Inhaled Corticosteroids in Asthma Management

A Thesis Presented to The Faculty of Pharmacy University of Santo Tomas Espana, Manila

In Partial Fulfillment of the Requirements for the Degree Bachelor of Science in Medical Technology

Angeli Mae Crisol Alyssa Marie Labajo Ana Carmela Samonte Alfonso Leandro Toreja Ken Edward Zata

ABSTRACT Asthma is a chronic inflammatory disease affecting lung airways. Corticosteroid is considered as a long-term asthma control medication that is taken regularly to control chronic symptoms and prevent asthma attacks. This study aims to determine the efficacy of Corticosteroids in the management of chronic inflammatory disease, Asthma, through the integration of findings from related studies. In order to identify the efficacy of corticosteroid in asthma management, several findings from researches that were conducted before were integrated to be analyzed through the use of meta-analysis. Comprehensive searches was done through following criteria to be able to identify the explanatory and response variable to be used in meta-analysis. After determining the control and intervening total, control and intervening experimental factors based on the results of the previous researches, factors were tested using Medical Calculator. Result showed that corticosteroid is used for prevention or management and not as a treatment for asthma.

CHAPTER I THE PROBLEM AND ITS BACKGROUND

Introduction Asthma is a complex, heterogenous disorder characterized by reversible obstruction of the lower airways. At all levels of persistent asthma, inhaled corticosteroids(ICSs) are well established as the mainstay in both children and adults. Most asthma medications work by relaxing bronchospasm (bronchodilators) or reducing

inflammation (corticosteroids). In the treatment of asthma, inhaled medications are generally preferred over tablet or liquid medicines, which are swallowed (oral medications). Inhaled medications act directly on the airway surface and airway muscles where the asthma problems initiate. Absorption of inhaled medications into the rest of the body is minimal. Therefore, adverse side effects are fewer as compared to oral medications Corticosteroids are used in the treatment of several lung diseases. They were introduced for the treatment of asthma shortly after their discovery in the 1950s and remain the most effective therapy available for asthma. However, side effects have limited their use, and there has therefore been considerable research into discovering new or related agents that retain the beneficial action on airways without unwanted effects. The introduction of inhaled steroids has been a major advance in the treatment of chronic inflammatory disease, inhaled steroids may even be considered as first-line therapy in all but mildest of cases. Oral steroids are indicated in the treatment of several other pulmonary eosinophilic syndromes. Inhaled Corticosteroids work at an equipotent dose and effectively and reproducible suppress the inflammatory processes in the airways of most asthmatics. Their clinical benefits includes decreased asthma symptoms, fewer exascerbations, fewer hospitalizations, decreased airway hyperresponsiveness, improved pulmonary function, decreased exhaled nitric oxide and fewer asthma-related deaths. However, there are relatively few adverse effects and this includes oral candidiasis, cough at the time of the inhalation, hoarse voice and dysphonia. Systemic effects of inhaled corticosteroids are dose related. More drug deposited in the lung, greater systemic absorption and the greater the systemic adverse effects. The systemic adverse effects are adrenocortical suppression, osteoporosis and bone fracture in adults, skin thinning and purpura, weight gain, cataracts in adults, glaucoma, diabetes mellitus, increased pulmonary infections and linear growth retardation. However, reported results occur in small number with limited follow-up. There are 25-30% of asthmatics require high doses to obtain and maintain control. These are the patients who are obese and smokers. Patients with this condition lead to add-on

medication such as long Acting B antagonists. Long Acting B- antagonists are good add-on for patients older than 12 years old. Thus, Corticosteroid preparations are given intravenously in the treatment of severe asthma (status asthmaticus), and oral preparations are used for long-term-therapy. Over the years Sseveral attempts have been made to treat asthma with inhalation steroid preparations. The greatest benefit from corticosteroid usage has been in aspiration pneumonia, fat embolism, and other chemical injuries to the airway. In the absence of any substantial data regarding complications from short term, high dose corticosteroid usage, it seems reasonable to use high dosages (Murray &Madel, 1994).

Objectives 1. The determination of the efficacy of Corticosteroids in the management of chronic inflammatory disease, Asthma through the integration of findings from related studies 2. The establishment of the level of efficacy of Corticosteroids in Asthma patients through the correlation of related studies. 3. The comparison of the cognitive outcomes, process measures, or effective outcomes of corticosteroids as a curative or control drug. Statement Of The Problem 1. What is the efficacy of Corticosteroids in the management of Asthma? 2. What is the level of efficacy of Corticosteroids vis--vis other drugs in Asthma patients? 3. What are the outcomes of efficacy of corticosteroids as a curative or control drug?

CHAPTER II REVIEW OF RELATED LITERATURE Since the understanding of adrenocorticotropic hormones, Corticosteroids have revolutionized the treatment of asthma. Corticosteroids are considered to be the mainstay of therapy of patients with all forms of persistent asthma. Inhaled corticosteroids fall under the controller type of medication since it provides long-term control of airway inflammation. Corticosteroids exhibits several functions such as: it inhibit many inflammatory processes at work in the asthmatic airway, improve the function of the lungs, reduce the number of asthma exacerbations, acute care hospitalizations for asthma, asthma mortality and morbidity, and most of all, it improve the quality of life (Barnes, 1998). Beclomethasonedipropionate, budesonide, flunisolide, fluricasone propionate, and

triamcinoloneacetonide are five different inhaled corticosteroids that are available in the United States. These inhaled corticosteroids are considered as the first-line agents of asthma and each has different anti-inflammatory potencies. Fluticasone are 50% propionate as potent is as the most potent. and Budesonide flunisolide and and

beclomethasonedipropionate

fluticasone,

triamcinoloneacetonide are 25% as potent as fluticasone (Crapo, 2004). Since asthma is very frequently allergic in its etiology, it would be expected that antihistamines and other popular agents for treating allergic rhinitis would be of value in the management of asthma. (Murray &Madel, 1994) Clinically, the systemic are now used as exacerbations, whereas the inhaled forms are used to reduce the degree of AHR and to improve symptoms. (Burton, Gee, & Hodgkin, 1977) However, practical experience has shown that the antihistamines are rarely of benefit in adult asthmatics, although they may be useful adjuvants in children. The main antiallergy drugs are the corticosteroids, but in the last few years some new drugs have been available, including cromolyn, diethylcarbazide, and immunosurpressive agents. Mechanism of Action The beneficial actions of corticosteroids in asthma have not been fully worked out, but the following important actions are involved: (1) inhibition of antibody formation, thereby preventing antigenantibody reactions; (2) inhibition of information or storage of messenger agents such as histamine, which are involved in the asthmatic response; and (3) inhibition of various cellular mechanisms involved in bronchoconstriction, by a nonspecific anti-inflammatory action. (Murray &Madel, 1994) In inhaled corticosteroids, glucocorticoids exhibit anti-inflammatory properties at both molecular and cellular levels. Inhaled corticosteroids diffuse readily across airway cell membranes to airway smooth muscles cells, where they bind the intracytoplasmicglucocorticoid receptor. The complex formed is then translocated into the nucleus, where it binds to specific sequences called glucocorticoid response

elements (GREs) on DNA upstream from the promoter regions of steroid-responsive genes. Glucocorticoids inhibit the ability of nuclear transcription factors to up-regulate the immune response. At cellular level, glucocorticoids result in a reduction in the number of eosinophils and activated T lymphocytes in the bronchoalveolarlavage fluid and airway epithelium. Inhaled Corticosteroids also improve the spirometric values and other measure of lung function. It may also exert long-term effects on the asthmatic airway by decreasing the development of irreversible airway changes. They can actually alter the natural history of asthma by reducing the development of fixed airflow limitation (Crapo, 2004). It also provides advantages when compared with other agents for the treatment of asthma. Stated below are the different Mode of Action of corticosteroids according to Burton, Gee and Hodgkin. Steroid Receptor Steroids enter target cells and bind to cytosolic receptors. The steroid-receptor complex is transported to the nucleus, where it binds to specific sequences on the upstream regulatory element of certain target genes; this results in increased or decreased transcription of the gene, which leads to increased or decreased protein synthesis. Lipocortin It is likely that lipocotin-1 is only one of many proteins that increased by steroids, but it does not explain the unitary mechanism of action of corticosteroids as once believed. Anti-inflammatory Effects There is compelling evidence that asthma and airway hyper responsive are due to an inflammatory process in the airways, and there are several components of this inflammatory response that might be inhibited by steroids. In animal studies, steroids prevent and reverse the increase in vascular permeability due to inflammatory mediators and may therefore lead to resolution of airway edema. Indeed, endogenous cortisol may be important in regulating vascular permeability responses to inflammatory mediators and a fall in cortisol at night could be contributory to increased edema and airway narrowing in asthmatic patients at night. Steroids also have direct inhibitory effect on mucous glycoprotein secretion from airway sub mucosal glands as well as indirect inhibitory effects by down-regulation of inflammatory stimuli.

Effect on Airway Functions Steroids have no direct effect on contractile responses of airway smooth muscle, and improvement in lung function is presumably due to an effect on the chronic airway inflammation and airway hyperresponsiveness. Methods of Delivery Corticosteroids that are administered through inhalation are topically active and have been shown to be as effective in the treatment of asthma as systematically administered glucocorticoids. (Crapo, 2004) Early experience showed the usefulness of corticosteroids and they have proved effective and with few major effects. It is necessary to use them for long periods of time and in a precise dose to gain an appropriate response. Compliance is major problem in the treatment of patients whose symptoms improve with these drugs; patients often forget or neglect to take them Adverse Effects Side effects occur primarily in taking high dosage in long periods of time. In particular, the effects on the bones and muscle in adults may be more serious than underlying asthma. Inhaled corticosteroids are as effective as oral corticosteroids and have a more favourable benefit-risk profile. Generally, the use of oral corticosteroids in chronic asthma should be restricted to patients with severe persistent asthma that is not controlled despite aggressive treatment with inhaled corticosteroids. Although inhaled corticosteroids are much less likely to induce man of these adverse events, they have been associated with the development of dose-dependent accelerated bone loss, oral candidiasis, and dysphonia and with depression of the hypothalamic-pituitary-adrenal axis. Since corticosteroids have an adverse effect of increased fracture risk, cataracts, and myopathy, elderly patients with asthma should use these treatments sparingly (Crapo, 2004). Bronchial Asthma Bronchial asthma is a clinical syndrome reflecting a hyperactive state of the bronchial airways to multiple factors including extrinsic allergens. By definition it is a disease that usually begins in childhood in a patient with a strong personal or family history of allergy. Asthma is manifested by widespread narrowing of the airways that change in severity either spontaneously or as a result of therapy. Allergists have long emphasized that immediate hypersensitivity, mediated by immune globulin E (IgE), plays an important role in the syndrome. Not all asthma is from extrinsic sources in the sense of being caused by allergic to inhalants or ingestants. The term intrinsic are for those cases where the cause lies within the patients body. This kind of asthma is not mediated by IgE, Asthmatic Bronchitis. Not all wheezes is asthma. Listed are other

conditions not mediated by IgE which may produce wheezing. These may coexist with each other or with true asthma. (Murray &Madel, 1994) Diseases That Are Accompanied By Wheezing Acute and chronic bronchitis and bronchiolitis due to bacteria, viruses, or fungi. Inhalation of irritants (e.g., smoke [including tobacco], dusts, fumes, chemicals, and air pollutants) Exercise-induced bronchospasm. Acute left ventricular failure or so-called cardiac asthma. Bronchial obstruction by an intraluminar foreign body. Neoplasm (e.g., bronchial adenoma or carcinoma causing partial localized obstruction) Carcinoid syndrome. Drug-induced causes (e.g., cholinergic drug intoxication, beta adrenergic blockade[propranolol], and overuse if isoproterenol cartridges) Acute Pulmonary embolism Miscellaneous causes occasionally associated with wheezing (e.g., polyarteritisnodosa, Loefflers syndrome, tropical eosinophilia, extrinsic allergic alveolitis, and aspirin hypersensitivity [which is generally associated with nasal polyps or sinusitis])

Asthmatic Bronchitis Asthmatic bronchitis is a condition in which a series of events similar to that describes for bronchial asthma is initiated by intrinsic rather than extrinsic allergens. Often there is a history of recurrent infections. Wheezing and cough productive of mucopurpulent, thick, viscid sputum and severe episodic respiratory distress constitute the full-blown condition. This disease is much more common than is usually recognized. Many patients have told that they have chronic bronchitis and are disappointed when it does not respond to standard therapy. The key to diagnosis lies in the finding of eosinophils in expectorated secretions, and/or in the blood. The presence of sputum eosinophilia is of the immediate prognostic significance: it indicates that the patient has a prominent component of reversible airways obstruction. If the clinical situation warrants it, oral, parental, or inhaled corticosteroids are indicated. As in bronchial asthma, the corticosteroid dosage should induce both blood and sputum eosinopenia. (Murray &Madel, 1994) Approaches to Asthma of Different Severity Levels: (Crapo, 2004) Mild Persistent Asthma

Patients with this type of asthma exhibit normal lung function, use inhaled 2-agonists more than two times per week, experience fewer than two nocturnal symptoms per month, and demonstrate peak flow variability of less than 20% to 30%. Inhaled corticosteroids are recommended as their first-line therapy. Moderate Persistent Asthma These patients demonstrate abnormal lung function, experience at least two episodes of nocturnal worsening of asthma per month, exhibit peak flow variability greater than 20% to 30%, and use inhaled 2-agonists daily. Inhaled steroids at moderate doses are the mainstay of therapy in this group. Severe Persistent Asthma These patients represent a therapeutic challenge because they often require several classes of medications, and their symptoms and lung function may be quite labile. Patients may already be taking oral corticosteroids but an add-on therapy is necessary because inhaled corticosteroids with or without oral corticosteroids will control asthma symptoms adequately.

CHAPTER III REASEARCH METHODOLOGY Meta-analysis is a systematic technique for reviewing, analysing, and summarising quantitative research studies on specific topics or questions. It involves analysing the summary data from many studies. In this study, the meta-analysis quantitatively integrates the findings from the researches regarding the management of acute bronchial asthma using inhaled corticosteroids. A comprehensive search of the literature was first conducted to locate appropriate studies to be included in this meta-analysis. This was performed through electronic searches on the internet from varying databases. Depending on the database, the search strategy is varied and search terms included: Corticosteroids, asthma, management of asthma. Moreover, every study had to meet the following inclusion/exclusion criteria: 1. The study had to include situation wherein asthma patients are the elements of the study

2. The study should include the effectiveness of Inhaled Corticosteroids in the management

3. of chronic inflammatory disease, Asthma. 4. The study had to describe the cognitive outcomes, process measures, or effective outcomes for both male and female groups. Studies with insufficient data for effect size calculations were excluded. 5. The research had to depict the outcomes as to the level of the effectivity of Corticosteroids.

Using these criteria, abstracts from electronic searches, references from primary studies and review articles were examined to identify potential studies.

CHAPTER IV PRESENTATION, ANALYSIS AND INTERPRETATION OF DATA In doing the meta-analysis, the studies related to the topic were further assessed according their significance and resulted into four researches used for the meta-analysis. After determining the control total, intervening total, control experimental, intervening experimental factor, they were tested using the Medical Calculator. The result of the meta-analysis showed that most of the researches were not significant in proving that corticosteroids are effective in the treatment of asthma bronchitis. This is because the metaanalysis plot (Forest Plot) showed that the fixed effects are less than 1, only one research showed a significant effect. The Forest Plot showed that corticosteroids are effective for management. The P-value is .

CHAPTER V SUMMARY AND CONCLUSION

All ICSs work at an equipotent dose, and ICSs are the most effective asthma controller medication currently available (see Table 5). However, the ICS dose response plateaus in the low-tomoderate dose range. In addition, about 2530% of asthmatics require high doses to obtain and maintain control. This subgroup includes smokers, obese individuals, and patients with a preponderance of neutrophilic inflammation. In such patients, even high doses of steroid might not control the persistent symptoms, which lead to consideration of add-on medications such as LABAs, oral steroid, and leukotriene antagonists. LABA is a good add-on, steroid-sparing therapy, especially in patients older than 12 years. Use of LABAs in patients less than 12 years old is controversial, due in large part to a paucity of data. Finally, although more study is needed, several randomized controlled trials suggest that in acute asthma ICS in addition to oral steroid may reduce admission rate and may be a useful adjunct in that venue.