actually up-regulated by GCs is secretory leukocyte protease inhibitor (SLPI). This enzyme is the major protease in the airways and is responsible for producing anti-inflammatory effects by countering the action of pro-inflammatory enzymes such as tryptase.
GCs also inhibit the transcription of most chemokines and cytokines involved in the inflammatory response in asthma. They inhibit their transcription by the inactivation of the transcription factor NF-kB. The substances which GC inhibit their transcription include the cytokines IL-3, IL-4, IL-5 and IL-6. Tissue necrosis factor (TNF-alpha) is a cytokine released from mast cells and macrophages during the initiation of the allergic reaction in asthma. It is responsible for the recruitment of many inflammatory cells such as neutrophils and eosinophils to the airways and also plays a role in the upregulation of cell adhesion molecules and generation of airway hyper-responsiveness (Thomas 2001). GCs also inhibit granulocyte-macrophage colony-stimulating factor (GM-CSF) which is a cytokine that stimulates stem cells to synthesise granulocytes and monocytes (immature macrophages). These cells all play an important role in generating and propagating the inflammatory response, so by inhibiting the production of this factor GCs bring about very strong anti-inflammatory reactions. Additionally, the chemokines: macrophage inhibitory protein (MIP-1alpha), RANTES and IL-8 are inhibited resulting in reduced activation of granulocytes.
Several steroid responsive genes such as the genes encoding chemokines and cytokines do not contain positive or negative GREs in their promoter region as seen above, and so do not have binding sites for the GC-GR complex. The complex therefore interacts directly with certain transcription factors, to which it binds to through leucine zipper interactions. Transcription factors that the complex interacts with include activating protein (AP-1), cAMP responsive element binding protein (CREB) and nuclear factor (NF)-kB. Interaction of the GC-GR complex with the heterodimeric AP-1 results in the inhibition of its binding to DNA which in turn inhibits the proliferation of anti-inflammatory cells as AP-1 may play a role in controlling this process. In unstimulated cells the heterodimer NF-kB is a cytoplasmic transcription factor, which when stimulated by certain cytokines translocates to the nucleus where it activates specific genes involved in the inflammatory response. The GC-GR complex acts to inhibit this process by interacting directly with the p65 subunit of NF-kB resulting in transrepression. This is a mechanism whereby one protein suppresses the activity of another; in this case the GC-GR complex is suppressing the activity of NF-kB. GCs may also inhibit NF-kB by up-regulating the production of an inhibitory protein IKB-alpha which binds to and inactivates NF-kB in the cytoplasm thereby hindering this transcription factor from translocating to the nucleus and activating pro-inflammatory genes. It has been suggested that there may be a direct protein-protein reaction between CREB and the GC-GR complex in the nucleus which increases cAMP levels and results in bronchodilation (van der Velden 1998).
Studies have proven that inhaled GCs may reduce the number and activation of inflammatory cells such as eosinophils, macrophages, T-lymphocytes and epithelial cells in the airways. These drugs have been seen to inhibit the cytokine-mediated survival of eosinophils by inhibiting the production of cytokines such as IL-5 and GM-CSF which are necessary for eosinophil survival. This results in a reduction in the number of eosinophils in the airways as they undergo apoptosis. GCs have not been observed to reduce the secretion of mediators from mast cells, but they may reduce the number of mast cells in the airways by inhibiting the cytokine-mediated proliferation of mast cells. In-vitro studies of rabbit, mouse and guinea pig tissue showed that macrophage secretion decreased upon treatment with the glucocorticoid- dexamethasone. This result was dose-dependent, so as the dose of dexamethasone increased, the secretion of complement proteins, enzymes and regulatory factors such as IL-1 from macrophages decreased. Also, secretions of collagenase, elastase and tPA (tissue plasminogen activator) which are macrophage educed were all significantly lowered upon treatment with dexamethasone (Werb 1978). GCs decrease the number of T-lymphocytes by direct inhibition of T-cell proliferation, but also by inhibition of the production of T Cell Growth Factor which stimulates long term T-cell proliferation. Airway epithelial shedding is greatly reduced in the presence of glucocorticoids (Gillis, Crabtree et al. 1979). They have also been shown to have a large effect on mucus secretion and microvascular leakage by inhibiting the production of prostaglandins, tumour necrosis factor alpha (TNF-alpha) and other pro-inflammatory proteins resulting in a decrease in both prostaglandins and TNF-alpha are usually present in large amounts in the airways of asthmatic patients. Inhaled GCs have also been proven to reduce hyperresponsiveness in the bronchi. A study on guinea pigs in which the inflammatory response has been triggered by inhaling trimellitic anhydride (TMA) dust which is a known spasmogen has shown that treatment with nebulised budenoside- a glucocorticoid is effective in reducing airway hyperresponsiveness (Hayes, Barnes et al. 1993). By reducing inflammation in the airways, inhaled glucocorticoids have been shown to decrease airway hyperresponsiveness to cold air, fog, exercise and common irritants such as metabisulphates, dust particles, sulphur dioxide and tobacco smoke which are all spasmogens that can initiate the acute stage of the asthmatic response.
WHY ARE THERE SO MANY DIFFERENT GLUCOCORTICOIDS?
The inhaled corticosteroids used in the treatment of asthma include beclomethasone dipropionate (BD), fluticasone propionate (FP) and budesonide. Inhaled glucocorticoids were originally developed as a measure to reduce the dose of oral corticosteroids which severely asthmatic patients were taking and hence reduce the level of side effects. However, it has been proven that the inhaled glucocorticoids lets several asthmatic patients on oral steroids discontinue the use of them and continue treatment on inhaled glucocorticoids exclusively. Inhaled glucocorticoids have over the years also become the preferred treatment for patients with even milder asthma as it has become apparent that some form of inflammation is present at almost every stage of the disease. Oral glucocorticoids are now only used in patients with very severe asthma where the inhaled steroids are observed to be ineffective.
With the establishment of the efficacy of inhaled glucocorticoids in the treatment of mild to severe asthma came a boom in the manufacture of many different inhaled glucocorticoids. Why are there so many? And what makes one glucocorticoid better than the other? The drugs have to be compared on many levels including: tissue uptake and distribution, receptor affinity, bioavailability clearance.
TISSUE UPTAKE AND DISTRIBUTION: The lipophilicity of a drug determines the rate of its tissue uptake and distribution. A lipophilic drug is one which is able to dissolve in fats, oils, non-polar solvents and other lipophilic substances. As mentioned previously, highly lipophilic drugs are advantageous as they are taken up faster and better distributed in the bronchi. Inhaled GCs with increased lipophilicity are more likely to be deposited on the epithelial cells subsequently leading to slow release from "the lung lipid compartment" which increases the duration for which the drug is active (Johnson 1996). The lipophilicity of a drug also increases its affinity for the receptor and extends the duration of time for which it occupies the receptor. However, highly hydrophilic steroids are advantageous in the sense that the rate of disintegration of the drug is increased. Highly lipophilic drugs remain deposited on the epithelial cells for longer and are more likely to be taken up systemically and produce undesirable systemic side effects.
RECEPTOR AFFINITY: Receptor affinity measures the "strength of the force of attraction" that the drug has for the receptor. This is very important as the degree of receptor affinity of a drug is usually indicative of the potency of that drug as an anti-inflammatory. A factor that particularly affects the receptor affinity of a drug is the configuration of the molecule (Johnson 1996). A drug which has a very similar shape and configuration to that of the endogenous ligand for the receptor will have a greater affinity for that receptor; these drugs will also have greater glucocorticoid-receptor stability. Receptor affinity is measured in comparison to other drugs in that drug class. Greater relative receptor affinity is desired because it is associated with a high rate of transcription which leads to an increased rate of production and inhibition of anti-inflammatory and pro-inflammatory mediators respectively. For instance, FP has a 3-fold greater affinity for the GC receptor than budesonide so a greater concentration of budesonide would be required to produce the same effect as a certain concentration of FP. However with high receptor affinity comes increased systemic side effects as the systemic receptors for GCs are identical to those in the lungs. The drug would show high affinity for these receptors and be more potent in producing systemic side effects.
comparison of receptor binding.jpg
Fig 2.Glucocorticoid Kinetics; diagram adapted from (Johnson 1996)
BIOAVAILABILITY: The bioavailability of a drug compares the amount of a drug the patient is exposed to, and the amount that actually reaches the systemic circulation. For most drugs, low bioavailability is desirable as indicates a high concentration of drugs at the required site of action and low concentrations systemically to produce side effects. The case of glucocorticoids is the same; FP- when taken orally has a bioavailability of 1 percent compared with the bioavailability of BDP which is 20 percent. However, this difference in bioavailability when taken orally is not present when these drugs are inhaled. There is not much variation in the bioavailability of GCs when they are administered via the inhaled route.
CLEARANCE: This is defined as the rate at which a drug is eliminated from the blood or plasma. High clearance means a low concentration of drug will be present in the systemic circulation at any given time resulting in less systemic side effects. Budesonide and FP are examples of glucocorticoids that undergo extensive first pass metabolism with clearance values of 84 litres per hour and 69 litres per hour respectively, so their systemic side effects are very limited. This is a quality that is highly sought-after in inhaled glucocorticoids.
A pro-drug is one that is administered in an inactive form which is metabolised into its active form once in the body. Beclomethasone dipropionate is currently the only marketed inhaled steroid that is administered in the pro-drug form. It is activated into its active metabolite- beclomethasone-17-monopropionate by esterases in the lung. Pro-drugs are advantageous as they limit the manifestation of local side effects such as oral candidiasis which occurs as a result of the drug being deposited in the mouth when inhaled. As the pro-drug is not active, it would not be able to produce these side effects as it would probably be swallowed before the activation could possibly take place.
Soft steroids have potent anti-inflammatory effects but low systemic concentrations which restricts unwanted side effects both locally and systematically. A soft drug is potent at its site of action but is rapidly inactivated in the systemic circulation by other methods other than hepatic enzymes (Hansel TT ), to minimise systemic side effects. Itrocinonide is a soft steroid that is inactivated by ubiquitous esterases in the body. This soft steroid has a receptor affinity comparable to that of budesonide and very little traces of intact drug were detected in the system even up to doses as high as 80mg. Despite all this, the efficacy of this drug is too low for clinical use. Although its receptor affinity is high, it is thought that the drug is present in too little concentrations at the site of action due to excessive hydrolysis in the target tissue (Bodor, Buchwald September 2006).
DOSAGE, METHOD OF DELIVERY AND COMBINATION THERAPY
In general, the dose-response curve of glucocorticoids is very shallow i.e. it plateaus very early, therefore large increases in dose do not yield a great amount of therapeutic benefits close to the plateau of the curve. However, this depends on the parameters being measured as the "response". When measuring airway hyperresponsiveness the curve keeps rising and the relationship is almost a linear one and the dose-response curve when measuring peak flow rate or FEV1 appears to be flatter in mild to moderate asthma than in severe asthma. It has also been observed that individual patients have their own unique dose-response curves when different parameters are measured, with some patients responding well to increased doses of inhaled corticosteroids and other not responding at all. However, it must be noted that increasing the dose of inhaled GCs will increase the risk and impact of side effects. Increasing the duration on which the patients are on these drugs will also increase the risk of systemic side effects. Patient compliance in asthma is very low, known to be at about 50 percent in the average asthmatic (L-P. Boulet, D.W. Cockcroft, J. Toogood, Y. Lacasse, J. Baskerville, F.E. Hargreave 1998). The dose of the drug directly affects patient compliance, for instance, a patient would more readily take a drug that only has to be taken once a day than a drug that must be taken three or four times a day.
Fig 3 shows the dose-response curve for inhaled steroids and the side effects: adapted from (Kankaanranta et al 2004)
The British National Formulary guidelines on the accepted dosage of inhaled GCs state that Beclomethasone Dipropionate should be taken at 200-400 micrograms twice daily in adults above the age of 16. This dose can be adjusted up to 800 micrograms when necessary. For children over the age of five, the recommended dose is 100-200 micrograms. For Fluticasone Propionate, the dose depends on the preparation of the drug. Flixotide (A&H) in adults should be taken at a dose of 100-500 micrograms twice daily and increased in accordance with the severity of the asthma. In children under the age of five, the dose for this drug is 50-100 micrograms daily and the dose may be increased with severity not exceeding 200 micrograms daily (The Joint Formulary Committee September 2009). Dosage requirements for other inhaled glucocorticoids can be found in The British National Formulary, September 2009 or at www.bnf.org.
Studies show that high doses in inhaled glucocorticoids have no extra therapeutic benefit than low-dose oral steroids in the treatment and maintenance of severe asthma. However, high dose inhaled steroids may yield less systemic side effects. Studies have also proven that adherence to low-dose inhaled GCs will reduce the risk of death due to asthma (Masoli, Holt et al. 2004).
It has been proven that the preparation of inhaled glucocorticoids have an effect on the potency of the drug and the level of systemic side effects. The preparation of these drugs also has an effect on the compliance of the patient. When delivered at the same dose by pressurised metered dose inhaler (pMDI), FP is more potent than BD, budesonide or any of the other available inhaled GCs. However, effectiveness of budesonide when delivered by Turbuhaler is equal to that of FP delivered by pMDI. Considering the level of side effects, budesonide when delivered by pMDI gives less systemic side effects than FP or BD delivered via the same inhaler. FP and BD have been observed to have the same level of systemic side effects when delivered by pMDI (O'Byrne, Pedersen 1998). In one study, patients gave feedback on the inhaler they most preferred. 40 percent of patients preferred the pMDI while 30 percent of patients preferred the DPI, commenting on the fact that it was easier to learn how to use. Technique is a problem faced by many newly diagnosed asthmatics and known asthmatics and does affect the outcome of trials assessing the efficacy of different inhalers. If the patient has not mastered how to correctly use an inhaler the delivery of drug to their bronchi may be significantly reduced (L-P. Boulet, D.W. Cockcroft, J. Toogood, Y. Lacasse, J. Baskerville, F.E. Hargreave 1998).
Combination therapy in asthma combines the use of a preventer drug-inhaled GC and a reliever drug- long acting beta-2-agonist. The reliever-long acting beta 2 agonist prevents the initiation and propagation of the immediate asthmatic response while the glucocorticoid prevents the late asthmatic response. Several studies have been conducted on the efficacy of combination therapy in the relieve and maintenance of asthma compared to available monotherapies and most of them have come to the same conclusion- combination therapies are more effective in treating asthma than available monotherapies . In addition, the use of combination therapy allows for a reduction in the dose of inhaled GCs taken by patients and reducing the dose of the beta 2 agonist (Pearlman David S., Stricker William et al. 1999). Reducing the dose of GCs would reduce the systemic side effects of these drugs, a characteristic that is highly advantageous.
A minute number of asthmatic patients are steroid resistant and so do not respond to the anti-inflammatory actions of steroids, making their asthma very difficult to manage. They present with persistent mild to moderate asthma. There appear to be many different causes of glucocorticoid resistance in asthma, a few are examined here.
A significant proportion of patients that are steroid resistant have an abnormality in the glucocorticoid-binding domain of the glucocorticoid receptor. This stops the correct binding of the glucocorticoid and therefore it is unable to exert its therapeutic effects.
In other patients, the GC-GR complex has a reduced affinity for monocytes and T-lymphocytes. A study observed a type of steroid resistance whereby the GC-GR complex has reduced affinity for T-lymphocytes which returns back to normal after 48 hours in media culture. Another type of steroid resistance was identified where there were reduced numbers of glucocorticoid receptors which had abnormal binding affinity not restricted to T-lymphocytes. However in this condition, numbers did not return to normal after 48 hours (Sher, Leung et al. 1994). A defect in the interaction of the GC-GR complex with transcription factors and T-lymphocytes can result in steroid resistance due to the inability of the GC to enhance or inhibit the production of anti-inflammatory and pro-inflammatory mediators.
Secondary steroid resistance due to down-regulation of the steroid receptor after the intake of oral prednisolone has been observed in some otherwise normal patients. Several cytokines activate transcription factors such as AP-1 and NF-kB. These activated transcription factors then form complexes with the GC-GR complex, reducing the number of available GR for the steroid to bind and thereby decreasing the patient's responsiveness to steroids (Szefler, Leung 1997).
Patients that are steroid resistant prove very difficult to treat and usually have spirometry tests on a very regular basis. They are given professional advice on suitable environmental control at home, work and in school especially areas of high allergen exposure. Appropriate bronchodilator advice is given to help relieve the symptoms of an acute attack.
Other drugs that provide anti-inflammatory relief in asthma include cromones, xanithines and anti-leukotrienes (Professor Jeremy Ward 2009).
Cromones (comprising of sodium cromoglycate) are "mast cell stabilisers"; they are thought to act on mast cells and eosinophils to prevent the immediate and late phase reactions and the increase in bronchial hyperresponsiveness. When taken regularly, cromones are effective in the management of mild to moderate asthma (Braunstein 1995).
Xanithines (such as theophylline) inhibit the phosphodiesterase enzyme which potentiates the production of cyclic AMP. They produce mast cell stabilisation and reduce the survival of eosinophils. However, these drugs have a very narrow therapeutic index which leads to numerous side effects.
Anti-leukotriene drugs are of two types- 5' lipoxygenase inhibitors which inhibit the production of leukotrienes and leukotriene receptor antagonists which inhibit the binding of leukotrienes to their receptors. Leukotrienes are eicosanoid inflammatory mediators by inhibiting their production and action, anti-inflammatory effects are observed.
ARE GLUCOCORTICOIDS THE PERFECT ANTI-INLAMMATORY DRUGS?
For any particular drug, there is a dose below which no clinically important systemic side effects are observed. This dose differs in steroids according to which steroid taken, the device through which it is delivered i.e. pMDI or DPI. Therefore the severity of the side effects observed is often dependent on the volume of drug absorbed systemically, the duration which the drug remains in the system before it is metabolised and the length of time the patient is on that drug.
The long-term use of inhaled GCs can have adverse effects on the bone density of some individuals, leading to osteoporosis. Bone formation is evaluated by measuring plasma levels of osteocalcin- a protein secreted by osteoblasts in the bone while bone resorption is assessed by measuring hydroxyproline and pyridinium and calcium cross-links in the urine. In a study conducted on pre-menopausal asthmatic women, bone density at the hip was measured and showed a dose-related fall (Israel, Banerjee et al. 2001). Post-menopausal women may be at an even greater risk of osteoporosis if on oestrogen replacement therapy. However, the lifestyle of asthmatic patients may in itself promote a fall in bone density due to lack of exercise and different dietary requirements. Fluticasone diproprionate has specifically been observed by one study to have no effect of bone density (Woodcock 1998) when taken at the recommended dose (Woodcock 1998); however another study has proven it to have more systemic bioactivity compared to other inhaled GCs which would increase the effect it would have on bone density (Lipworth 1999). With the introduction of novel therapies such as combination drugs, patients are less reliant on high doses of glucocorticoids thereby reducing the incidence of osteoporosis among asthmatic individuals.
There has been great concern over the potential for inhaled glucocorticoids to reduce growth rate in children and teenagers. However, due to the difficulty in conducting growth studies in children, a lot of this data is questionable. Difficulties encountered when measuring the growth rate of children include the fact that children grow in spurts and there are seasonal variations in growth. A controlled prospective study showed that long-term inhaled budesonide did not stunt the growth of children with asthma (Agertoft, Pedersen 1994). Conversely, a meta-analysis on the rate of growth of children taking inhaled GCs for asthma showed that height and weight growth curves were slightly lower than normal and children started puberty later than non-asthmatic children (Lipworth 1999). However, the same could be said for any chronic disease. Due to the difficulty in management of such conditions, children do tend to grow at a slower rate. Also, starting puberty at a later age may have no effect on the final height of the child as s/he will just carry on growing for longer to reach their normal adult height.
The hypothalamic-pituitary-adrenal axis (HPA-axis) is a complex set of interactions including feedback communications which form a large part of the body's neuroendocrine system involved in maintaining function of many systems. Interruption or damage to this system could cause an adrenal crisis. A study shows that with inhaled GC doses above 1.5mg/day adrenal suppression was discernible (Lipworth 1999). Fluticasone diproprionate showed a greater potency for adrenal suppression compared to other common inhaled GCs. Studies show that inhaled GCs given at the right dose do not cause any disruption to the to the HPA-axis (Goldstein, Konig 1983).
Cataracts and glaucoma are two uncommon unwanted side effects associated with inhaled steroids. There is much dispute over whether there is a clinically significant correlation between inhaled GCs and cataracts and glaucoma. A study of 370 patients in an urban town of Australia showed there is a correlation between the use of inhaled GCs and the development of posterior subcapsular and nuclear cataracts (Cumming, Mitchell et al. 1997). However, another study on 140 children and young adults showed there was no association between the use of inhaled GC therapy on its own and the development of posterior subcapsular cataracts. These findings though contradictory, are indicative of the current notions on the association of cataracts with inhaled GC therapy (Abuekteish, Kirkpatrick et al. 1995). The risk of ocular hypertension and closed-angle glaucoma is very minute for patients on inhaled GCs. Patients who go on to develop these conditions usually have a family history of the disease.
Easy bruising and skin thinning are also reported unwanted side effects of inhaled GCs. In a study comparing 202 patients taking inhaled GCs to 204 patients not on inhaled GCs; a small increased risk of easy bruising and skin thinning was recorded in the patients taking glucocorticoids (Mak, Melchor et al. 1992). This risk was higher in older female patients. No increased risk of easy bruising and skin thinning has been found in children.
Local side effects of inhaled GCs are not uncommon. However, these conditions do no cause morbidity and are managed well clinically. Oral candidiasis (thrush) is a yeast fungal infection that can present with the use of inhaled steroids. Decreased local immunity for such fungi could be what brings about this disease. Up to 40 percent of patients on inhaled GCs test positive for mouth swabs for the fungi Candida albicans (Geddes 1992). The use of pMDI seems to lower the incidence of thrush as does mouth rinsing after the use of the inhaler (Saad Alotaibi, Farhan Alshammari KBFM ). Dysphonia is another local side effect that can occur with the use of inhaled GCs (Hanania, Chapman et al. 1995). Dysphonia refers to unclear throat systems that lead to disorders of the voice and a dose-dependent hoarseness has been observed in patients on beclomethasone dipropionate or budesonide. Uncommon local side effects of inhaled GCs include perioral dermatitis- dermatitis which is prominent around the mouth area. It is caused by the deposition of steroids around the mouth and the frequency of presentation of this condition in children depends on the inhaler used (Nicholas J. Roland, Rajiv K. Bhalla et al. ). It is most associated with the use nebulizers. In a study of 639 asthmatic children treated with BD or budesonide, 21.9 percent of them reported increased thirst (Dubus, Marguet et al. 2001). This is thought to be caused by irritation of the throat or could be an early expression of the signs oral candidiasis.
The therapeutic anti-inflammatory effects of inhaled glucocorticoids in the treatment of asthma are rivalled by no other drug presently on the market. These drugs exert their actions on a very wide range of cells and tissues, bringing about their anti-inflammatory effects by employing multiple methods at the cellular and nuclear level. Inhaled glucocorticoids were initially manufactured to reduce the side effects of their oral counterparts. These side effects have been greatly reduced but are far from being completely eradicated. The benefits of using these drugs far outweigh the risks involved. However the benefits are observed in studies of patients which show that treatment with glucocorticoids inhibits inflammation of the bronchi by reducing the concentration and amount of inflammatory mediators and cells. Patients undergoing treatment with these drugs show a marked improvement in lung function tests such as peak expiratory flow rate and FEV1. Clinically significant side effects are rarely observed at the generally prescribed doses, making inhaled glucocorticoids the best treatment in their class of drugs for the treatment of asthma.